CADTH Reimbursement Review

Belumosudil (Rezurock)

Sponsor: sanofi-aventis Canada Inc.

Therapeutic area: Graft-versus-host disease

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information of Application Submitted for Review

cGVHD = chronic graft-vs.-host disease; NOC = Notice of Compliance.

Sources: Sponsor’s submission package for review of belumosudil and belumosudil product monograph.^1,2

Introduction

Hematopoietic stem cell transplant (HSCT) provides stem cells to patients whose bone marrow has been affected by disease, chemotherapy, or radiation.³ The 2 main types of HSCT are autologous and allogeneic HSCT (allo-HSCT).³ Allo-HSCT can have curative potential; however, there is a risk that the donor’s stem cells will die or be destroyed by the recipient (i.e., patient) or that the donor’s immune cells will attack healthy cells in the recipient; the latter is called graft-versus-host disease (GVHD).³ Chronic GVHD (cGVHD) can involve a single organ or multiple organs throughout the body, can last for months to a lifetime, and is the leading cause of late morbidity and death after an allo-HSCT.^4,5 Patients with cGVHD face a multifaceted disease burden comprising physical, functional, and psychosocial deficits, all of which have a profound negative impact on health-related quality of life (HRQoL).^6,7 It is estimated that cGVHD occurs in 35% to 50% of patients who undergo an allo-HSCT.⁸ Most patients experience cGVHD onset in the first year after an allo-HSCT, but about 5% to 10% of patients may not develop signs or symptoms until later.⁹

The treatment goals for cGVHD are to prolong survival, alleviate symptoms, control disease activity, prevent damage and disability, and maintain or improve HRQoL without causing extensive toxicity or other harms.¹⁰ The clinical experts consulted by CADTH also noted the importance of managing the adverse effects of therapies, such as increased risk of infections. First-line treatment consists of topical or systemic corticosteroids (CSs), with or without calcineurin inhibitors (CNIs), and is generally considered standard across clinical practice guidelines for managing cGVHD.¹¹ In Canada, second-line options include extracorporeal photopheresis (ECP), mycophenolate mofetil, etanercept, low-dose methotrexate, infliximab, mammalian target of rapamycin (mTOR) inhibitors, imatinib, rituximab, ruxolitinib, ibrutinib, low-dose interleukin (IL) 2 (IL-2), pulsed cyclophosphamide, and pentostatin.¹² There is a lack of consensus for standard second- and subsequent-line cGVHD therapies due to insufficient evidence to recommend any treatment over another and, according to the clinical experts, therapies after the first line depend on the site of disease presentation as well as the varying availability of treatments across jurisdictions.¹² Only ruxolitinib and ibrutinib have Health Canada indications for the treatment of cGVHD in adults and pediatric patients aged 12 years and older whose condition has an inadequate response to CSs or other systemic therapies, and the treatment of cGVHD in patients aged 1 year and older after the failure of 1 or more lines of systemic therapy, respectively.^13,14

Belumosudil is a selective oral inhibitor of Rho-associated, coiled-coil-containing protein kinase-2 (ROCK2) and ROCK1, and is indicated for the treatment of adult and pediatric patients aged 12 years and older with cGVHD after the failure of at least 2 prior lines of systemic therapy.¹ The recommended dosage of belumosudil is 200 mg given orally once daily with food at approximately the same time each day.¹ Treatment should continue until the progression of cGVHD that requires a new systemic therapy or the occurrence of unacceptable toxicity.¹ No dose adjustments are required in adolescents aged 12 to 18 years or in patients aged 65 years or older.¹ Although no patients under the age of 18 were enrolled in the clinical development program, Health Canada indicated that the use of belumosudil in pediatric patients aged 12 years and older is supported by: evidence from studies in adults with additional population pharmacokinetic data, the expectation that drug exposure is similar between adults and pediatric patients age 12 years and older, and that the disease course is sufficiently similar in adult and pediatric patients to allow for data extrapolation.¹ The sponsor has requested reimbursement as per the approved Health Canada indication.²

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of belumosudil 200 mg once-daily oral tablets in the treatment of adult and pediatric patients aged 12 years and older with cGVHD after the failure of at least 2 prior lines of systemic therapy.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from the clinical experts consulted by CADTH for the purpose of this review.

Patient Input

One joint input was submitted by 2 patient groups, the Leukemia and Lymphoma Society of Canada and Myeloma Canada, based on information gathered from a survey of 62 respondents conducted in July 2023 for the CADTH review of belumosudil.

The patient groups emphasized that the experience of going through cancer treatment, stem cell transplant, and receiving a GVHD diagnosis is disheartening and terrifying for both patients and caregivers. Respondents indicated that the full range of GVHD symptoms significantly affects their physical and mental health and daily activities and has detrimental effects on their HRQoL. Many patients lose their independence and require caregiver support to manage the disease.

Despite being necessary to treat cGVHD, the respondents described the negative impact of CS treatment, including the many physical, neurologic, and circulatory side effects that greatly impact HRQoL. According to the input, patients and caregivers seek a treatment that enables them to continue with their daily lives, is more accessible, improves overall survival (OS), and preserves their HRQoL, with minimal impact on work or school, finances, and social, physical, and mental health.

Of the 5 respondents who indicated having experience with belumosudil, 3 stated that the drug had a positive impact on their lives, allowed them to reduce steroid dosage, and was tolerable with minimal side effects.

Clinician Input

Input From the 2 Clinical Experts Consulted by CADTH

According to the clinical experts consulted by CADTH, there is a lack of good treatment options beyond second-line therapy for patients with cGVHD. As a result, patients with refractory or progressive disease experience an impact on their HRQoL, an impact on their ability to work and study, and have an increased risk of mortality due to cGVHD, associated organ impairment, and risk of infections.

The clinical experts indicated that belumosudil would be used as per the Health Canada indication in the third-line setting and would likely be used in combination with CSs, and that earlier use in the first- or second-line setting would require evidence from good-quality randomized controlled trials (RCTs). As per the clinical experts, patients with moderate to severe cGVHD whose condition is refractory or who are intolerant to 2 prior lines of therapy would most likely receive belumosudil.

The experts stated that partial response (PR) and complete response (CR) as well as the maintenance of stable disease with a clinically meaningful reduction in CS dose are indicators in clinical practice that a patient is responding to treatment. Improvement in functional status and symptoms and an ability to return to school or work were also noted as being important outcomes.

The reasons for discontinuing treatment identified by the clinical experts included disease progression (based on signs, symptoms, examination, laboratory tests) or having stable disease that still required significant amounts of CSs that cannot be tapered. The experts also noted meaningful adverse effects, such as derangement of liver function tests or significant gastrointestinal upset due to belumosudil, as being a reason to stop. Lastly, disease resolution in which a patient has stopped other immunosuppressants (or who may be on low-dose CSs, e.g., 10 mg) with symptom resolution is a third reason. The experts highlighted that stopping treatment in the last instance is done cautiously, as patients can experience disease flares when going off treatment.

The clinical experts noted that stem cell transplant specialists should initiate belumosudil in either a community or hospital setting, and treatment decisions may involve other specialists (e.g., respirologists).

Clinician Group Input

Two clinician groups, the Ontario Health (Cancer Care Ontario) (OH-CCO) Hematology Cancer Drug Advisory Committee and Cell Therapy Transplant Canada (CTTC) provided input for the CADTH review of belumosudil. Perspectives from OH-CCO clinicians were obtained through videoconferencing. CTTC gathered the information through a literature review and a discussion with the CTTC board of directors and the standing committee of program directors.

Input from the clinician groups was largely aligned with that of the clinical experts consulted by CADTH. The clinician groups reiterated the variation in standard practice for treatment beyond second-line therapy based on the local funding of available options. OH-CCO indicated that responsiveness and tolerability vary among patients and that oral therapies are often preferred, while CTTC noted that current treatments are suboptimal and require high doses and prolonged use of CSs, which have many adverse effects. According to the clinician groups, the outcomes used to assess response to treatment include standard GVHD response criteria, significant functional and HRQoL improvements, and patients showing stable disease but with a significant reduction of immunosuppressive treatments. The 2 clinician groups agreed that treatment discontinuation should be considered in patients with significant intolerance or cGVHD progression. According to OH-CCO, patients receiving belumosudil should be managed by cGVHD specialists practising in inpatient or outpatient settings, while CTTC added that the drug should be prescribed only by specialists working in a clinical setting associated with allo-HSCT programs for patients whose condition is refractory to steroids or ruxolitinib.

Drug Program Input

The drug programs asked questions about: how belumosudil compares with ibrutinib, belumosudil’s place in therapy, which systemic therapies are acceptable before trying belumosudil, how frequently patients should be assessed to continue treatment, how treatment discontinuation is assessed, whether cGVHD treatments can be combined, whether belumosudil can be used in patients who have experienced a failure of other treatments or who have acute GVHD (aGVHD), and how treatments should be prioritized.

The clinical experts consulted by CADTH acknowledged there was no evidence available for belumosudil versus ibrutinib, making it difficult to compare the 2 drugs. They also stated that belumosudil would be used as per its Health Canada indication and that there would need to be good RCT evidence to support using belumosudil as an earlier line of therapy. The experts noted that any 2 systemic therapies for the treatment of cGVHD (including CSs and ECP) count toward the requirement of a failure of at least 2 prior systemic treatments before accessing belumosudil. The clinical experts agreed that first authorization should be for 6 months, with renewal for patients who have experienced an overall response (i.e., CR or PR, or stable disease with significant reduction in steroid doses) every 6 months. They also indicated that drug discontinuation should occur upon cGVHD progression, but patients should continue to be treated for cGVHD if they experience a relapse of the underlying hematological malignancy (both conditions need to be treated). According to the clinical experts, treatment for cGVHD would not be indefinite for most patients but should be tapered cautiously to assess response and relapse. They noted there is no specific number of doses or years during which a patient would continue treatment, and a small number of patients who are intolerant to tapering require lifelong therapy. The experts expect that belumosudil could be used alongside other treatments for cGVHD and that it would be possible to give belumosudil to patients if they had demonstrated intolerance to other medications for cGVHD. There is currently no Health Canada indication for the use of belumosudil in the treatment of patients with aGVHD. Given the lack of direct and indirect evidence, the experts indicated that it would be challenging to prioritize treatment options for cGVHD.

Clinical Evidence

Systematic Review

Description of Studies

Study KD025 to 213 (N = |||) is a phase II, open-label study with a latest data cut-off date of ||||||||| ||| ||||.^15,16 Eligible patients had to be 12 years of age or older with active cGVHD and had to have undergone an allo-HSCT and received 2 to 5 prior lines of therapy for cGVHD. Study KD025 to 208 (N = 54) is a phase IIa, dose-escalation, ongoing, open-label study with a latest data cut-off date of |||| ||| ||||.^17,18 Eligible patients had to be 18 years of age or older with active cGVHD and had to have undergone an allogeneic bone marrow transplant or allo-HSCT and received 1 to 3 prior lines of therapy for cGVHD (not including ECP). In study KD025 to 213 and study KD025 to 208, || patients and 17 patients, respectively, received belumosudil 200 mg once daily and there were no relevant comparator or control groups in either study (belumosudil 200 mg twice daily and belumosudil 400 mg once daily are outside of the Health Canada indication for the indication under review and are not further discussed in this CADTH report). Patients were permitted to have concomitant treatment with standard of care systemic cGVHD therapies, such as CNIs, sirolimus, mycophenolate mofetil, methotrexate, rituximab, ECP, or topical or organ-specific therapies if they had been on a stable regimen; however, initiation of a new systemic therapy was not permitted. The primary outcome of both studies was overall response rate (ORR) by investigator assessment, measured on day 1 of each 28-day cycle for cycles 2 to 5 and every other cycle thereafter until clinically meaningful disease progression or end of treatment (EOT). ORR was the only end point controlled for multiple testing. Secondary outcomes of interest to the CADTH review included duration of response (DOR), time to response (TTR), failure-free survival (FFS), OS, Lee Symptom Scale (LSS) score, and safety outcomes. Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health summary scores for physical and mental functioning were exploratory outcomes in study KD025 to 213. Although the studies had 4 definitions for DOR, according to the clinical experts consulted by CADTH, the tertiary and secondary DOR definitions were considered to be the most clinically relevant. The tertiary definition of DOR was the time from first documented response to the time of initiation of a new systemic cGVHD therapy or death (reviewed by a clinical team).^15,17 The secondary definition of DOR was the time from first documented response to the time of first documented lack of response (LR).

The median age of patients was 53 years (range, 21 years to 77 years) in study KD025 to 213 and 50 years (range, 20 years to 63 years) in study KD025 to 208. There were no patients younger than 20 years old in the relevant datasets to support the pediatric portion of the indication. In both studies, more than 76% of patients had a Karnofsky Performance Score of 80 or higher, the median time from cGVHD diagnosis to study enrolment was approximately 25 months, and more than 70% of patients had severe cGVHD, according to the 2014 National Institutes of Health (NIH) consensus criteria. In total, 100% of patients in study KD025 to 213 and 88% of patients in study KD025 to 208 had 2 or more prior lines of therapy. CSs were the most common prior cGVHD treatment (more than 99%) followed by tacrolimus in study KD025 to 213 (||%) and sirolimus in study KD025 to 208 (59%).

Efficacy Results

ORR by Investigator Assessment

In study KD025 to 213, the ORR was 72.7% (95% confidence interval [CI], 60.4% to 83.0%; P < 0.0001) as of the primary analysis cut-off date (February 19, 2020, 6 months after enrolment of 126 patients into the modified intention-to-treat [mITT] population). In study KD025 to 208, the ORR was 64.7% (95% CI, 38.3% to 85.8%) as of the primary reporting data cut-off date (February 19, 2020, corresponding to the primary analysis data cut-off date for study KD025 to 213).

At the latest cut-off date for study KD025 to 213 (||||||||| ||| ||||), after median |||| (range, ||| || ||||) months of follow-up, the ORR was ||||| (95% CI, ||||| || |||||). At the latest cut-off date for study KD025 to 208 (|||| ||| ||||), after median |||| (range, ||| || ||||) months of follow-up, the ORR was ||||| (95% CI, ||||| || |||||). The findings for ORR appeared to be generally similar across the subgroups.

Duration of Response

Of the patients who responded to treatment (n = ||), the median Kaplan-Meier (KM) estimate for tertiary DOR (time from first response to initiation of a new cGVHD therapy or death) was ||||| weeks (95% CI lower bound = |||| weeks; upper bound not reached) in study KD025 to 213; in study KD025 to 208, the median KM estimate for tertiary DOR was not reached (95% CI lower bound = ||| weeks; upper bound not reached). At 24 weeks, the KM estimate of the event-free probability for tertiary DOR was ||% (95% CI, ||| || |||) in study KD025 to 213 and ||| (95% CI, ||| || |||) in study KD025 to 208.

The median KM estimate for secondary DOR (time from first response to time of first LR) was |||| weeks (95% CI, |||| to ||||) in study KD025 to 213; in study KD025 to 208, the median KM estimate for secondary DOR was |||| weeks (95% CI lower bound = ||| weeks; upper bound not reached). At 24 weeks, the KM estimate of the event-free probability for secondary DOR was ||| (95% CI, ||| || |||) in study KD025 to 213 and ||| (95% CI, ||| || |||) in study KD025 to 208.

Time to Response

Based on the responder population, the median TTR was ||| weeks (range, ||| to |||| weeks) in study KD025 to 213 and 8.1 weeks (range, 7.9 to 26.1 weeks) in study KD025 to 208. At weeks 8 and 12, the cumulative response rate was ||||% and ||||%, respectively, in study KD025 to 213, and ||||% and ||||%, respectively, in study KD025 to 208.

Failure-Free Survival

The median KM estimate for FFS was |||| weeks (95% CI, |||| to ||||) in study KD025 to 213 and 10.6 weeks (95% CI lower bound = 3.8 weeks; upper bound not reached) in study KD025 to 208. According to the KM estimate, the FFS probability was ||% (95% CI, ||| || ||||) at 12 months in study KD025 to 213, and 47% (95% CI, 23% to 68%) at 12 months in study KD025 to 208.

Overall Survival

The median KM estimate for OS was not reached in either study KD025 to 213 or study KD025 to 208. According to the KM estimate, the OS probability was ||% (95% CI, ||% to ||%) at 12 months in study KD025 to 213 and ||% (95% CI, ||% to ||%) at 12 months in study KD025 to 208.

LSS Score

The LSS score measures changes in symptom burden using 30 items over 7 domains, where a higher score indicates more bothersome symptoms. A 7-point or greater reduction in score was considered clinically meaningful.¹⁹ In study KD025 to 213, || patients (||||%) had a 7-point or greater reduction in LSS score from baseline. In study KD025 to 208, 9 patients (52.9%) had a 7-point or greater reduction in LSS score from baseline.

PROMIS Global Health Summary Scores for Physical and Mental Functioning

The PROMIS Global Health score assesses general health, ability to carry out physical activities, emotional problems, fatigue, and pain.¹⁵ Two summary scores are determined for physical and mental functioning, with higher scores indicating better functioning. In study KD025 to 213, || patients (||||%) had a 4.7-point or greater change from baseline for physical health and || patients (||||%) had a 4.7-point or greater change from baseline for mental health. This outcome was not assessed in study KD025 to 208.

Harms Results

Most patients experienced at least 1 treatment-emergent adverse event (TEAE) in study KD025 to 213 (||||%) and study KD025 to 208 (100%). The most common TEAEs were diarrhea (||||%) and fatigue (||||%) in study KD025 to 213, and upper respiratory tract infection (52.9%), diarrhea (35.3%), fatigue (35.3%), nausea (35.3%), and increased alanine aminotransferase (35.3%) in study KD025 to 208.

In study KD025 to 213, ||||% of patients experienced a serious adverse event (SAE), while ||||% of patients in study KD025 to 208 experienced an SAE. Pneumonia (|||%) was the most frequently reported SAE in study KD025 to 213. No other SAEs occurred in more than 3 patients in either study.

In study KD025 to 213, ||||% of patients stopped belumosudil due to an adverse event (AE), while ||||% of patients in study KD025 to 208 stopped the drug due to an AE.

Overall, || patients died in study KD025 to 213 (reasons included hemothorax, aspiration and respiratory failure, septic shock and multiple organ dysfunction, and recurrent acute myeloid leukemia), and 0 patients died in study KD025 to 208.

Based on the Health Canada product monograph warnings and precautions, hematologic (blood and lymphatic system disorders) and immune (infections and infestations) AEs were identified as being important to the CADTH review. Overall, ||||% of patients in study KD025 to 213 and ||||% of patients in study KD025 to 208 experienced an AE related to blood or lymphatic system disorders; anemia was the most common AE, reported by |||% and ||||% of patients in study KD025 to 213 and study KD025 to 208, respectively. For infections and infestations, ||||% or patients in study KD025 to 213 and ||||% of patients in study KD025 to 208 experienced an AE. Upper respiratory tract infection was the most common AE, reported by ||||% and ||||% of patients in study KD025 to 213 and study KD025 to 208, respectively.

Critical Appraisal

The main limitations with both studies are the lack of a control (or comparator) group and lack of randomization to a valid comparator, resulting in a high risk of bias due to confounding and uncertainty in causal conclusions between the study drug and possible benefits or harms. Another limitation was the knowledge of treatment assignment, resulting in an increased risk of performance bias (particularly for subjective measures) and of potentially overestimating the treatment effect of belumosudil. All patients had discontinued from the study and treatment by the latest data cut-off date and there is an increased risk of attrition bias due to missing outcomes data for longer-term results. The findings of time-to-event analyses and later time points had few patients at risk and therefore may be unstable.

Between the studies, 94 patients received the approved 200 mg once-daily dosage for a median treatment duration of around 9 months, which is a relatively small number of patients compared with the total number who could potentially receive belumosudil (i.e., those with active cGVHD who have received at least 2 prior lines of systemic therapy) for a somewhat short duration, considering that treatment can be for years. This may be especially true for OS, where few events were captured and a longer follow-up would be needed to understand the full effect of belumosudil on mortality. Also, there were no data available for patients younger than 20 years of age to support the Health Canada indication for patients aged from 12 years to younger than 20 years, though the clinical experts were of the opinion that the results for adults could be generalizable to a younger patient population, and belumosudil gained regulatory approval for a population aged 12 years and older based on pharmacokinetic analyses indicating that age and body mass did not have a clinically meaningful effect on drug pharmacokinetics.^20,21 Racial diversity was limited in the study (compared with what is expected in Canadian practice), and the prior and concomitant cGVHD therapies differed from the experts’ experience in treating patients with cGVHD (which may be due to varying availability of treatments across jurisdictions and the studies taking place in the US).

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^22,23 Although GRADE guidance is not available for noncomparative studies, the CADTH review team assessed the pivotal trials for study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for trials with only a single relevant treatment group (i.e., no valid comparator) started at very low certainty with no opportunity for rating up.

The selection of outcomes for the GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with the clinical experts, and the input received from the patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: response to treatment (ORR by investigator assessment, tertiary and secondary DOR, TTR, and FFS), survival (OS), disease-specific measure of symptoms (LSS scores), HRQoL (PROMIS Global Health summary scores), and harms (SAEs).

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of a clinically important effect for ORR, tertiary and secondary DOR, TTR, FFS, and OS, based on a threshold informed by the clinical experts consulted by CADTH for this review. The target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for the number of patients who had an LSS score or PROMIS Global Health summary score greater than or equal to the minimal important differences (MIDs) identified from the literature and who experienced SAEs.

For the GRADE assessments, the findings from study KD025 to 213 and study KD025 to 208 were considered together (except for PROMIS, which was assessed only in study KD025 to 213) and summarized narratively by outcome because the studies were similar in population, intervention, design, and outcome measures.

Results of GRADE Assessments

Table 2 presents the narrative GRADE summary of findings for belumosudil for patients with cGVHD.

Long-Term Extension Studies

Data from the latest cut-off dates for the ongoing studies (KD025 to 213 and KD025 to 208) were included in the main report. No additional long-term extension studies were submitted in the systematic review evidence.

Indirect Comparisons

Description of Feasibility Assessment

No direct comparative data for the use of belumosudil for the treatment of patients aged 12 years and older with cGVHD were submitted by the sponsor. As a result, a systematic literature review was conducted to identify efficacy and safety evidence of belumosudil versus other treatments for patients with cGVHD after an allo-HSCT whose condition has failed to respond to prior therapy.²⁵ It was known that no RCTs were available for belumosudil versus other active therapies for cGVHD; therefore, the feasibility of conducting a valid population-adjusted indirect comparison (PAIC) was assessed and was determined to be infeasible.

Table 2: GRADE Summary of Findings for Belumosudil for Patients With cGVHD (Studies KD025 to 213 and KD025 to 208)

cGVHD = chronic graft-vs.-host disease; CI = confidence interval; CR = complete response; DOR = duration of response; FFS = failure-free survival; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; HRQoL = health-related quality of life; KM = Kaplan-Meier; LSS = Lee Symptom Scale; mITT = modified intention to treat; ORR = overall response rate; OS = overall survival; PR = partial response; PROMIS = Patient-Reported Outcomes Measurement Information System; SAE = serious adverse event; TTR = time to response.

Note: All serious concerns with the study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias are documented in the table footnotes.

^aIn the absence of a relevant comparator group and knowledge of treatment assignment, conclusions about efficacy relative to any comparator cannot be drawn and the certainty of evidence is started at very low and cannot be rated up.

^bDid not rate down for indirectness. No pediatric patients were included in the trials (i.e., the evidence is representative of adult patients); however, the clinical experts consulted by CADTH believed it would be reasonable to generalize the findings to children aged 12 years and older.

^cORR (CR or PR) by investigator assessment at 6 months was the only end point to be tested statistically and controlled for multiplicity in study KD025 to 213; other end points were presented only descriptively.

^dRated down 1 level for serious imprecision. Analysis included only || patients for mITT analyses and || patients for responder analyses, and/or is based on a small number of events; there is potential for instability in the estimate and overestimation of the true effect.²⁴

^eTertiary DOR was defined as the time from first documented response to the time of initiation of a new systemic cGVHD therapy or death.

^fResponder population consisted of patients in the mITT population who experienced a PR or CR at any postbaseline assessment.

^gSecondary DOR was defined as the time from first documented response to the time of first documented lack of response, new treatment, or death.

^hRated down 1 level for serious imprecision. In both studies the 95% CI lower bound crossed the conservative threshold of clinically important benefit of 40% suggested by clinical experts.

Sources: Clinical Study Reports for study KD025 to 213¹⁵ and study KD025 to 208,¹⁷ Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ The details included in the table are from the sponsor’s summary of clinical evidence.

Critical Appraisal

Compared with the data available for belumosudil, potential comparator studies were heterogeneous with respect to patient characteristics, study designs (e.g., eligibility criteria, length of follow-up, timing of assessments, and outcome measures), and data availability. Specifically, the CADTH review team scrutinized the potential to perform an indirect treatment comparison (ITC) versus the 2 main comparators of relevance, ruxolitinib and ibrutinib. Compared with studies of the comparators, the KD205 to 213 study of belumosudil enrolled patients with more prior lines of therapy and more severe disease. Given the small number of patients enrolled in the studies and the fact that the eligible population in the belumosudil trial was narrower, the CADTH review team agreed it would not have been feasible to perform a valid PAIC that fully adjusted for the differences in populations across the trials. However, as noted by Health Canada,²⁰ this is an important limitation of the belumosudil KD205 to 213 trial that may have been foreseen. Given that the trial was initiated in 2018 (after Health Canada’s approval of ibrutinib), it may have been possible at the outset to align enrolment criteria to facilitate a valid ITC with both ibrutinib and ruxolitinib.

Studies Addressing Gaps in the Evidence From the Systematic Review

Description of Studies

Due to the lack of head-to-head data and the inability to conduct an ITC, 1 observational study using inverse probability of treatment weighting (IPTW) was summarized to provide indirect comparative evidence in the treatment of belumosudil versus best available therapy (BAT) for patients with cGVHD.¹¹ The observational study was conducted using real-world data from the US Optum Clinformatics Data Mart database and pooled results from the main studies (KD025 to 213 and KD025 to 208).

From the database, patients were eligible if they had at least 1 inpatient or outpatient claim with a diagnosis code for cGVHD from January 1, 2000, to the most recent available data; had at least 3 systemic lines of therapy after cGVHD diagnosis (first-line therapy must have been CSs); were 12 years of age or older; and had at least 6 months of continuous enrolment with medical and pharmacy benefits before the third line of therapy. BAT included ECP, mycophenolate mofetil, imatinib, rituximab, mTOR inhibitors, ruxolitinib, CNIs, methotrexate, ibrutinib, pentostatin, etanercept, abatacept, alemtuzumab, hydroxychloroquine, and IL-2. IPTW methods were used in an attempt to reduce the risk of bias due to confounding that would result from differences in populations across the 2 study arms. The primary outcome was FFS and secondary outcomes included rate of OS and safety events.

Efficacy Results

Median FFS was |||| months (95% CI, |||| to ||||) in the belumosudil group and ||| months (95% CI, ||| to ||||) in the BAT group (hazard ratio [HR] = ||||; 95% CI, |||| || ||||). Median OS was not estimable for the belumosudil group and was |||| months (95% CI, ||||| to |||||) for the BAT group (HR = ||||; 95% CI, |||| || ||||).

Harms Results

The most common AEs in the belumosudil group were infections (||||%), fatigue or asthenia (||||%), and nausea or vomiting (||||%). The most common AEs in the BAT group were infections (||||%), dyspnea (||||%), hypertension (||||%), and anemia (||||%).

Critical Appraisal

There were numerous internal validity concerns including: lack of a valid comparator, missing data for variables of interest, heterogeneity in baseline characteristics (even after IPTW procedures were applied), differences in study designs that cannot be adjusted for, and increased risk of inaccuracies in the claims database due to patients changing insurance plans and the possible miscoding of claims. Therefore, it was not possible to draw firm conclusions on how belumosudil compares with BAT from the data, as they are considered to be at high risk of bias. Moreover, data for both belumosudil 200 mg once daily and belumosudil 200 mg twice daily appeared to be pooled in the analyses, though only the former dose has a Health Canada indication for the treatment of cGVHD. Despite the use of real-world data, which could improve generalizability, the internal validity issues minimize the utility and applicability of the findings to clinical practice in Canada.

Conclusions

cGVHD is a complex, multisystem disease and there is a need for safe and effective treatments that help prolong survival, alleviate symptoms, and improve HRQoL. Evidence from 2 phase II, open-label clinical studies in adult patients with cGVHD (n = ||) were included in the review for belumosudil, and both studies lacked an appropriate comparator or control group. Such a study design does not allow for definitive conclusions about the efficacy and safety of belumosudil versus any comparator, as the effect estimates are likely to be confounded by concomitant treatments and the natural history of the disease. Indirect comparisons with relevant alternatives were deemed infeasible and a submitted observational IPTW study comparing belumosudil with BAT was at high risk of bias due to residual confounding. Nevertheless, study KD025 to 213 met its primary outcome of an ORR greater than 30% at 6 months of treatment; the majority of responses were partial and fewer patients experienced CR. The treatment effect point estimates for response and survival outcomes were considered potentially clinically meaningful by the clinical experts. Although there were MIDs for LSS and PROMIS from the literature, it was not clear whether the number of patients who reached the MIDs was large enough to indicate a meaningful benefit from belumosudil. Harms results were potentially confounded by the use of concomitant treatments, though the clinical experts felt that these harms would generally be manageable with adequate care. There was a relatively small number of patients who received the Health Canada–approved dosage (belumosudil 200 mg once daily) in either study and there is additional uncertainty in the long term results due to discontinuations and the immaturity of the survival data. The clinical experts indicated that the study results were generalizable, acknowledging the lack of data for patients younger than 20 years of age in the studies. It was determined that an ITC was not feasible and the sponsor-submitted observational IPTW study comparing belumosudil with BAT had important limitations (i.e., heterogeneity, missing outcomes), preventing meaningful conclusions from being made. Overall, due to the lack of informative direct and indirect evidence, it is very uncertain how belumosudil compares with other cGVHD treatments in terms of efficacy and safety.

While the results of the included studies aligned with the clinical experts’ expectation that belumosudil would address the unmet needs in this patient population, there were important limitations in the included studies, leading to uncertainty in the evidence due to the trials having only a single relevant treatment group and no valid comparator.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of belumosudil 200 mg once-daily oral tablets in the treatment of adult and pediatric patients aged 12 years and older with cGVHD after failure of at least 2 prior lines of systemic therapy.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

HSCT provides stem cells to patients whose bone marrow has been affected by disease, chemotherapy, or radiation.³ The 2 main types of stem cell transplant are autologous and allo-HSCT.³ Allo-HSCT uses stem cells from either a matched related or unrelated donor, whereas the stem cell donor and recipient are the same individual for autologous HSCT.³ According to the CTTC National Bone Marrow Transplant Registry, there were 13,033 transplants performed in Canada between 2008 to 2019, of which 5,672 (43.5%) were allogeneic and 7,361 (56.5%) were autologous.²⁶ CTTC estimates that approximately 2,200 HSCTs are performed annually in Canada, of which around 1,200 are autologous and 1,000 are allo-HSCTs.²⁷ While an allo-HSCT has curative potential, there is a risk that the donor’s stem cells will die or be destroyed by the recipient (i.e., patient), or that the donor’s immune cells will attack healthy cells in the recipient; the latter is called GVHD.⁴ GVHD is a serious complication of allo-HSCT caused by a donor’s T-cells (graft) viewing the recipient’s healthy cells as foreign and attacking these cells.^4,28,29 Consequently, GVHD substantially compromises the clinical and HRQoL benefits and curative potential of allo-HSCT for various underlying malignancies.

GVHD is often classified into 2 main categories: aGVHD and cGVHD. Each type affects different organs and tissues and has different signs and symptoms, and patients may develop 1, both, or neither type following an allo-HSCT.⁴ Acute GVHD typically affects the skin, gastrointestinal tract, or liver. Chronic GVHD normally involves a single organ or multiple organs (e.g., eyes, mouth, skin, nails, scalp, hair, gastrointestinal tract, lungs, liver, muscles, joints, and genitalia) and can last from months to a lifetime.⁴ Patients with cGVHD face a multifaceted disease burden comprising physical, functional, and psychosocial deficits, all of which have a profound negative impact on HRQoL.^6,7 It is the leading cause of late morbidity and death after an allo-HSCT.^4,5 Although aGVHD and cGVHD share similarities and can overlap at times, each condition involves distinct pathologic processes and they differ in their clinical presentation.³⁰ Currently, there are no identified biomarkers for the diagnosis or assessment of GVHD disease activity or to differentiate between acute and chronic forms. As a result, the diagnosis is based on clinical presentation and patient interviews.¹⁰ Ongoing inflammation and chronic fibrosis of cGVHD can lead to lasting disability and nonrelapse mortality.^4,5 The median time to onset of cGVHD is estimated to be 162 days after transplant.³¹

In 2005, the NIH Consensus Development Project on Criteria for Clinical Trials in Chronic GVHD put forth standardized criteria for the diagnosis of cGVHD that were subsequently updated in 2014.^10,32 It is recommended that a cGVHD diagnosis be distinct from an aGVHD diagnosis, with the presence of at least 1 diagnostic manifestation of cGVHD or at least 1 distinctive manifestation confirmed by a pertinent biopsy, laboratory tests (e.g., pulmonary function tests, Schirmer test), evaluation by a specialist (ophthalmologist, gynecologist) or radiographic imaging showing cGVHD in the same or another organ, unless stated otherwise.^10,32 Confirmatory biopsy, organ-specific testing, or imaging can be used to confirm the presence of cGVHD.¹⁰ However, confirmatory testing is not always feasible and is not mandatory if a patient has at least 1 of the diagnostic findings of cGVHD.¹⁰

Following a diagnosis of cGVHD, the severity of the disease is usually categorized as mild, moderate, or severe.⁶ The NIH Consensus Development Project has also developed a comprehensive framework for the clinical scoring of affected organ systems and for global scoring of cGVHD based on the degree of organ impact and functional impairment for the categories of mild, moderate, or severe. Mild disease involves 2 or fewer organs with a score of no more than 1 and no lung involvement. Moderate disease involves 3 or more organs with a score of 1, or at least 1 nonlung organ with a score of 2, or lung involvement with a score of 1. Severe disease involves at least 1 organ with a score of 3 or lung involvement with a score of 2 or 3.

The pathophysiology of cGVHD includes inflammation, humoral immunity, cell-mediated immunity, and fibrosis involving both T-cells and B-cells.¹⁰ The disease process is characterized by the overproduction of proinflammatory cytokines (IL-17 and IL-21) and overactivation of proinflammatory T-cells and B-cells, which leads to an overproduction of antibodies.³³ Increasing severity of cGVHD impacts survival, as the global severity scores based on mild, moderate, or severe staging criteria for cGVHD developed by the NIH are significantly associated with both nonrelapse mortality and OS.^32,34 While mild GVHD is associated with a good prognosis, patients with severe GVHD have a poor prognosis and the 2-year OS rate is estimated to be 97%, 86%, and 62% in patients with mild, moderate, and severe GVHD, respectively.³⁴

Reports from the literature estimate that cGVHD occurs in 35% to 50% of patients who undergo an allo-HSCT.⁸ There is a lack of information on the prevalence of cGVHD in Canada. A US claims-based analysis from 2013 to 2018 found that the projected prevalence of cGVHD was 14,017 individual patients.³⁵ Within 3 years of an allo-HSCT, 42% of patients developed cGVHD.³⁵ While most patients experience the onset of cGVHD in the first year after an allo-HSCT, about 5% to 10% of patients may not develop signs and symptoms until later.⁹

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

The treatment goals for cGVHD are to prolong survival and alleviate symptoms while also controlling disease activity, preventing damage and disability, and maintaining or improving HRQoL without causing extensive toxicity or other harms.¹⁰

In general, cGVHD is treated based on disease severity and the number and types of organs affected. First-line therapy consists of topical or systemic CSs, with or without CNIs, and is generally considered standard across clinical practice guidelines for managing cGVHD.¹¹ Patients with mild, localized skin disease are typically treated with topicals, while patients with moderate to severe disease are treated with systemic CSs alone or in combination with CNIs or other immunosuppressants.¹¹ CSs and immunosuppressants are associated with various limitations, such as increased risk in malignancy relapse, infections, myopathy, cataracts, hyperglycemia, decline in bone mass, and avascular necrosis.¹¹ Therefore, it is recommended that CSs be tapered in those who experience clinical improvements to decrease the risk of associated toxicities.¹¹ However, for approximately 50% to 60% of patients, their condition fails to respond to treatment or the response is not durable, or they are unable to taper CSs and require second-line drugs to manage the cGVHD.¹¹

Although guidelines recommend a standard first-line therapy, there is a lack of consensus for standard second- and subsequent-line therapies because there is insufficient evidence to recommend any 1 treatment over another, and because there is variation in patient management and which treatments are accessible across jurisdictions.¹² In Canada, second-line options for the treatment of cGVHD include: ECP, mycophenolate mofetil, etanercept, low-dose methotrexate, infliximab, mTOR inhibitors (e.g., sirolimus), imatinib, rituximab, ruxolitinib, ibrutinib, low-dose IL-2, pulsed cyclophosphamide, and pentostatin (rare cases).¹¹ Of note, only ruxolitinib and ibrutinib have Health Canada indications for the treatment of cGVHD in adult and pediatric patients aged 12 years and older who have had an inadequate response to CSs or other systemic therapies, and for the treatment of pediatric patients aged 1 year and older with cGVHD after failure of 1 or more lines of systemic therapy, respectively.^13,14 The sponsor stated that, at this time, there is no drug specifically indicated for patients with cGVHD whose condition has failed to respond to or who are intolerant to 2 or more prior lines of therapy, which is the expected place in therapy for belumosudil (i.e., third line or later).

Drug Under Review

Key characteristics of belumosudil are summarized along with other treatments available for cGVHD in Table 3 and Table 4.

Belumosudil (Rezurock) is indicated for the treatment of adult and pediatric patients aged 12 years and older with cGVHD after the failure of at least 2 prior lines of systemic therapy.¹ The recommended dosage of belumosudil is 200 mg once daily given orally with food at approximately the same time each day. Treatment should continue until the progression of cGVHD that requires a new systemic therapy, or the occurrence of unacceptable toxicity. No dose adjustments are required in adolescents aged 12 to 18 years or in patients aged 65 years or older.¹ No patients under the age of 18 were enrolled in the clinical development program. The Health Canada product monograph indicates that the use of belumosudil in pediatric patients aged 12 years and older is supported by evidence from studies in adults with additional population pharmacokinetic data, demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of drug substance, that the exposure of drug substance is expected to be similar between adults and pediatric patients aged 12 years and older, and that the course of disease is sufficiently similar in adult and pediatric patients to allow the extrapolation of data in adults to these pediatric patients.¹

Belumosudil is a selective oral inhibitor of ROCK2 and ROCK1, with 50% inhibitory concentration values of approximately 100 nM and 3 μM, respectively.¹ ROCK2 plays an integral role in the cytokine cascade and the differentiation of cell types that lead to GVHD.³⁶ ROCK2 phosphorylates the interferon regulatory factor 4 transcription factor necessary to produce IL-17 and IL-21. The ROCK2 signalling that controls the phosphorylation of signal transducer and activator of transcription 3 is necessary for T helper 17 (Th17) cells to differentiate into follicular helper T-cells which, in turn, promote the production of self-reactive mature B-cells. Decreasing ROCK2 signalling that regulates the phosphorylation of signal transducer and activator of transcription 5 reduces the percentage of regulatory T-cells and increases the secretion of IL-10, which decreases the preponderance of Th17 cells and follicular helper T-cells. ROCK2 also regulates the expression of genes associated with fibrosis induced by transforming growth factor beta. Due to inhibition with belumosudil, ROCK2 signalling is reduced, which may serve to restore immune homeostasis, modulate rather than suppress immune function, and avoid aberrant, fibrotic tissue repair.³⁶

The sponsor has requested reimbursement as per the approved Health Canada indication.² Belumosudil underwent a standard review at Health Canada and was issued a Notice of Compliance on March 23, 2022.² Belumosudil has not been previously reviewed by CADTH.

Table 3: Key Characteristics of Belumosudil, Cyclosporine, Tacrolimus, Ruxolitinib, Ibrutinib, Rituximab, and Imatinib

b.i.d. = twice daily; cGVHD = chronic graft-vs.-host disease; CNI = calcineurin inhibitor; CYP3A = cytochrome P450, family 3, subfamily A; GVHD = graft-vs.-host disease; HBV = hepatitis B virus; JAK = Janus kinase; JAKi = Janus kinase inhibitor; LVEF = left ventricular ejection fraction; PML = progressive multifocal leukoencephalopathy; q.d. = once daily; ROCK = Rho-associated, coiled-coil-containing protein kinase; SC = subcutaneous.

^aHealth Canada–approved indication.

Sources: Product monographs for belumosudil, cyclosporine, tacrolimus, ruxolitinib, ibrutinib, rituximab, and imatinib.^{1,13,14,37-40}

Table 4: Key Characteristics of Everolimus, Sirolimus, Infliximab, Methotrexate, Mycophenolate Mofetil, Pentostatin, and ECP

8-MOP = 8-methoxypsoralen; ADA = adenosine deaminase; DHFR = dihydrofolate reductase; ECP = extracorporeal photopheresis; mTOR = mammalian target of rapamycin; q.d. = once daily; SC = subcutaneous; UVA = UV A.

^aHealth Canada–approved indication.

Sources: Product monographs for everolimus, sirolimus, infliximab, methotrexate, mycophenolate mofetil, and pentostatin, and literature review of ECP.^41-47

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by 2 patient groups. The full original patient input received by CADTH has been included in the stakeholder section of this report.

A joint input was submitted by 2 patient groups, the Leukemia and Lymphoma Society of Canada and Myeloma Canada, which responded to CADTH’s call for patient input for the current review of belumosudil for the treatment of adult and pediatric patients aged 12 years and older with cGVHD after the failure of at least 2 prior lines of systemic therapy.

The patient group emphasized that the uncertainty of a GVHD diagnosis after the rigorous cancer and stem cell transplant experience can be nerve-wracking, disheartening, and terrifying for patients and caregivers. Respondents indicated that the full range of GVHD symptoms significantly affects their physical and mental health and daily activities, and has detrimental effects on their HRQoL. They described how the disease affects various parts of the body, including the eyes, skin, lungs, and mouth. Many patients lose their independence and require caregiver support to manage their symptoms.

The patient group stated that managing cGVHD generally requires CS treatment, which can have many physical, neurologic, and circulatory side effects and greatly impacts patient and caregiver HRQoL. It was noted that patients can experience extreme emotions while recovering from the trauma of cancer and stem cell transplant experiences.

According to the patient group input, patients and caregivers seek a treatment that enables them to continue their daily lives and routines throughout the treatment course and that is more accessible, improves OS, and preserves their HRQoL with minimal impact on work, finances, and social, physical, and mental health.

Of the 5 respondents who indicated having experience with belumosudil, 3 stated that the drug had a positive impact on their lives, allowed them to reduce steroid dosage, and was very tolerable with minimal side effects.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of cGVHD.

Unmet Needs

According to the clinical experts consulted by CADTH, there is a lack of good treatment options beyond second-line therapy for patients with cGVHD. As a result, patients with refractory or progressive disease have impaired HRQoL, an impaired ability to work and study, and an increased risk of mortality-associated organ impairment and risk of infections.

Place in Therapy

The clinical experts indicated that belumosudil would be used as per the Health Canada indication after the failure of 2 systemic treatments and would likely be used in combination with CSs. The experts also noted there would need to be good RCT evidence to support using CSs with belumosudil in a first-line setting, and ruxolitinib is currently preferred as a second-line therapy.

Patient Population

As per the clinical experts, those with moderate to severe cGVHD whose condition is refractory to or who are intolerant to 2 prior lines of therapy are most likely to receive belumosudil. The response to prior lines of therapies would be assessed based on clinical signs and symptoms, NIH clinical grading (including laboratory tests), and/or pulmonary function tests.

Assessing the Response Treatment

The experts stated that PR and CR as well as the maintenance of stable disease with a clinically meaningful reduction in CS dose are indicators in clinical practice that a patient is responding to treatment. Improvement in functional status, symptoms, and ability to return to school or work were also important outcomes.

Discontinuing Treatment

The clinical experts stated that treatment should be discontinued in patients who experience cGVHD progression (based on signs, symptoms, examination, laboratory tests) or have stable disease but still require significant amounts of CSs that cannot be tapered. The experts also noted meaningful adverse effects, such as derangement of liver function tests or significant gastrointestinal upset due to belumosudil as also being reasons to stop treatment. Lastly, disease resolution in which a patient has stopped other immunosuppressants (or who may be on low-dose CSs, e.g., 10 mg) with symptom resolution is a third reason. The experts highlighted that stopping treatment in the last instance is done cautiously, as patients can experience disease flares when going off treatment.

Prescribing Considerations

The clinical experts noted that stem cell transplant specialists should initiate belumosudil in either a community or hospital setting, and treatment decisions may involve other specialists (e.g., respirologists).

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by 2 clinician groups. The full original clinician group input received by CADTH has been included in the stakeholder section of this report.

Two clinician groups, the OH-CCO Hematology Cancer Drug Advisory Committee and CTTC responded to CADTH’s call for clinician group input. Clinician perspectives from OH-CCO were obtained through videoconferencing. CTTC gathered the information through a literature review and a discussion with the CTTC board of directors and the standing committee of program directors.

According to the clinician groups, there are multiple third-line treatments available for cGVHD and variability in standard practice based on local funding of available options. OH-CCO added that responsiveness and tolerability to available therapies vary between patients, and oral therapies are often preferred. As per CTTC, current available treatments are suboptimal and require high doses and prolonged use of CSs, which are associated with an increased risk of opportunistic infections, osteoporosis, and avascular necrosis. Therefore, new therapies that reduce the mortality and symptom burden associated with steroid-refractory cGVHD are urgently needed, especially for steroid-refractory pulmonary cGVHD and cGVHD with fibrotic and sclerotic manifestations.

As per the clinician groups, standard GVHD response criteria, significant functional improvements, and better HRQoL are outcomes used to determine whether a patient is responding to treatment. CTTC indicated that a patient showing no significant change in GVHD severity but with a meaningful reduction in immunosuppressive treatments is deemed to be benefiting from the therapy.

The clinician groups agreed that the discontinuation of therapy should be considered in patients with significant intolerance or disease progression. CTTC specified that therapy with belumosudil would require prolonged treatment (greater than 1 year) until no further resolution or stable residual fibrotic changes are present.

OH-CCO stated that the treatment of patients with cGVHD with belumosudil should be managed by cGVHD specialists practising in outpatient settings; however, patients with severe disease may require treatment as an inpatient. CTTC added that this therapy should be prescribed only for patients with steroid- or ruxolitinib-refractory cGVHD by specialists working in a clinical setting associated with allo-HSCT programs.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

aGVHD = acute graft-vs.-host disease; cGVHD = chronic graft-vs.-host disease; CNI = calcineurin inhibitor; CR = complete response; CS = corticosteroid; ECP = extracorporeal photopheresis; NIH = National Institutes of Health; PR = partial response; RCT = randomized controlled trial.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of belumosudil 200 mg once-daily oral tablets in the treatment of adult and pediatric patients aged 12 years and older with cGVHD after the failure of at least 2 prior lines of systemic therapy. The focus will be placed on comparing belumosudil with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of belumosudil is presented in 4 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section would include sponsor-submitted long-term extension studies; however, none were submitted. The third section would include sponsor-submitted ITCs; in this case, the sponsor submitted a feasibility assessment but no indirect comparison. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

The clinical evidence from the following is included in the CADTH review and appraised in this document:

• Two clinical studies or RCTs (with a single-arm relevant to this report) identified in the systematic review

• One feasibility assessment for ITCs

• One additional study addressing gaps in the evidence.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Description of Studies

The 2 studies included in the systematic review are summarized in Table 6. Only information for drug doses that align with the Health Canada product monograph (i.e., belumosudil 200 mg once daily) is presented in the CADTH report.

Study KD025 to 213 is a phase II, open-label study conducted at 33 sites in the US that began on October 11, 2018, and is now complete, with a primary analysis data cut-off date of February 19, 2020, and a latest data cut-off date of ||||||||| ||| ||||.^15,16 In total, ||| patients were randomized in a 1:1 ratio to either belumosudil 200 mg once daily (N = ||) or belumosudil 200 mg twice daily (N = ||), and || individuals were randomized but not treated. Randomization was stratified by prior treatment with ibrutinib (yes or no) and severe cGVHD (yes or no). Severe GVHD was defined according to the NIH cGVHD severity definitions as GVHD with at least 1 organ with a score of 3 or an NIH lung score of 2 or 3.¹⁰ Figure 1 shows the study design for study KD025 to 213.

Study KD025 to 208 is a phase IIa, dose-escalation, open-label study conducted at 7 sites in the US that began on September 27, 2016, and is ongoing, with a primary reporting data cut-off date of February 19, 2020, and a latest data cut-off date of |||| ||| ||||.^17,18 In total, 54 patients were enrolled into 3 sequential cohorts of belumosudil 200 mg once daily (N = 17), belumosudil 200 mg twice daily (N = 16), and belumosudil 400 mg once daily (N = 21). Prior to the enrolment of subsequent cohorts, the safety data in each previous cohort were evaluated after 8 patients had reached 2 months of treatment.

Both studies had a screening period (14 days and 28 days for study KD025 to 213 and study KD025 to 208, respectively) to assess eligibility. The study treatment continued in 28-day cycles until clinically significant disease progression in study KD025 to 213, or for 24 weeks of therapy in study KD025 to 208. Patients were followed up for 4 weeks in both studies and may have continued treatment for up to 3 years. The primary end point in the studies was ORR per investigator assessment (measured on day 1 of each cycle for cycles 2 to 5 and every other cycle thereafter until clinically meaningful disease progression or EOT). The secondary outcomes of interest for the CADTH review were similar between the 2 studies and included DOR, TTR, FFS, OS, LSS score, and safety outcomes. PROMIS Global Health summary scores were exploratory outcomes in study KD025 to 213.

Table 6: Details of Studies Included in the Systematic Review

aGVHD = acute graft-vs.-host disease; allo-HSCT = allogeneic hematopoietic stem cell transplant; ALT = alanine aminotransferase; AST = aspartate aminotransferase; b.i.d. = twice daily; cGVHD = chronic graft-vs.-host disease; CNI = calcineurin inhibitor; CS = corticosteroid; CYP3A4 = cytochrome P450, family 3, subfamily A, member 4; DOR = duration of response; ECP = extracorporeal photopheresis; EOT = end of treatment; FEV₁ = forced expiratory volume in 1 second; FFS = failure-free survival; GC = glucocorticoid; GFR = glomerular filtration rate; GSR = global severity rating; GVHD = graft-vs.-host disease; HSCT = hematopoietic stem cell transplant; IL = interleukin; KARA = Kadmon algorithmic response assessment; LSS = Lee Symptom Scale; NA = not applicable; NIH = National Institutes of Health; ORR = overall response rate; OS = overall survival; PD = pharmacodynamics; PFT = pulmonary function test; PK = pharmacokinetics; PROMIS = Patient-Reported Outcomes Measurement Information System; q.d. = once daily; Th17 = helper T-cell 17; Treg = regulatory T-cell; TTNT = time to next treatment; TTR = time to response; ULN = upper limit of normal.

^aThe number of patients in the study as of the latest data cut-off date (||||||||| ||| ||||).

^bThe Health Canada–approved dosage for belumosudil is 200 mg q.d. and results are reported only for this treatment group or cohort. Patients were treated with belumosudil until clinically significant disease progression.

^cAs per the NIH consensus development project on clinical trials in cGVHD response criteria.³²

Sources: Clinical Study Reports for study KD025 to 213¹⁵ and study KD025 to 208¹⁷ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Figure 1: Study Design for Study KD025 to 213

BID = twice daily; cGVHD = chronic graft-versus-host disease; DOR = duration of response; FFS = failure-free survival; HCT = hematopoietic cell transplant; IA = interim analysis; KD025 = belumosudil; LSS = Lee symptom score; ORR = overall response rate; PA = primary analysis; PK = pharmacokinetics; QD = once daily; Y/N = yes or no.

Sources: Study KD025 to 213 Clinical Study Report¹⁵ and sponsor’s summary of clinical evidence.¹¹

Populations

Inclusion and Exclusion Criteria

In study KD025 to 213, eligible patients had to be at least 12 years of age or older with active cGVHD and had to have undergone an allo-HSCT, received 2 to 5 prior lines of therapy for cGVHD, and received stable glucocorticoid (GC) therapy for at least 2 weeks before screening. Patients were excluded if there was evidence of histological relapse of underlying cancer of posttransplant lymphoproliferative disease, or they were receiving ibrutinib at the time of screening. In each group, the study aimed to enrol at least 10% of patients who had previously received ibrutinib.

In study KD025 to 208, eligible patients had to be 18 years of age or older with active cGVHD and had to have undergone an allogeneic bone marrow transplant or allo-HSCT, received 1 to 3 prior lines of therapy for cGVHD (excluding ECP), and received GC therapy with or without CNI therapy for cGVHD. Patients were excluded if they had aGVHD or received an investigational GVHD treatment.

Interventions

In study KD025 to 213, patients received belumosudil 200 mg once daily in 28-day cycles until clinically significant progression of disease (i.e., requiring a new systemic therapy for cGVHD), histologic recurrence of the underlying malignancy, unacceptable toxicity, death, lost to follow-up, or investigator decision. The drug was tapered after a sustained response for 6 months and cessation of all other immunosuppressants for at least 3 months as follows: belumosudil 200 mg once daily, then belumosudil 200 mg once every other day for 2 cycles, then discontinued. Patients who had not progressed or responded when belumosudil was discontinued and who came off the study for reasons other than AEs were tapered off belumosudil by reducing the dose every 2 cycles. Patients were permitted to have concomitant treatment with standard of care systemic cGVHD therapies, such as CNIs (tacrolimus, cyclosporine), sirolimus, mycophenolate mofetil, methotrexate, rituximab, ECP, or topical or organ-specific therapies if they had been on a stable regimen; however, initiation of a new systemic therapy was not permitted. CS dose data were collected throughout the study and doses may have been tapered by the investigator after at least 2 weeks after belumosudil administration. Transient increases in CS dosing (that did not exceed 1 mg/kg/day of a prednisone equivalent) were permitted to treat cGVHD flares, but the dose had to be reduced back to the prerandomization dose within 6 weeks. Situations where the CS dose remained elevated for more than 6 weeks, or if a patient experienced more than 2 episodes of cGVHD flares that required increased CS therapy in the first 6 months of belumosudil treatment, were considered treatment failures.

In study KD025 to 208, patients received belumosudil 200 mg once daily in 28-day cycles until disease progression or unacceptable toxicity. If at least 25% of the patients in a cohort experienced grade 2 liver toxicity or a grade 3 or higher AE in the same organ or body system, or if at least 25% of patients in a cohort were discontinued for toxicity that persisted for 14 days, then dose escalation to the next cohort was halted and all patients in that dose cohort received a reduced dose. Patients could receive concomitant CS and CNI therapy and, after 4 weeks of belumosudil treatment, CS treatment could be tapered at the investigator’s discretion.

Dose interruptions of up to 14 days were permitted, though patients were discontinued if interruptions were longer or if more than 1 dose reduction was required. Furthermore, treatment continued until the clinically significant progression of cGVHD (defined as disease progression that required the addition of new systemic therapy), histologic recurrence of underlying malignancy, unacceptable toxicity, investigator decision, patient preference or withdrawal of consent, lost to follow-up, sponsor decision, or death.

Outcomes

A list of efficacy end points assessed in this Clinical Review is provided in Table 7, followed by descriptions of the outcome measures in Table 8. The summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review according to the clinical experts consulted by CADTH, stakeholder input from patient and clinician groups and public drug plans, and the sponsor’s pharmacoeconomic model. Using the same considerations, the CADTH review team selected end points that were considered to be most relevant to inform CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing the deliberations of CADTH’s expert committee were also assessed using GRADE.

The following considerations went into the selection of the efficacy outcomes summarized in the report and assessed using GRADE:

• Response to treatment was noted as being a current unmet need, according to the authors of clinician group input. As per the clinical experts and clinician group input, response criteria are typically used to assess patients receiving treatment for cGVHD in practice.

• Survival was identified as being a high priority according to the patient group input. It was also highlighted in the clinician group input that cGVHD greatly impacts mortality.

• HRQoL and reducing symptom burden were identified as being priorities in the patient group input and clinician group input. The LSS is a patient-reported, disease-specific measure of symptoms. PROMIS is a generic measure of health that was used in the sponsor’s pharmacoeconomic model after statistical mapping to the EQ-5D.

• Harms of treatment were also noted as being important in the patient group input, clinician group input, and by the clinical experts.

Table 7: Outcomes Summarized From the Studies Included in the Systematic Review

cGVHD = chronic graft-vs.-host disease; CR = complete response; CS = corticosteroid; DOR = duration of response; FFS = failure-free survival; GRADE = Grading of Recommendations Assessment, Development, and Evaluation; GSR = global severity rating; LSS = Lee Symptom Scale; ORR = overall response rate; OS = overall survival; PR = partial response; PROMIS = Patient-Reported Outcomes Measurement Information System; SAE = serious adverse event; TTNT = time to next treatment; TTR = time to response.

^aAs per the National Institutes of Health consensus development project on clinical trials in cGVHD response criteria.

^bStatistical testing for this end point was adjusted for multiple comparisons.

^cOutcome considered to be informative for the clinical management of patients with cGVHD but not included for GRADE assessment. Outcome has been included in Appendix 1.

Sources: Clinical Study Reports for study KD025 to 213¹⁵ and study KD025 to 208¹⁷ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Primary Outcome

ORR by Investigator Assessment

The primary outcome in both studies was ORR at the 6-month follow-up by investigator assessment.^15,17 ORR was defined as the proportion of patients who experienced a CR or PR based on the cGVHD response assessment performed on day 1 of cycle 2 through cycle 5, and then day 1 of every other cycle thereafter, as well as the EOT visit (in KD025 to 208 only). Overall response was assessed according to the 2014 NIH consensus criteria using the scores from 9 organ systems (i.e., skin, eyes, mouth, esophagus, upper gastrointestinal tract, lower gastrointestinal tract, liver, lungs, and joints and fascia) as well as the global severity rating (GSR).⁵⁰ Response was assessed relative to the baseline (cycle 1 day 1) cGVHD assessment. The overall response at each assessment time point was categorized as a CR, PR, or LR, where LR included unchanged (LR-U), mixed (LR-M), and progression (LR-P) as detailed subsequently.

• CR: Resolution of all cGVHD manifestations in each organ or site

• PR: Improvement in at least 1 organ or site without progression in any other organ or site

• LR:

  • LR-M: CR or PR in at least 1 organ accompanied by progression in another organ; response was considered progression for the purposes of the analysis

  • LR-U: Outcomes that did not meet the criteria for CR, PR, LR-M, or LR-P

  • LR-P: Progression in at least 1 organ or site without a response in any other organ or site

If a treated patient was lost to follow-up without a response assessment, the patient was counted as a nonresponder.

Secondary Outcomes

Duration of Response

According to the clinical experts consulted by CADTH, the tertiary and secondary DOR definitions were considered to be the most clinically relevant. The tertiary definition of DOR was the time from first documented response to the time of initiation of a new systemic cGVHD therapy or death (reviewed by a clinical team).^15,17 The secondary definition of DOR was the time from first documented response to the time of first documented LR. The sponsor also included a primary definition of DOR, which was the time from first documented response to the time of first documented deterioration from best response (e.g., CR to PR or PR to LR). For primary and secondary DOR, censoring occurred at the last documented response assessment or, if due to LR or the initiation of a new systemic therapy occurred immediately after 2 or more missed response assessments, then the event date was set as 4 weeks (1 cycle) after the last documented response assessment before this event. For tertiary DOR, censoring occurred at the last response assessment or long-term follow-up assessment, whichever was the latest and available. DOR was measured only in patients who were responders at time points similar to ORR.

Time to Response

TTR was defined as the time from first treatment to the time of first documentation of response.^15,17 TTR analyses were only conducted for patients who were responders and were also evaluated at the organ level. TTR was measured only in patients who were responders at time points similar to ORR up to week 48. Results were also provided by organ system (Appendix 1).

Failure-Free Survival

FFS was defined as the time from the first dose of belumosudil to the time of the first event that included the initiation of a new cGVHD therapy, nonrelapse mortality, or recurrent malignancy (i.e., of underlying disease).^15,17 Censoring for FFS was performed according to the last response assessment or long-term follow-up assessment, whichever was the latest and available.

Time to Next Treatment

Time to next treatment (TTNT) was measured as the time from the first dose of belumosudil to the time of new systemic cGVHD treatment, censored by the last response assessment or the long-term follow-up assessment, whichever was the latest and available.^15,17 This outcome was considered useful in informing the clinical management of individual patients with cGVHD, but not critical to decision-making, and is summarized in Appendix 1.

Overall Survival

OS was defined as the time from the first dose of belumosudil to the date of death due to any cause.^15,17

Change in LSS Score

Changes in symptom burden were explored using the 7-day LSS score.^15,17 Symptom burden was assessed on day 1 of each cycle beginning with cycle 1 until EOT. The questionnaire consists of 30 items over 7 domains (i.e., skin, eyes and mouth, breathing, eating and digestion, muscles and joints, energy, and emotional distress). Patients indicate the degree of bother due to symptoms over the past 7 days on a scale ranging from 0 to 4, with higher values indicating worse symptoms. A domain score is calculated for each domain using the mean of all items completed if more than 50% were answered and normalizing to a 0 to 100 scale. A summary score is calculated as the average of all nonmissing domain scores if more than 50% of them are nonmissing. A higher score indicates more bothersome symptoms. A 7-point or greater reduction in the summary score is considered clinically meaningful.¹⁹ This outcome was assessed at baseline, day 1 of cycle 2 through cycle 5, then day 1 of every other cycle thereafter, and at EOT.

Change in Corticosteroid Dose

The change in systemic CS dose as mg/kg/day prednisone equivalent over time was measured.^15,17 Dose equivalencies were as follows: 1 mg prednisone was equivalent to 4 mg hydrocortisone, 0.8 mg methylprednisolone, 0.15 mg dexamethasone, and 0.8 mg triamcinolone. Systemic CS dose over time, change and percent change from baseline to the greatest CS dose reduction during belumosudil treatment, number and percentage of patients who reduced systemic CS use, and number and percentage of patients who ever discontinued systemic CS use during belumosudil treatment were evaluated. Data were collected throughout the study until 28 days after the last dose of the study drug. Transient CS dose increases of 1 mg/kg/day or lower were permitted to treat disease flares but had to have been reduced to the prerandomization dose within 6 weeks; otherwise, belumosudil treatment was considered to have failed in the patient. A patient who experienced 3 or more disease flares requiring an increased CS dose during the first 6 months of belumosudil treatment was also considered a belumosudil treatment failure. This outcome was considered useful in informing the clinical management of individual patients with cGVHD but not critical to decision-making, and is summarized in Appendix 1.

Safety

Safety was assessed by the proportion of patients who experienced AEs (coded using Medical Dictionary for Regulatory Activities version 20.0), SAEs, withdrawals due to AEs, and deaths.^15,17 Data were collected throughout the study until 28 days after the last dose of the study drug. Hematologic and immune AEs were notable harms included in the CADTH review.

Exploratory Outcomes

Change in PROMIS Global Health Summary Scores for Physical and Mental Functioning

The PROMIS Global Health score was developed using mixed qualitative and quantitative methods and used item response therapy-calibrated item banks for numerous patient-reported symptoms and functional domains.¹⁵ It includes 6 questions pertaining to general health, including the patient’s rating of their general health as excellent, very good, good, fair, or poor. In addition, there is a question about the patient’s ability to carry out everyday physical activities (responses include completely, mostly, moderately, a little, or not at all) and a question pertaining to emotional problems such as feeling anxious, depressed, or irritable over the last 7 days (responses include never, rarely, sometimes, often, or always). Two summary scores were determined for physical and mental functioning, with higher scores indicating better functioning. There are also 2 questions regarding average fatigue (responses include none, mild, moderate, severe, and very severe) and average pain (rated on a scale from 0 = no pain to 10 = worst pain imaginable). This outcome was assessed at baseline, day 1 of cycle 2 through cycle 5, then day 1 of every other cycle thereafter, and at EOT.

Table 8: Summary of Outcome Measures and Their Measurement Properties

cGVHD = chronic graft-vs.-host disease; GVHD = graft-vs.-host disease; LSS = Lee Symptom Scale; MID = minimal important difference; PROMIS = Patient-Reported Outcomes Measurement Information System.

Statistical Analysis

Sample Size and Power Calculation

In study KD025 to 213, the sample size was based on the primary efficacy outcome (to demonstrate an ORR greater than 30%, i.e., the lower bound of the ORR CI was greater than 30%) and the following considerations.¹⁵ Based on the sponsor’s consultation with key opinion leaders, a 30% ORR was considered clinically meaningful in the population of interest.⁴⁸ The interim analysis had a 0.0025 1-sided alpha spending function. Based on data from study KD025 to 208, a true ORR of 55% was assumed in patients with cGVHD after 1 to 3 prior lines of systemic therapy. In study KD025 to 208, the ORR was 65% in cohort 1 (200 mg once daily) as of September 13, 2018. Based on data from the same study, a 10% dropout rate was assumed. Dropouts were defined as discontinuations from belumosudil treatment before any response assessment due to reasons other than an AE related to belumosudil or cGVHD progression. Protocol Amendment 1 planned for 126 patients to be enrolled with 63 patients per treatment group based on the assumption of a 55% true ORR, 10% dropout rate, 90% power, and a 2-sided alpha of 0.045 to demonstrate an ORR larger than 30% in a single-arm study. According to Protocol Amendment 2, the planned sample size increased from 126 to 166 patients with the additional 40 patients (20 of whom would be adolescents) to be enrolled in a site-specific companion study.

In study KD025 to 208, a sample size of 16 patients per cohort was planned corresponding to more than 90% probability of at least 1 patient experiencing an AE with an underlying rate of at least 14% and more than 80% probability of at least 1 patient experiencing an AE that has an underlying rate of at least 10%.¹⁷ Assuming a best ORR of 25%, which the sponsor determined to be clinically meaningful, the study was expected to have approximately 90% probability to show a response in at least 2 patients per cohort.⁴⁹ The study was not powered to show significant differences between cohorts with respect to efficacy or safety analyses.⁴⁹

Statistical Testing

In study KD025 to 213, statistical analyses included the calculation of point estimates and 95% CIs by the Clopper-Pearson (exact) method for the primary outcome. The first analysis (interim) was conducted approximately 2 months after 126 patients were enrolled into the mITT population, which used a nominal 1-sided alpha of 0.0025, though there was no early study termination for efficacy and the data are not presented in this CADTH report. The second analysis (primary) was conducted approximately 6 months after 126 patients were enrolled into the mITT population, with a 1-sided alpha of 0.0225 (or 0.025 if the ORRs of both treatment groups were significant at interim). The third analysis (follow-up) was conducted approximately 12 months after 126 patients had been enrolled into the mITT population.

In study KD025 to 208, the point estimate for ORR was presented with 95% CIs calculated by the Clopper-Pearson (exact) method. No formal hypothesis testing was undertaken. The study was not powered to show significant differences between cohorts for efficacy or safety analyses and there was no early stopping for efficacy.⁴⁹ The follow-up analysis was conducted 1 year after the last patient was enrolled.

Multiple Testing Procedure

Only the primary outcome of study KD025 to 213 was adjusted for multiple comparisons using the Hochberg procedure. A 1-sided alpha of 0.0025 (for each treatment arm) was reserved for the interim analysis. The 2-sided 99.5% CIs were calculated for both treatment groups to assess efficacy. The primary analysis used a 1-sided alpha of 0.0225 (for each treatment arm) and, likewise, the 2-sided 95.5% CIs were calculated. For the remaining end points, only descriptive statistics were provided.

Data Imputation Methods

Missing data were not imputed for either study. Instead, they were reported as missing and, for categorical data, were not used to calculate percentages.

Subgroup Analyses

The following prespecified subgroup analyses were performed for ORR and DOR end points in study KD025 to 213: prior ibrutinib use (yes versus no), severe cGVHD at screening (yes versus no), number of organs involved at baseline (less than 4 versus 4 or more), number of prior lines of therapy (4 or fewer versus more than 4), duration of cGVHD before enrolment (by 50th percentile), baseline CS dose level (by 50th percentile), lung involvement at baseline (yes versus no), concomitant medication proton pump inhibitor use on cycle 1 day 1 (yes versus no), sex (female versus male), age (younger than 65 years old versus 65 years and older), and race (white versus not white).

Similarly, the following prespecified subgroup analyses were performed in study KD025 to 208: number of prior lines of therapy (1 versus 2 or more), number of organs involved at baseline (less than 4 versus 4 or more), baseline severity (severe versus not severe, where baseline activity assessment was used as a surrogate), concomitant medication proton pump inhibitor use on cycle 1 day 1 (yes versus no), refractory to most recent line of therapy before enrolment (yes versus no).

All subgroups were exploratory with no adjustment for multiplicity.

Sensitivity Analyses

No sensitivity analyses were conducted for either study.

Secondary Outcomes of the Studies

In study KD025 to 213, all secondary and exploratory outcomes were reported descriptively (KM estimates, landmark analyses, and changes from baseline) without multiplicity adjustment. In study KD025 to 208, outcomes were reported in a similar fashion, and none were adjusted for multiplicity due to the exploratory nature of the study. Landmark analyses for DOR were performed for the number and percentage of patients with a response sustained for at least 12, 20, 24, 32, 36, and 48 weeks and landmark analyses for FFS and OS were conducted at 6, 12, 18, and 24 months.

Analysis Populations

The analysis populations of the included studies are summarized in Table 9.

Table 9: Analysis Populations of Study KD025 to 213 and Study KD025 to 208

CR = complete response; DOR = duration of response; mITT = modified intention to treat; PR = partial response; TRR = time to response.

Sources: Clinical Study Report for study KD025 to 213¹⁵ and study KD025 to 208⁷ and the sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Results

Patient Disposition

The patient disposition of the included studies is summarized in Table 10. In study KD025 to 213 (data cut-off ||||||||| ||| ||||), of the ||| individuals screened, ||| (||||%) were randomized, with ineligibility being the most common reason for screening failure. Subsequently, || patients were randomized to receive belumosudil 200 mg once daily, and all but 1 patient was treated with the study drug. In study KD025 to 208 (data cut-off |||| ||| ||||), || individuals were screened, of whom || (||||%) were randomized, with ineligibility being the most common reason for screening failure. Of the randomized population, 17 patients received belumosudil 200 mg once daily. At the data cut-off dates, the median follow-ups were |||| months (range, ||| to ||||) for study KD025 to 213 and |||| months (range, ||| to ||||) for study KD025 to 208.

The proportion of responders was higher in study KD025 to 213 (||||%) compared with study KD025 to 208 (||||%), though the apparent difference may be due to the small number of patients in the latter study. All patients had discontinued from both the treatment and the studies as of the latest data cut-off dates. Physician or investigator decision (||||%) was the most common reason for treatment discontinuation in study KD025 to 213, while disease progression (||||%) was the most common reason in study KD025 to 208 (it was not clear if this was a progression of the underlying malignancy or cGVHD). Study termination by the sponsor (||||%) and death (||||%) were the most common reasons for study discontinuation in study KD025 to 213 and study KD025 to 208, respectively.

Table 10: Summary of Patient Disposition From Study KD025 to 213 and Study KD025 to 208 (mITT Population)

cGVHD = chronic graft-vs.-host disease; mITT = modified intention to treat; NR = not reported; q.d. = once daily.

^aThe number of patients screened in the overall study, which included treatment groups that received doses outside of the Health Canada indication.

^bAs per Protocol Amendment 2 (|||| || ||||) in KD025 to 213, the expected number of patients to be enrolled was increased from 126 to |||. The additional || patients were to include || adolescents and || adults to be enrolled in a site-specific companion study and the study enrolment period was revised from 12 months to 24 months. As a result, in the updated 3-year long-term analysis, a total of || patients were randomized to the belumosudil 200 mg q.d. group, of which || patient was randomized and not treated, resulting in a total of || patients in the mITT population for the updated analysis.

^cStudy KD025 to 208 did not differentiate between progression of cGVHD and progression of underlying malignancy.

Note: Data are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Baseline Characteristics

The baseline characteristics of the patients in the included studies are summarized in Table 11 and are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

In study KD025 to 213, the median age of patients was 53 years (range, 21 to 77 years) and there were more males (||%) than females (||%). In study KD025 to 208, the median age of patients was 50 years (range, 20 to 63 years) and there were also more males (77%) than females (23%). In both studies, most patients had a Karnofsky Performance Score of 80 or higher, the median time from cGVHD diagnosis to study enrolment was approximately 25 months, and more than 70% of patients had severe cGVHD, according to the 2014 NIH consensus criteria. Acute myelogenous leukemia, myelodysplastic syndrome, and acute lymphocytic leukemia were the most common indications for transplant in study KD025 to 213, while acute myelogenous leukemia, acute lymphocytic leukemia, and non-Hodgkin lymphoma were the most common indications in study KD025 to 208. The median number of organs involved was 4 (range, 0 to 7) with more than half of patients having at least 4 organs involved in both studies. In total, 100% of patients in study KD025 to 213 and 88% of patients in study KD025 to 208 had received 2 or more prior lines of therapy. CSs were the most common prior cGVHD treatment among all patients (more than 99%), with the next most common being tacrolimus in study KD025 to 213 (||%) and sirolimus in study KD025 to 208 (||%).

Table 11: Summary of Baseline Characteristics From Study KD025 to 213 and Study KD025 to 208 (mITT Population)

cGVHD = chronic graft-vs.-host disease; HLA = human lymphocyte antigen; mITT = modified intention to treat; NIH = National Institutes of Health; q.d. = once daily.

Note: Data are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

^aDisease severity was determined using NIH Global Severity of cGVHD scoring.

Sources: Clinical Study Report for study KD025 to 213¹⁵ and study KD025 to 208¹⁷ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Exposure to Study Treatments

Exposure to study treatments and concomitant medication use are summarized in Table 12. As of the latest data cut-off dates, the median treatment durations with belumosudil 200 mg once daily were ||| months (range, ||| to |||| months) and ||| months (range, ||| to |||| months) in study KD025 to 213 and study KD025 to 208, respectively. Mean and median adherence were greater than ||% and 99%, respectively, in the 2 studies. All patients received some form of concomitant medication during the studies, with prednisone being the most common (||| || |||%) followed by systemic tacrolimus (||| || ||%).

Table 12: Summary of Patient Exposure From Study KD025 to 213 and Study KD025 to 208 (mITT Population)

cGVHD = chronic graft-vs.-host disease; ECP = extracorporeal photopheresis; mITT = modified intention to treat; NR = not reported; q.d. = once daily; SD = standard deviation.

Note: Data are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 ||| |||| ||| ||||, for study KD025 to 208.

^aRelative dose intensity (%) calculated as actual dose intensity (mg/day) divided by planned dose intensity (mg/day) multiplied by 100.

^bMore than 15% of patients in either study.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Efficacy

Summarized within the main report are the outcomes considered most relevant to inform CADTH’s expert committee deliberations. Appendix 1 contains additional efficacy outcomes considered to be useful in guiding the clinical management of individual patients with cGVHD but that were not critical to informing deliberations. These included response by organ system and GSR assessment, TTNT, and prednisone-equivalent dose of CSs.

ORR by Investigator Assessment

ORR results are summarized in Table 13. ORR interim analysis results for study KD025 to 213 had a P value of less than 0.001 using a 1-sided alpha of 0.0025 (data not included in this CADTH report).

In study KD025 to 213, the ORR was 72.7% (95% CI, 60.4% to 83.0%; P < 0.0001) as of the primary analysis cut-off date (February 19, 2020), 6 months after enrolment of 126 patients into the mITT population. Overall, 3 patients (4.5%) had a CR, 45 patients (68.2%) had a PR, 15 (22.7%) had an LR, and 3 (4.5%) had no response assessment. In study KD025 to 208, the ORR was 64.7% (95% CI, 38.3% to 85.8%) as of the primary reporting data cut-off date (February 19, 2020), and all responders had a PR. The 6 remaining patients (35.3%) had an LR.

As of the latest cut-off date for study KD025 to 213 (||||||||| ||| ||||), the ORR was ||||| (95% CI, ||||| || |||||). Overall, || patients (|||%) had a CR, || patients (||||%) had a PR, || patients (||||%) had an LR, and patients || (|||%) had no response assessment. As of the latest cut-off date for study KD025 to 208 (|||| ||| ||||), the ORR was ||||% (95% CI, ||||| || |||||). Overall, || patients (||||%) had a PR and || patients (||||%) had an LR. The findings for ORR appeared to be generally similar across the subgroups.

Table 13: Summary of Overall Response Rate From Study KD025 to 213 and Study KD025 to 208 (mITT Population)

CI = confidence interval; CR = complete response; mITT = modified intention to treat; NA = not applicable; ORR = overall response rate; PR = partial response; q.d. = once daily.

^aBased on a data cut-off of February 19, 2020, for both studies. For study KD205 to 213, the primary analysis cut-off date corresponds with 6 months after last patient, first visit.

^bThe 2-sided exact CI was calculated using the Clopper-Pearson method.

^cHochberg multiplicity–adjusted P value.

^dResults are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||| for study KD025 to 208. As per Protocol Amendment 2 in KD025 to 213, the expected number of enrolled patients was increased, thus accounting for the larger number of patients at the later data cut-off.

Sources: Clinical Study Report for study KD025 to 213¹⁵ and study KD025 to 208,¹⁷ Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

DOR

The clinical experts consulted by CADTH indicated that the tertiary and secondary DOR definitions were the most relevant to clinical practice and their results are summarized in Table 14.

Of patients who responded to treatment (n = ||), the KM estimate for the median tertiary DOR was ||||| weeks (95% CI lower bound = |||| weeks; upper bound not reached) in study KD025 to 213 and was not reached (95% CI lower bound = 8.1 weeks; upper bound not reached) in study KD025 to 208. At 24 weeks, the KM estimate for tertiary DOR event-free probability was ||% (95% CI, ||| || ||%) in study KD025 to 213 and ||% (95% CI, ||| || ||%) in study KD025 to 208.

The KM estimate for median secondary DOR was |||| weeks (95% CI, |||| to ||||) in study KD025 to 213 and |||| weeks (95% CI lower bound = |||; upper bound not reached) in study KD025 to 208. At 24 weeks, the KM estimate for the secondary DOR event-free probability was ||% (95% CI, ||| || ||%) in study KD025 to 213 and ||% weeks (95% CI, ||| || ||%) in study KD025 to 208.

TTR

TTR results are summarized in Table 15.

Based on the responder population, the median TTR was ||| weeks (range, ||| to |||| weeks) in study KD025 to 213 and ||| weeks (range, ||| to |||| weeks) in study KD025 to 208. At weeks 8 and 12, the cumulative response rates were ||||% and ||||%, respectively, in study KD025 to 213 and ||||% and ||||%, respectively, in study KD025 to 208.

Table 14: Summary of DOR From Study KD025 to 213 and Study KD025 to 208 (Responder Population)

CI = confidence interval; DOR = duration of response; KM = Kaplan-Meier; q.d. = once daily.

^aCIs were calculated using the KM method.

Note: Results are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and the sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Table 15: Summary of TTR From Study KD025 to 213 and Study KD025 to 208 (Responder Population)

q.d. = once daily; TTR = time to response.

Note: Results are based on a data cut-off of ||||||||| ||| ||||| for study KD025 to 213 and |||| ||| ||||| for study KD025 to 208.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

FFS

FFS results are summarized in Table 16.

The median KM estimate for FFS was |||| weeks (95% CI, |||| to ||||) in study KD025 to 213 and |||| weeks (95% CI lower bound = ||| weeks; upper bound not reached) in study KD025 to 208. According to the KM estimate, ||% of patients (95% CI, ||| || ||%) maintained FFS at 12 months in study KD025 to 213 and ||% (95% CI, ||| || ||%) at 12 months in study KD025 to 208.

Table 16: Summary of Failure-Free Survival From Study KD025 to 213 and Study KD025 to 208 (mITT Population)

cGVHD = chronic graft-vs.-host disease; CI = confidence interval; FFS = failure-free survival; KM = Kaplan-Meier; mITT = modified intention to treat; q.d. = once daily.

Note: Results are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Overall Survival

OS results are summarized in Table 17.

The median KM estimate for OS was not reached in either study KD025 to 213 or study KD025 to 208. According to the KM estimate, the OS probability was ||% (95% CI, ||| || ||%) at 12 months in study KD025 to 213 and ||% (95% CI, ||| || ||%) at 12 months in study KD025 to 208.

Table 17: Summary of Overall Survival From Study KD025 to 213 and Study KD025 to 208 (mITT Population)

cGVHD = chronic graft-vs.-host disease; CI = confidence interval; KM = Kaplan-Meier; mITT = modified intention to treat; NA = not applicable; OS = overall survival; q.d. = once daily.

Note: Results are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

LSS Score

LSS scores results are summarized in Table 18.

In study KD025 to 213, || patients (||||%) had a 7-point or greater reduction in LSS score from baseline. In study KD025 to 208, 9 patients (52.9%) had a 7-point or greater reduction in LSS score from baseline.

Table 18: Summary of Lee Symptom Scale Score From Study KD025 to 213 and Study KD025 to 208 (mITT Population)

LSS = Lee Symptom Scale; mITT = modified intention to treat; q.d. = once daily.

Note: Results are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

PROMIS Global Health Summary Scores for Physical and Mental Functioning

PROMIS results are summarized in Table 19.

In study KD025 to 213, || patients (||||%) had a 4.7-point or greater change from baseline for physical health and || patients (||||%) had a 4.7-point or greater change from baseline for mental health. This outcome was not assessed in study KD025 to 208.

Table 19: Summary of PROMIS Global Health Summary Scores for Physical and Mental Functioning From Study KD025 to 213 (mITT Population)

mITT = modified intention to treat; PROMIS = Patient-Reported Outcomes Measurement Information System; q.d. = once daily.

Note: Results are based on a data cut-off of ||||||||| ||| ||||| for study KD025 to 213.

Source: Study KD025 to 213 Clinical Study Report addendum¹⁶ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Change in CS Dose

Change in CS dose results are summarized in Table 24 of Appendix 1.

In study KD025 to 213, || patients (||||%) reduced their CS dose and || (||||%) discontinued CS usage while receiving belumosudil. In study KD025 to 208, || patients (||||%) reduced their CS dose and 4 (23.5%) discontinued CS usage while receiving belumosudil.

Harms

Harms results as of the latest data cut-off date are summarized in Table 20.

Adverse Events

Most patients experienced at least 1 TEAE in study KD025 to 213 (||||%) and study KD025 to 208 (100%). The most common TEAEs were diarrhea (||||%) and fatigue (||||%) in study KD025 to 213 and upper respiratory tract infection (||||%), diarrhea, fatigue, nausea, and increased alanine aminotransferase (||||% each) in study KD025 to 208.

Serious Adverse Events

In study KD025 to 213, ||||% of patients experienced an SAE while 29.4% of patients in study KD025 to 208 experienced an SAE. Pneumonia (|||%) was the most frequently reported SAE in study KD025 to 213. No other SAEs occurred in more than 3 patients in either study.

Withdrawals Due to Adverse Events

In study KD025 to 213, ||||% of patients stopped belumosudil 200 mg due to an AE, while ||||% of patients in study KD025 to 208 stopped belumosudil due to an AE.

Mortality

Overall, || patients died in study KD025 to 213 (due to hemothorax, aspiration and respiratory failure, septic shock and multiple organ dysfunction, and recurrent acute myeloid leukemia) and 0 patients died in study KD025 to 208.

Notable Harms

Based on the Health Canada product monograph warnings and precautions, hematologic and immune AEs were identified as being important to the CADTH review. Hematologic and immune AEs were coded as blood and lymphatic system disorders and infections and infestations, respectively.

Under the heading of blood and lymphatic system disorders, ||||% of patients in study KD025 to 213 and ||||% of patients in study KD025 to 208 experienced an AE. Anemia was the most common AE reported by |||% and ||||% of patients in study KD025 to 213 and study KD025 to 208, respectively.

For infections and infestations, ||||% or patients in study KD025 to 213 and ||||% of patients in study KD025 to 208 experienced an AE. Upper respiratory tract infection was the most common AE reported by ||||% and ||||% of patients in study KD025 to 213 and study KD025 to 208, respectively.

Table 20: Summary of Harms Results From Study KD025 to 213 and Study KD025 to 208 (Safety Population)

AE = adverse event; NR = not reported; q.d. = once daily; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

^aMost common TEAEs by preferred term occurring in at least 25% of patients in either treatment group.

^bMost common SAEs and withdrawals due to AEs by preferred term occurring in at least 3 patients in either treatment group.

^cAEs of special interest to the CADTH review included hematologic and immune AEs (coded as blood and lymphatic system disorders and infections and infestations, respectively). Data reported for specific events that occurred in at least 15% of patients in either treatment group.

Note: Results are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Critical Appraisal

Internal Validity

Although there were other treatment groups in study KD025 to 213 and study KD025 to 208, they were for doses that do not have a Health Canada indication for the treatment of patients with cGVHD. Therefore, the limitations that apply to single-arm studies also apply to the interpretation of the results for the belumosudil 200 mg once-daily groups.

The main limitations with both studies are the lack of valid control (or comparator) groups, resulting in a high risk of bias due to confounding and uncertainty in causal conclusions between the study drug and treatment benefits or harms. Without a valid comparison group to control for known and unknown effect modifiers, it is not possible to distinguish the observed treatment effect (benefits or harms) from a placebo effect, natural history of the disease, impact from concomitant therapies, patient characteristics, or other unaccounted for variables.⁵⁶ According to Health Canada, a study without a proper comparator may be interpreted as though there would be no response in the absence of the study drug, which may not be true, given the various other treatment options available for cGVHD, or the dose of a prior medication could be optimized to improve response.²⁰

Another limitation common to both studies was the knowledge of treatment assignment by both patients and investigators. As a result, there is an increased risk of detection bias, particularly for semi-objective (e.g., ORR) and subjective measures (patient-reported outcomes and harms outcomes), and of potentially overestimating the treatment effect of belumosudil if patients and investigators believed the study drug was likely to provide a benefit. In study KD025 to 213, patients must have been receiving a stable GC dose or cGVHD regimen for at least 2 weeks before screening and could not be receiving concurrent ibrutinib during the study. However, it is possible that cGVHD regimens require more than 2 weeks to reach full effect and the 2-week minimum may not have been enough time to discern treatment benefits or harms between belumosudil and a concomitant cGVHD treatment. Again, there is the risk of overestimating the ORR and/or harms attributed to belumosudil. Additionally, TTR results may have been confounded by the fact that patients could have started concomitant medications 2 or more weeks before study screening, and those medications may not have reached peak efficacy. The lack of standardized patient management in cGVHD has made the validity of FFS uncertain, since physicians can have differing opinions on when to administer a new treatment.⁵⁷ Also, without an appropriate comparator group, the OS results are not very informative and the data are immature in the studies.²⁰ In general, the LSS had adequate validity, reliability, and responsiveness based on evidence from the literature, though there was no such evidence for the PROMIS assessment for patients with cGVHD. The MIDs suggested by the sponsor for the LSS and PROMIS were supported by estimates identified from the literature; however, for both instruments, distribution-based methods (0.5 times the standard deviation) were used to estimate the MIDs internally from study data as opposed to using an anchor-based approach, the latter of which is the preferred method.^53,54 Although standardized NIH consensus criteria were used and many of the end points were objective or semi-objective in nature (i.e., ORR, DOR, TTR, FFS, and OS), responses were not evaluated by an independent review committee and there is still an increased risk of bias due to knowledge of treatment assignment.

Missing data were not imputed in the trials and no sensitivity analyses were performed to investigate the impact of the missing data. The censoring mechanisms used for the time-to-event analyses appear to be appropriate, though there may be uncertainty in the estimates at later time points as the number of patients at risk declines. As of the latest data cut-off date, 100% of patients in either study had discontinued from the treatment and the study, and only || patients in study KD025 to 208 (and no patients in study KD025 to 213) had completed the follow-up. Since patients who continue with treatment and continue to provide data tend to be healthier than those who discontinue early, there is an increased risk of attrition bias, which may be amplified by the relatively small sample sizes. Moreover, nearly ||% of patients discontinued from study KD025 to 213 due to study termination by the sponsor (almost ||% of patients from study KD025 to 208), though there are few details explaining why, and it is uncertain what impact this had on the results.

Due to the potential for confounding and unavoidable bias, it is difficult to make firm conclusions based on the efficacy and safety data available.

External Validity

Between the studies, || patients received the approved 200 mg once-daily dose for a median treatment duration of around 9 months, which is a relatively small number of patients compared with the total number who could potentially receive belumosudil (active cGVHD after at least 2 prior lines of systemic therapy) for a somewhat short duration, considering that treatment can be for years.

Although the indication includes pediatric patients as young as 12 years of age, there were no data available for patients younger than 20 years of age in study KD025 to 213 (pediatric patients were not eligible for study KD025 to 208). The Health Canada product monograph indicated that the use of belumosudil in pediatric patients 12 years of age and older is supported by evidence from studies in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of the drug substance, that the exposure of the drug substance is expected to be similar between adults and pediatric patients age 12 years and older, and that the course of disease is sufficiently similar in adult and pediatric patients to allow the extrapolation of data in adults to these pediatric patients.¹ The clinical experts consulted by CADTH were of the opinion that the results for adults could be generalizable to a younger patient population.

To be eligible, patients must have had a Karnofsky Performance Scale score of at least 60 (at least 40 in study KD025 to 208), a glomerular filtration rate of at least 30 mL/min/1.73 m², a forced expiratory volume in 1 second (FEV₁) of 40% or more (study KD025 to 213), and fewer than 6 prior lines of systemic cGVHD treatment. One clinical expert consulted by CADTH suggested that although patients with low FEV₁ or an NIH lung score of 3 were excluded, these patients could potentially be treated with belumosudil in practice. Based on the study baseline characteristics, the clinical experts were of the opinion that the study patients were generally similar to those who could receive belumosudil in clinical practice in Canada, with 2 exceptions. The experts pointed out that racial diversity was limited in the study (compared with what is expected in Canadian practice), and the prior and concomitant cGVHD therapies differed from their experience in treating patients with cGVHD (which may be due to varying availability of treatments across jurisdictions and the studies taking place in the US). Nearly all patients enrolled in the studies had reported at least 2 prior lines of therapy; however, it was not clear whether other treatments had failed, which is stipulated in the Health Canada indication; therefore, it is unclear whether the study populations align perfectly with the indicated population for belumosudil. All study sites were in the US and the clinical experts noted it is possible there are differences between clinical practice and patient management between Canada and the US.

No direct evidence was submitted for the CADTH review for how belumosudil compares with other cGVHD therapies, which is an important limitation since there are many on- and off-label treatments. Without an appropriate comparator in the studies, it is challenging to contextualize and apply the results to the population of patients who may receive belumosudil in practice. Patients were ineligible if they were receiving ibrutinib, and it is unknown what effect ibrutinib would have in combination with belumosudil.

Only the primary end point of ORR at 6 months was controlled for multiplicity in the studies and all other secondary and exploratory outcomes were presented descriptively. The FDA considered the 6-month time period to be reasonable to observe a response without risking possible harms with continued treatment.^20,21 There has been debate over which definition of DOR is the most useful and the results for each definition can differ considerably.²⁰ The experts confirmed that the LSS and PROMIS are not typically used in clinical practice, based on their experience, though they may be used in other clinics across Canada and provide useful information that is important to patients and clinicians.

The available efficacy and safety evidence provide a relatively short-term outlook on treatment with belumosudil. Considering the external validity limitations and that the issues with internal validity remain, the clinical experts indicated that the results of the study could be generalized to patients who would be eligible for belumosudil in Canada.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^22,23

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Although GRADE guidance is not available for noncomparative studies, the CADTH review team assessed pivotal trials that lacked a valid comparator for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for trials that lacked a valid comparator started at very low certainty with no opportunity for rating up.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of a clinically important effect for ORR, tertiary and secondary DOR, TTR, FFS, and OS based on a threshold informed by the clinical experts consulted by CADTH for this review. The target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for the number of patients with an LSS score or PROMIS Global Health summary score greater than or equal to the MIDs identified from the literature and who experienced an SAE.

For the GRADE assessments, the findings from study KD025 to 213 and study KD025 to 208 were considered together (except for PROMIS, which was assessed only in study KD025 to 213) and summarized narratively per outcome because the studies were similar in population, intervention, design, and outcome measures.

Results of GRADE Assessments

Table 2 presents the narrative GRADE summary of findings for belumosudil for patients with cGVHD.

Long-Term Extension Studies

Data from the latest cut-off dates for the ongoing studies (study KD025 to 213 and study KD025 to 208) were included in the main report. No additional long-term extension studies were submitted by the sponsor.

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Objectives and Methods for the Summary of Indirect Evidence

No direct comparative data for the use of belumosudil for the treatment of addenda years and older with cGVHD were submitted by the sponsor. As a result, a systematic literature review was conducted to identify efficacy and safety evidence of belumosudil versus other treatments for patients with cGVHD after an allo-HSCT and whose prior therapy failed.²⁵ It was known that no RCTs were available for belumosudil versus other active therapies for cGVHD; therefore, the feasibility of conducting a PAIC was assessed.

The sponsor also submitted data for a naive indirect comparison of belumosudil versus BAT. A brief summary of the comparison between belumosudil, ibrutinib, and ruxolitinib for ORR, FFS, OS, LSS, and discontinuation due to AEs has been included in Table 26 of this CADTH report.

According to the submitted technical report, differences in study designs (e.g., eligibility criteria, length of follow-up, timing of assessments, and outcome measures) as well as the availability and variability of key prognostic factors would result in substantial heterogeneity precluding the feasibility of a PAIC; therefore, no indirect comparisons were conducted.

CADTH’s review of the sponsor’s feasibility assessment is provided subsequently.

Description of the Feasibility Assessment

The sponsor conducted a feasibility assessment to determine whether the clinical evidence identified from the literature search for the treatment of patients with cGVHD following an allo-HSCT and whose condition failed to respond to prior therapy was sufficiently similar to permit valid comparison in an ITC.²⁵ The authors reported that they performed the systematic literature review following National Institute for Health and Care Excellence (NICE) technology appraisal guidance⁵⁸ and the Cochrane Handbook for Systematic Reviews of Interventions,⁵⁹ and reported the systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.⁶⁰ The review followed an a priori protocol and the literature search was comprehensive up to April 30, 2022. The study eligibility criteria for the ITC literature search were similar to that submitted for the belumosudil systematic review (described in the main report). The exceptions were the exclusion of: adolescent patients (aged 12 years and older); etanercept, infliximab, and mTOR inhibitors (everolimus, sirolimus) as comparators; and the HRQoL outcomes in the belumosudil systematic review, which were not part of the ITC literature search eligibility criteria. Data extraction from the included studies was conducted by a single reviewer with verification by another. The risk of bias of RCTs was assessed using the Cochrane Risk of Bias Tool version 2.0,⁶¹ with other studies evaluated using the Downs and Black checklist.⁶²

A total of 610 records were identified from the database searches, of which 31 records from 22 unique studies (21 full-text publications and 1 conference abstract) were included for review; 3 were RCTs and the remaining were single-arm trials. The authors indicated that 1 of the 3 RCTs had an increased risk of bias because it lacked information on allocation concealment, and all of the trials were open-label. Among the 18 single-arm trials, 14 were considered low quality and 4 were moderate quality. The evidence included 8 studies for ECP, 4 for rituximab, 4 for imatinib, 2 for belumosudil, 2 for ibrutinib, and 2 for ruxolitinib. The patient enrolment dates ranged from 2001 to 2019, and it is likely that patient management and the treatments available have changed in that time. Most studies had a primary outcome of response rate, and the secondary outcomes often included OS, FFS, LSS, reduction in CS dose, and safety. Ten studies measured baseline cGVHD severity using NIH Global Severity scoring, which appears to be consistent with the measure used in the main clinical studies described in the CADTH report. However, there was additional variability in patient characteristics (mean age ranged from 26 years to 62 years), prior therapies (median, 1 to 4 treatments; range, 1 to 7 treatments), outcome definitions, assessment time points (range, 2 to 29 months), and the availability of results data from studies (e.g., ORR was reported in 19 studies, while disease progression, OS, and FFS were reported in 7 studies each).

Three main criteria were used to assess comparability with the belumosudil trials. Of the 20 studies (2 belumosudil studies were removed), 5 were excluded because they were conducted in countries not of interest (i.e., Asian countries). From the remaining 15 studies, 13 were excluded due to having patients who received fewer than 2 prior lines of therapy. Both of the remaining 2 studies were deemed to have differences in populations or design that made them not comparable with those in the belumosudil studies (due to patient dissimilarity, heterogeneity in outcome measures, and missing data for outcomes of interest) and thus were excluded. Of note, the phase III REACH3 trial⁶³ that investigated the effect of ruxolitinib 10 mg twice daily versus BAT in patients with moderate or severe GC-refractory or GC-dependent cGVHD with a history of 1 prior line of therapy was excluded due to misalignment of the inclusion criteria between the REACH3 trial and those for belumosudil (1 prior line of therapy versus 2 or more lines of therapy, respectively), and the population and outcomes data were not reported by line of therapy.

Appraisal of the Feasibility Assessment

Ibrutinib and ruxolitinib appear to be the main comparators for belumosudil, considering that both drugs have Health Canada indications for the second- or later-line treatment of patients with cGVHD.^13,14,20 The efficacy and safety of both belumosudil and ibrutinib were assessed in small single-arm trials (or only 1 arm of relevance to this review), while ruxolitinib was assessed in a somewhat larger RCT versus BAT. As a result of differences in eligibility criteria, the belumosudil KD205 to 213 trial enrolled patients with more prior lines of therapy and more severe disease, based on NIH criteria,⁶³ or a larger number of involved organs.⁶⁴ Given the small size of the studies (especially the single-arm trial of ibrutinib; n = 42), and the fact that the eligible population in the belumosudil trial required more prior lines of therapy, the CADTH review team agreed it would not have been feasible to conduct a valid PAIC that fully adjusted for the differences in populations between the belumosudil and ibrutinib or ruxolitinib trials. However, the CADTH review team agrees with the assessment of Health Canada²⁰ that this is an important limitation of the belumosudil KD205 to 213 trial. Given that the trial initiated in 2018 (after the Health Canada approval of ibrutinib), it may have been possible at the outset to enrol populations that were similar to facilitate a valid indirect comparison to ibrutinib. Alignment of eligibility criteria would have similarly facilitated an indirect comparison with the ruxolitinib arm of the REACH3 trial. There were also differences between belumosudil and other treatments for cGVHD in the study design (e.g., study dates and possible changes in patient management over time, assessment time points, and the availability of data for outcomes of interest) and populations (e.g., patient characteristics and prior treatments) that make it challenging to compare them and make meaningful efficacy or safety conclusions.

Studies Addressing Gaps in the Systematic Review Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Table 21: Summary of Gaps in the Systematic Review Evidence

BAT = best available therapy; CI = confidence interval; FFS = failure-free survival; HR = hazard ratio; IPTW = inverse probability of treatment weighting; ITC = indirect treatment comparison; OS = overall survival.

Source: Sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Description of Studies

Due to the lack of head-to-head data and the inability to conduct an ITC, 1 observational study using IPTW has been summarized to provide indirect comparative evidence for belumosudil versus BAT for patients with cGVHD (Table 21).¹¹

Populations

The observational study was conducted using real-world individual patient data from the US Optum Clinformatics Data Mart database and results from the belumosudil studies (KD025 to 213 and KD025 to 208). According to the sponsor, since all study centres in the belumosudil trials were in the US, a US database was used in an attempt to include comparable patient populations and health care practices. From the database, patients were eligible if they met the following criteria: had at least 1 inpatient or outpatient claim with a diagnosis code for cGVHD from ||||||| || ||||, to the most recent available data; had at least 3 systemic lines of therapy after cGVHD diagnosis (first-line therapy must have been CSs); were 12 years of age or older; and had at least 6 months of continuous enrolment with medical and pharmacy benefits before the third line of therapy.

Interventions

Based on the information provided by the sponsor, it appears as though data for both belumosudil 200 mg once daily and belumosudil 200 mg twice daily were pooled for this analysis, although the Health Canada–recommended dose is the former for the treatment of cGVHD. BAT included the following treatments: ECP, mycophenolate mofetil, imatinib, rituximab, mTOR inhibitors (e.g., sirolimus, temsirolimus, everolimus), ruxolitinib, CNIs (e.g., tacrolimus, cyclosporine), methotrexate, ibrutinib, pentostatin, etanercept, abatacept, alemtuzumab, hydroxychloroquine, and IL-2.

Outcomes

The primary outcome in the observational study was FFS and key secondary outcomes included rate of OS, TTNT, safety events, reduction in CS use, and reduction in CNI use. FFS and OS were defined in the observational study similarly to the belumosudil studies. A list of specific safety events with International Classification of Diseases codes and their frequencies was included as well. It is likely that there are nuanced differences in the results due to the claims data being restricted by the end date for medical coverage enrolment or the end of the medical record, safety events being coded differently between clinical trials and the claims database, and that the assessment time points likely varied.

Statistical Analysis

Details of the IPTW methods and information on data extraction or how time-to-event analyses were undertaken were not available to be appraised. IPTW methods were used in an attempt to minimize the potential for confounding within included variables chosen after discussion with clinicians (i.e., age, sex, race, time from cGVHD diagnosis to the index date, number of prior lines of therapy, aGVHD history, and underlying disease history [i.e., the indication for the allograft]). It was also noted that other potential effect modifiers, such as organ involvement, were not available from the data. The index date was defined as the third to sixth line of therapy and patients could contribute multiple observations for each eligible line of therapy until the earliest medical coverage disenrollment or the end of the study. According to the sponsor’s summary, an unbiased choice for time zero (from multiple eligible times) would be to use a single eligible time (e.g., the first eligible time or a random eligible time), but it was decided that this would reduce the sample size and instead, all eligible times (or a subset thereof) were included. To adjust for patients contributing multiple data points, the robust sandwich variance estimator was used.⁶⁵ The sponsor stated that a simulation study demonstrated good performance when selecting multiple lines of therapy.⁶⁶

Results

Patient Disposition

Baseline Characteristics

Patients in the belumosudil group (N = |||||) and BAT group (N = |||) had a mean age of approximately ||| years, |||% to |||% were male, more than |||% had moderate to severe cGVHD, and both groups had a mean of ||| prior lines of therapy. There were notable differences in some postweighted baseline characteristics, such as that all patients in the belumosudil group received a transplant versus only two-thirds in the BAT group, and patients in the belumosudil group tended to have a greater number of involved organs compared with the BAT group.

Efficacy

Median FFS was ||| months (95% CI, || to |||) in the belumosudil group and ||| months (95% CI, ||| to |||) in the BAT group (HR = |||; 95% CI, ||| |||| ||||). The KM estimate of FFS probability at 12 months was |||% (95% CI, ||| |||| ||||) in the belumosudil group and |||% (95% CI, ||| |||| ||||) in the BAT group. The key drivers of failure differed between the groups; the key driver in the belumosudil group was the initiation of subsequent treatment and was relapse of malignancy in the BAT group.

Median OS was not reached for the belumosudil group and ||| months (95% CI, ||| to |||) for the BAT group (HR = |||; 95% CI, ||| |||| ||||). The KM estimate of OS probability at 12 months was ||| % (95% CI, ||| ||||) in the belumosudil group and ||| % (95% CI, ||| |||| ||||) in the BAT group.

Harms

Harms results are summarized in Table 22. The most common AEs in the belumosudil group were infections (|||%), fatigue or asthenia (|||%), and nausea or vomiting (|||%). The most common AEs in the BAT group were infections (|||%), dyspnea (|||%), hypertension (|||%), and anemia (|||%).

Critical Appraisal

Internal Validity

One of the major concerns with the observational study is the potential for selection bias and residual confounding as a result of the lack of randomization of patients. There was also limited information on how patients were selected from the claims data, and there may have been selection bias in the process. By relying solely on clinician opinion and not consulting the literature, it is possible that the methods used to decide which prognostic factors and effect modifiers to include were inadequate. The observational study required patients from the claims dataset to have at least 3 systemic lines of therapy, which does not align with the inclusion criteria of the belumosudil studies (between 1 and 5 prior systemic treatments). Furthermore, there were insufficient data to include all the variables of interest and several baseline characteristics remained imbalanced after IPTW procedures were applied. There was no differentiation between moderate and severe cGVHD (potentially imbalanced), and there were notable differences between treatment groups in the amount of organ involvement, number of organs involved, and use of prior lines of therapy. It would not have been possible for the analyses to adjust for the different study designs (i.e., trial versus retrospective cohort study) and there would be heterogeneity around decisions for when a new treatment is started, potential missing data, and patients lost to follow-up, which were not described within the study. There was no assessment of residual confounding and the potential for bias is high. It was unclear if there was a protocol for the observational study and there is the possibility of selective outcome reporting, especially considering that ORR, DOR, and TTR were not included in the study, despite these being key outcomes in the belumosudil studies. It is likely that there were differences in outcome definitions and assessment time points between the belumosudil studies and the claims data. The sponsor noted that the identification of relapses in the claims data may be unreliable and suggested that the same event could have been counted more than once for patients, thus artificially inflating the numbers, though it was not possible to verify this suggestion. The sponsor also noted the risk of inaccuracies in the claims database due to patients changing insurance plans and the possible miscoding of claims. It is not possible to predict the direction bias this may have introduced. Sensitivity analyses were attempted but did not adequately correct for the incongruencies. Therefore, both the efficacy and safety results of this study should be considered in light of the limitations, and it is not possible to make firm conclusions based on the findings.

Table 22: Summary of Harms Results From the Sponsor-Submitted Observational Study

AE = adverse event; BAT = best available therapy; TEAE = treatment-emergent adverse event.

^aMost common TEAEs by preferred term occurring in at least 25% of patients in either treatment group.

Source: Sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

External Validity

Claims data from the US Optum Clinformatics Data Mart database could have been from as early as the year |||| and health care practices have likely changed since then. It appears that the results from the main clinical studies for belumosudil once daily and twice daily were pooled, though only the belumosudil 200 mg once-daily dose is approved by Health Canada for the treatment of cGVHD. Moreover, it is unclear how relevant it is to pool all other available treatments as a comparator (i.e., BAT) versus comparing belumosudil with the most relevant individual treatments for cGVHD. There also remains a lack of data for pediatric patients that was not clearly supplemented by the observational data. Other limitations include the relatively small number of patients (around ||| patients) in each treatment group and the limited long-term data available. Despite the use of real-world data, which could improve the generalizability of the results, the internal validity issues minimize the utility and applicability of the findings to clinical practice in Canada.

Discussion

cGVHD is a complex, multisystem disease that leads to significant morbidity and mortality after an allo-HSCT.⁶⁷ It is estimated that 10% to 25% of patients who receive an allo-HSCT die from cGVHD complications.^67,68 Although there are various treatment options for cGVHD, many do not have a Health Canada indication for the disease and not all patients respond to all treatments. Treatment duration can be for many years beginning with CSs (with or without CNIs) as standard first-line therapy, though patients may require additional treatments and there is little consensus on what is the best second-line treatment for these patients.^11,12,67 Moreover, the clinical experts highlighted that there are few effective and safe options after second-line therapy, at which point patients tend to have a variable response to subsequent treatments. Belumosudil is indicated for the treatment of patients 12 years of age and older with cGVHD after the failure of at least 2 prior systemic treatments.¹

Summary of Available Evidence

Two phase II, open-label studies were included in the sponsor’s systematic review of the efficacy and safety of belumosudil 200 mg once daily in patients with cGVHD. In total, || patients and || patients in study KD025 to 213 and study KD025 to 208, respectively, received the Health Canada–approved dose, and there was no relevant comparator or control group in either study. Patients received belumosudil in 28-day cycles until clinically significant disease progression (i.e., requiring a new systemic therapy for cGVHD), histologic recurrence of the underlying malignancy, unacceptable toxicity, death, lost to follow-up, investigator decision, or EOT. The primary end point in both studies was ORR by investigator assessment. Secondary and exploratory end points of interest to the CADTH review included DOR, TTR, FFS, OS, LSS score, PROMIS Global Health summary scores, and safety outcomes. Patients in the studies had a median age of || years (range, || years to || years) in study KD025 to 213 and 50 years (range, 20 years to 63 years) in study KD025 to 208. In both studies, more than 70% of patients had severe cGVHD according to the 2014 NIH consensus criteria and 100% of patients in study KD025 to 213 and 88% of patients in study KD025 to 208 had 2 or more prior lines of therapy. There were no patients younger than 20 years old in the relevant datasets to support the pediatric portion of the indication.

No indirect evidence was included in the sponsor’s submission to CADTH. The sponsor submitted a feasibility assessment for performing an ITC for belumosudil versus other cGVHD treatments and concluded it would not be reasonable to conduct an indirect comparison due to the heterogeneity in patient characteristics, study designs, and data reported across studies.

The sponsor also submitted an observational study using IPTW methods to address the gaps in the evidence, which used pooled results from the main clinical studies and real-world data from the US Optum Clinformatics Data Mart database to provide comparative evidence for the treatment of belumosudil versus BAT in patients with cGVHD. Patients were selected from the database if they had cGVHD, had had at least 3 systemic lines of therapy after cGVHD diagnosis, and were at least 12 years old. BAT included ECP, mycophenolate mofetil, imatinib, rituximab, mTOR inhibitors, ruxolitinib, CNIs, methotrexate, ibrutinib, pentostatin, etanercept, abatacept, alemtuzumab, hydroxychloroquine, and IL-2. Outcomes of interest included FFS, OS, and safety events.

Interpretation of Results

The lack of a valid comparator in the pivotal studies means it is not possible to attribute the observed efficacy and safety findings to belumosudil with certainty, as these would be confounded by potential placebo effects, the use of concomitant treatments, and the natural history of the disease. Furthermore, 100% of patients in the studies had discontinued from both the treatment and the study and, given the minimal information provided for why patients stopped as well as the reasons and timing of censoring, it is difficult to assess what impact this had on the results. The observational IPTW study attempted to provide a comparison of belumosudil versus BAT for some outcomes, but this study had numerous methodological limitations and was at high risk of bias due to residual confounding. As a result, the available evidence was deemed insufficient to draw definitive conclusions about the efficacy of belumosudil in inducing a response versus any comparator. Herein, the findings are contextualized based on clinical expert feedback about how the results from the study might compare to the usual clinical course of cGVHD. It is also worth noting that the clinical experts indicated it might be reasonable to conduct a single-arm study in patients whose disease fails to respond to at least 2 prior lines of systemic therapy due to the limited treatment options for this patient population, and it is unethical to randomize such patients to no treatment (i.e., placebo). However, the decision to enrol patients that differed systematically from those in the relevant comparator trials limited the feasibility of performing any valid ITCs.

Efficacy

Response to treatment was noted as being an important outcome in the clinician group input and by the clinical experts. Study KD025 to 213 reached its primary end point, demonstrating an ORR of greater than 30% at 6 months of belumosudil treatment; the clinical experts consulted by CADTH noted the findings to be clinically important. The FDA considered 6 months of treatment to be a sufficient period of time that allows for a potentially clinically meaningful overall response without risking possible adverse effects from continuing treatment, so long as the response was durable.^20,21 Overall response consisted of CR or PR, though it was largely driven by patients with PR. Of the 2 response types, CR is a clear clinical benefit, but it is less obvious how much clinical benefit there is with PR.⁵⁷ The descriptive subgroup analysis results appeared generally consistent with the primary analysis, though they included a small number of patients. Although study KD025 to 208 was exploratory in nature and no statistical analyses were conducted, the results supported study KD025 to 213.

There is some debate over which of the 4 DOR definitions is most informative, and results for each outcome can vary considerably but must take into account that each definition is interpretable.²⁰ The tertiary DOR definition measures time from first response to initiation of a new systemic cGVHD therapy (reflecting patient management) or death, which the clinical experts suggested was the most informative measure of treatment durability, followed by secondary DOR.²¹ The secondary definition measures the time to first decline in response, but does not account for treatable flares that do not require new treatment.⁶⁹ The clinical experts suggested that the results for event-free probability for both the secondary and tertiary DOR were clinically important, as they exceeded 40%, though findings for secondary DOR were less promising and imprecise. The median TTR suggested that response may occur relatively quickly; the median TTR in study KD025 to 203 was ||| weeks and ||% of responders experienced a response within 16 weeks. At 12 months, the probability of maintaining FFS (i.e., not having started a new cGVHD therapy, nonrelapse mortality, or recurrent malignancy) was estimated to be ||% (95% CI, ||| || ||%) in study KD025 to 213, which the clinical experts believed to be clinically important; the findings were supported by study KD025 to 208; however, the validity of FFS has been questioned due to the lack of standardized patient management, such as deciding when a new treatment is given (physicians must discern between disease flare and disease progression, and which next treatment is suitable and when to provide it) and the differing availability of treatments.⁵⁷ Response outcomes may have been confounded by the fact that patients could have been on other stable concomitant treatments (at least 2 weeks before screening), which may or may not have reached peak efficacy by the time patients started belumosudil.²¹

Input from the patient group, clinician group, and clinical experts indicated that survival was an important outcome. The probability of survival at 12 months was ||% (95% CI, ||| || ||%) in study KD025 to 213, which the clinical experts found to be clinically important. Without a proper comparator group, OS results are not very informative and no conclusions could be made about belumosudil on OS.²⁰ One of the main limitations with both of the survival outcomes was the immaturity of the data and the medians and/or CIs not being reached in the study; longer follow-up will be required to fully understand whether the drug addresses patients’ needs for treatment that improves survival.

HRQoL was identified as an important outcome to patients and caregivers in the patient input, clinician group input, and by the clinical experts. LSS is a disease-specific measure of symptoms, while PROMIS is a generic measure that assesses a patient’s overall health as well as physical, emotional, and social aspects of their life. More than half of the patients reached the 7-point MID for the LSS in study KD025 to 213 (similar proportion in study KD025 to 208). More than a third of patients reached the 4.7-point MID for the PROMIS physical health assessment and fewer than half of the patients reached the 4.7-point MID for the PROMIS mental health assessment in study KD025 to 213 (outcome not assessed in study KD025 to 208). Among patients who reach the respective MIDs, it is unclear what the minimum number of patients would need to be for belumosudil to be considered beneficial. The interpretation of the results is limited due to the lack of a control group, assessor’s knowledge of treatment assignment, and missing data over time as more patients discontinued, which increased the risk of confounding, performance bias, and attrition bias.

The patient and clinician input noted the importance of reducing the dose or eliminating the use of CSs, citing the adverse effects to which the drugs are often linked. In the 2 studies, between ||% and ||% of patients reduced their CS dose, while approximately a quarter of patients in either study were able to discontinue CS usage while being treated with belumosudil. However, interpretation of the results may be hindered by the limited details available for this outcome. It was unclear whether any reduction in dose (even a very minor change) was counted, how long patients reduced or discontinued CSs, and how many patients increased their dose during the studies. Additional details would help to clarify whether belumosudil helps patients avoid CS usage and the associated side effects.

Although there were no pediatric patients in the studies, belumosudil gained regulatory approval for patients aged 12 years and older based on pharmacokinetic analyses indicating that age and body mass did not have a clinically meaningful effect on drug pharmacokinetics.^20,21 Based on similar disease characteristics and management, the clinical experts indicated it would be reasonable to generalize the study results from adult patients to pediatric patients aged 12 years and older. Upon review of the baseline characteristics, the clinical experts felt the patients in the studies generally represented the patients in Canada who could receive belumosudil. Although most patients across the studies had had 2 prior treatments for cGVHD, it was not stated whether these were treatment failures (or if patients had stopped for other reasons), which is stipulated in the Health Canada indication. The clinical experts also explained that patients who need additional cGVHD treatments tend to have variable responses to later lines of therapy. The experts also indicated that it would be ideal to treat patients with belumosudil early on (i.e., after failure of 2 systemic treatments); however, this may not be the case for many patients in practice who have already received a number of therapies. Due to the limited number of effective and safe cGVHD treatments, the clinical experts stated that once a patient’s disease fails to respond to belumosudil, the management strategy largely remains the same: use the next-best treatment available at that time and that is accessible. Belumosudil is an oral drug, which may offer a benefit over other treatments that require special administration or monitoring, and the clinical experts reiterated the need for effective and safe later-line therapies for patients with cGVHD.

Harms

As of the latest data cut-off, the median durations of exposure to belumosudil 200 mg once daily were ||| months to ||| months in the studies. Nearly all patients reported at least 1 AE, between ||% and ||% of patients reported an SAE, ||% to ||% stopped treatment due to an AE, and there were || deaths in study KD025 to 213. Notable harms of interest for the CADTH review included hematologic (blood and lymphatic system disorders) and immune (infections and infestations) AEs. Between ||% and ||% of patients reported a blood and lymphatic system disorder AE, with anemia being the most frequently reported event, while ||% to ||% of patients reported an infection and infestation AE, with upper respiratory tract infection as the most frequently reported event.

According to the patient group input CADTH received, it is important that new treatments produce fewer side effects compared with currently available treatments. Due to the lack of an appropriate comparator group or control group in the studies, it is difficult to confirm a causal association between belumosudil and any particular harms and, moreover, whether the drug adequately addresses patients’ needs.^20,69 Based on the eligibility criteria, patients in the studies may have been healthier than the broader population who could receive belumosudil in practice and discontinuations, as well as rates and types of AEs, could reflect that. It is also more likely that a healthier patient is better able to tolerate an adverse effect and willing to remain on the study drug, thereby lowering the number of patients who withdraw from treatment compared with clinical practice. According to the FDA, elevated transaminase levels, anemia, lymphocytopenia, headache, nausea, and diarrhea were noted as potential risks in early studies of belumosudil for other disease areas as well as in healthy volunteers, though these risks may be reduced by optimizing the drug dose.^21,69 Since patients were allowed to continue receiving stable systemic treatment and to use GCs to treat flares, it is possible that these treatments were responsible for some AEs, but it is difficult to know without an adequate control group.^21,69 The clinical experts indicated that the reported AEs were reasonable for what is known about cGVHD and the study treatments (belumosudil and concomitant drugs) and that with appropriate care, the AEs would be manageable for many patients.

Conclusion

cGVHD is a complex, multisystem disease and there is a need for safe and effective treatments that help prolong survival, alleviate symptoms, and improve HRQoL. Evidence from 2 phase II, open-label clinical studies in adult patients with cGVHD (n = ||) were included in the review for belumosudil and both studies lacked an appropriate comparator or control group. Such a study design does not allow for definitive conclusions about the efficacy and safety of belumosudil versus any comparator, as the effect estimates are likely to be confounded by concomitant treatments and the natural history of the disease. Indirect comparisons with relevant alternatives were deemed infeasible and a submitted observational IPTW study comparing belumosudil with BAT was at high risk of bias due to residual confounding. Nevertheless, study KD025 to 213 met its primary outcome of an ORR greater than 30% at 6 months of treatment; the majority of responses were partial and fewer patients experienced CR. The treatment effect point estimates for response and survival outcomes were considered potentially clinically meaningful by the clinical experts. Although there were MIDs for LSS and PROMIS from the literature, it was not clear whether the number of patients who reached the MIDs was large enough to indicate a meaningful benefit from belumosudil. Harms results were potentially confounded by the use of concomitant treatments, though the clinical experts felt these harms would generally be manageable with adequate care. There was a relatively small number of patients who received the Health Canada–approved dosage (belumosudil 200 mg once daily) in either study, and there is additional uncertainty in the long term results due to discontinuations and the immaturity of the survival data. The clinical experts indicated that the study results were generalizable, acknowledging the lack of data for patients younger than 20 years of age in the studies. It was determined that an ITC was not feasible and the sponsor-submitted observational IPTW study comparing belumosudil with BAT had important limitations (i.e., heterogeneity, missing outcomes), preventing meaningful conclusions from being made. Overall, due to the lack of informative direct and indirect evidence, it is very uncertain how belumosudil compares with other cGVHD treatments in terms of efficacy and safety.

While the results of the included studies aligned with the clinical experts’ expectation that belumosudil would address the unmet needs in this patient population, there were important limitations in the included studies leading to uncertainty in the evidence due to the trials having only a single relevant treatment group and no valid comparator.

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Appendix 1: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Response by Organ System and GSR Assessment

Table 23 summarizes the best response (CR or PR) assessment for 9 organs: skin, eyes, mouth, esophagus, upper gastrointestinal tract, lower gastrointestinal tract, liver, lungs, and joints and fascia.^15,17 For organs other than the lungs, the system was considered to be “involved” if the baseline score was greater than 0, unless all response assessments were “not evaluable.” Otherwise, the system was considered “not involved” if the baseline score was 0, unless a CR or PR assessments caused clinical review to confirm baseline involvement. Lungs were considered “involved” if FEV₁ was less than 75%, unless all responses were “not evaluable,” and “not involved” if FEV₁ was at least 75%. Response assessments were categorized into 1 of the following statuses: CR, PR, progression, not evaluable, or stable. Response rate by organ system was only measured in patients who were responders at similar time points to ORR up to week 48. This outcome was considered useful in informing the clinical management of individual patients with cGVHD, but not critical to decision-making. Response by organ system and GSR assessment results are summarized in Table 23.

Table 23: Summary of Response by Organ System and GSR Assessment From Study KD025 to 213 and Study KD025 to 208 (mITT Population)

CR = complete response; GSR = global severity rating; mITT = modified intention to treat; PR = partial response; q.d. = once daily.

Note: Results are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

TTNT

TTNT was measured as the time from the first dose of belumosudil to the time of new systemic cGVHD treatment, censored by the last response assessment or the long-term follow-up assessment, whichever was the latest and available.^15,17 This outcome was considered useful in informing the clinical management of individual patients with cGVHD, but not critical to decision-making. TTNT results are summarized in Table 24.

Table 24: Summary of Time to Next Treatment From Studies KD025 to 213 and KD025 to 208 (mITT Population)

cGVHD = chronic graft-vs.-host disease; CI = confidence interval; KM = Kaplan-Meier; mITT = modified intention to treat; q.d. = once daily; TTNT = time to next treatment.

Note: Results are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

^aThe probability of a patient not needing a new systemic treatment.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Prednisone-Equivalent Dose of CSs

The change in systemic CS dose as mg/kg/day prednisone equivalent over time was measured.^15,17 Dose equivalencies were as follows: 1 mg prednisone was equivalent to 4 mg hydrocortisone, 0.8 mg methylprednisolone, 0.15 mg dexamethasone, and 0.8 mg triamcinolone. Systemic CS dose over time, change and percent change from baseline to the greatest CS dose reduction during belumosudil treatment, number and percentage of patients who reduced systemic CS use, and number and percentage of patients who ever discontinued systemic CS use during belumosudil treatment were evaluated. Data were collected throughout the study until 28 days after the last dose of the study drug. Transient CS dose increases of 1 mg/kg/day or lower were permitted to treat disease flares but must have been reduced to the prerandomization dose within 6 weeks; otherwise, belumosudil treatment was considered to have failed in the patient. A patient who experienced 3 or more disease flares requiring increased CS dose during the first 6 months of belumosudil treatment was also considered a belumosudil treatment failure. This outcome was considered useful in informing the clinical management of individual patients with cGVHD, but not critical to decision-making. The prednisone-equivalent dose of CS results is summarized in Table 25.

Table 25: Summary of Prednisone-Equivalent Dose of Corticosteroids From Study KD025 to 213 and Study KD025 to 208 (mITT Population)

CS = corticosteroid; mITT = modified intention to treat; q.d. = once daily.

Note: Results are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Sources: Clinical Study Report addenda for study KD025 to 213¹⁶ and study KD025 to 208¹⁸ and sponsor’s summary of clinical evidence.¹¹ Details included in the table are from the sponsor’s summary of clinical evidence.

Table 26: Efficacy and Safety Results for Naive Indirect Comparison of Belumosudil, Ruxolitinib, and Ibrutinib

AE = adverse event; cGVHD = chronic graft-vs.-host disease; CR = complete response; FFS = failure-free survival; LSS = Lee Symptom Scale; NIH = National Institutes of Health; NR = not reported; ORR = overall response rate; OS = overall survival; PR = partial response; q.d. = once daily.

^aData were not reported for the population of interest (i.e., patients who received belumosudil 200 mg q.d.), and instead, results were pooled for the study.

^bData were not reported for a population consistent with the rest of the table (i.e., N = 66 patients) in study KD025 to 213.

Source: Sponsor-submitted feasibility assessment.²⁵

Appendix 2: Summary and Appraisal of Pooled Data From Study KD025-213 and Study KD025-208

Note that this appendix has not been copy-edited.

Objective

The objective of this Appendix is to summarize and critically appraise the pooled data from study KD025 to 213 and study KD025 to 208 that were provided by the sponsor.⁷² This summary informed the pharmacoeconomic evaluation.

Methods

The sponsor noted that study KD025 to 213 and study KD025 to 208 were similar in study design, end points (though different exploratory outcomes between the studies), frequency of efficacy and safety assessments, and eligibility criteria. The pooled analysis that was relevant to the CADTH review included only patients who had received belumosudil 200 mg once daily in the studies and had experience with at least 2 prior lines of therapy. The data cut-off dates were consistent with the individual studies in the main report: ||||||||| ||| ||||| for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Results

Pooled efficacy results are summarized in Table 27 and pooled safety results are summarized in Table 28.

Table 27: Summary of Pooled Efficacy Analysis for Patients Who Received at Least 2 Prior Lines of Therapy

CI = confidence interval; CR = complete response; DOR = duration of response; FFS = failure-free survival; ORR = overall response rate; OS = overall survival; PR = partial response; q.d. = once daily; TTR = time to response.

^aPatients who responded.

Note: Results are based on a data cut-off of ||||||||| ||| ||||, for study KD025 to 213 and |||| ||| ||||, for study KD025 to 208.

Source: Sponsor-provided request for additional information (requested September 8, 2023, response received September 15, 2023).⁷²

Table 28: Summary of Pooled Safety Analysis for Patients Who Received at Least 2 Prior Lines of Therapy