CADTH Reimbursement Review

Asciminib (Scemblix)

Sponsor: Novartis Pharmaceuticals Canada Inc.

Therapeutic area: Philadelphia chromosome-positive chronic myeloid leukemia

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.

Introduction

Chronic myeloid leukemia (CML) is a clonal bone marrow (BM) stem cell disorder resulting in the unregulated growth of myeloid precursor cells and production of excessive neutrophils, eosinophils, and basophils in the BM.¹ Blood and BM cells in patients with CML usually contain a characteristic chromosomal abnormality known as the Philadelphia chromosome (Ph), the result of a balanced translocation between chromosomes 9 and 22.² The incidence rate of CML across all ages and sexes in Canada, excluding Quebec, ranged from 510 cases in 2011 to 585 cases in 2018. This corresponds to an incidence rate of 2.0 per 100,000 population in 2018.³

The majority of patients (greater than 95%) with CML are in chronic phase (CP) at diagnosis.⁴ The use of oral tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL kinase represents the standard of care for patients with newly diagnosed CP-CML. Imatinib was the first drug in this class to be approved, and reports of improvements in population-based CML outcomes can largely be attributed to the use of this drug.⁵ Roughly one-third of patients treated with imatinib will discontinue therapy, either because of intolerance from side effects or loss of response due to drug resistance. The second-generation TKIs, dasatinib, nilotinib, and bosutinib have a much smaller spectrum of resistance mutations, but none are able to overcome the T315I mutation. These drugs have similar efficacy when used as second-line therapies.^6,7 Ponatinib is a third-generation TKI with activity against wild-type and mutant BCR-ABL, though it is associated with serious toxicity, including cardiovascular, cerebrovascular, and peripheral vascular events.^6,7

Asciminib is a potent inhibitor of ABL/BCR-ABL1 tyrosine kinase with a novel mode of action. It inhibits the ABL1 kinase activity of the BCR-ABL1 fusion oncoprotein, by specifically targeting the ABL myristoyl pocket (STAMP). Asciminib is administered as an oral tablet at a dosage of 80 mg daily and has received a Notice of Compliance (NOC) from Health Canada for the treatment of adult patients with Ph positive (Ph+) CP-CML previously treated with 2 or more TKIs.

The objective of this review is to perform a systematic review of the beneficial and harmful effects of asciminib 40 mg oral tablets for the treatment of adult patients with Ph+ CP-CML previously treated with 2 or more TKIs.

Stakeholder Perspectives

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

Patient Input

Two patient group submissions were received: 1 from the Chronic Myelogenous Leukemia Society of Canada and 1 from the Lymphoma and Leukemia Society of Canada (LLSC) and the Canadian CML Network. The Chronic Myelogenous Leukemia Society of Canada gathered information from 10 patients with CML and their caregivers through remote surveys and interviews between January and February 2022. The LLSC and the Canadian CML Network conducted an anonymous online survey collaboratively for patients with CML between November 30, 2021, and January 3, 2022. Overall, 16 participants responded to this survey, of which 11 were patients with CML and 5 were a caregiver, friend, or family member of a patient with CML.

According to the submission from the Chronic Myelogenous Leukemia Society of Canada, most patients do not feel sick at the time they are diagnosed with CML in CP, but patients are overwhelmed and physically and emotionally drained due to the financial stress associated with the cost of treatment and frequent appointments and testing. Family members also suffer as the family routine changes significantly and caregivers and/or spouses become more responsible for household management. In both submissions, patients described numerous side effects to the various TKIs, such as fatigue, muscle cramps or pain, rash, joint pain, headaches, fluid retention, and serious cardiovascular problems. It was clear that side effects can seriously impact patients’ quality of life. Those who responded to the LLSC and Canadian CML Network survey indicated that daily life was impacted through moderate impacts on ability to exercise, ability to work, mental health, ability to concentrate, ability to travel, personal image, and ability to continue daily activities. Similarly, respondent indicated moderate impacts of stress, anxiety and/or worry, difficulty sleeping, loss of sexual desire, financial impacts, interruption of life goals and/or accomplishments, and depression.

Patients identified extended survival, improved quality of life, minimization of side effects, and a return to normal life as being important. The majority of patients treated with asciminib rated a positive impact of this treatment on their ability to perform daily activities. All of respondents who had experience with asciminib treatment agreed (11%) or strongly agreed (89%) that asciminib improved health-related quality of life (HRQoL), and all would recommend this treatment to other patients diagnosed with CML.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

Two clinical experts with experience in the diagnosis and management of CML highlighted the need for more treatment options to be made available for patients that have received 2 or more prior TKIs. Ponatinib has been shown to be effective in this setting but has serious safety concerns and patients with cardiovascular risk factors will be contraindicated and have limited options available. Asciminib would likely become the preferred treatment used in the third line. The clinical experts noted that the end point of major molecular response (MMR) is a clinically useful measure of response, and that treatment discontinuation should be assessed according to European LeukemiaNet (ELN) guidelines for treatment failure or the inability of the patient to tolerate treatment.

Clinician Group Input

Clinician group input on the review of asciminib for the treatment of adult patients with Ph+ CML in CP previously treated with 2 or more TKIs was received from 2 groups: Ontario Health – Cancer Care Ontario Hematology Drug Advisory Committee (2 clinicians) and a peer group of hematologists across Canada who are involved in treating patients with CML (14 clinicians). The clinician groups both highlighted that the least suitable patients for asciminib would be those in accelerated phase (AP) or blast crisis (BC), and the second group emphasized that tolerance is important for treatment adherence, which affects suppression of the leukemic clone.

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 drug plans identified implementation issues related to relevant comparators; considerations for initiation, prescribing, and discontinuation of therapy; generalizability; funding algorithm; care provision; system issues; and economic considerations. The clinical experts consulted by CADTH for this review weighed evidence from the included study and other clinical considerations to provide responses to the drug plan’s implementation questions.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

ASCEMBL (N = 233) is a phase III, open-label, randomized study of asciminib compared to bosutinib in patients with CP-CML who had received 2 or more TKIs and experienced treatment failure or intolerance to the most recent TKI. The primary objective of ASCEMBL was to determine the efficacy of asciminib (40 mg twice daily) as compared to bosutinib (500 mg daily) in achieving MMR at the 24-week time point. HRQoL, overall survival (OS), progression-free survival (PFS), and complete cytogenetic response (CCyR) were secondary end points in the trial. Patients were treated until treatment failure or intolerance. Patients in the bosutinib group were permitted to switch to asciminib if they experienced treatment failure. The end of study was defined as 96 weeks after the last patient received their first dose or up to 48 weeks after the last patient switched from bosutinib to asciminib. The mean age in both groups was 51.0 years with a slightly higher proportion of males in the asciminib group (52.2%) compared to the bosutinib group (40.8%). The proportion of patients who identified as Hispanic or Latino was higher in the bosutinib group (22.4%) compared to the asciminib group (9.6%). There were differences in baseline characteristics of important prognostic factors, such as number of prior TKIs and reason for prior TKI discontinuation.

Efficacy Results

Key efficacy outcomes are summarized in Table 2.

Health-Related Quality of Life

Baseline mean EQ visual analogue scale (VAS) (higher scores indicate better HRQoL) was 71.3 (standard deviation [SD] = 21.71) in the asciminib group and 74.2 (SD = 18.79) in the bosutinib group. Mean change from baseline at week 24 was 7.5 (SD = 23.36) in the asciminib group (N = 106) and 0.5 (SD = 17.87) in the bosutinib group (N = 38); this outcome was not tested statistically.

OS and PFS

OS and PFS outcomes were immature at the time of primary analysis (May 25, 2020; mean duration of follow-up = 15.6 months) and at the updated data cut-off (January 1, 2021; mean duration of follow-up = 23.0 months). At the primary analysis, 2.5% of patients in the asciminib group and 1.3% of patients in the bosutinib group experienced a survival event and 4.5% of patients in the asciminib group and 6.6% of patients in the bosutinib group experienced a progression event.

Major Molecular Response

MMR at the 24-week time point was the primary end point of ASCEMBL. At the primary analysis, the MMR rate at 24 weeks in the asciminib group was 25.48% (95% confidence interval [CI], 18.87% to 33.04%) and in the bosutinib group it was 13.16% (95% CI, 6.49% to 22.87%). The primary end point was based on a common risk stratification of major cytogenetic response (MCyR) versus no MCyR at baseline and the difference in MMR rate based on common risk difference was 12.24% (95% CI, 2.19% to 22.30%) with a P value of 0.029. At the updated data cut-off at 48 weeks, the MMR rate was 26.11% (95% CI, 19.44% to 33.72%) in the asciminib group and 11.84% (95% CI, 5.56% to 21.29%) in the bosutinib group; the difference in response rate based on common risk difference was 16.09% (95% CI, 5.69% to 26.49%; not tested statistically).

Complete Cytogenetic Response

The CCyR at 24 weeks in the asciminib group was 40.78% (95% CI, 31.20% to 50.90%) and in the bosutinib group was 24.19% (95% CI, 14.22% to 36.74%). Assessed by common risk stratification of MCyR versus no MCyR at baseline, the difference in response rate based on common risk difference was 17.30% (95% CI, 3.62% to 30.99%). At the updated data cut-off, the difference in response rate at 48 weeks based on common risk difference was 19.05% (95% CI, 4.87 to 33.24). This analysis was not adjusted for multiplicity.

Duration of Response

At the time of primary analysis, 5.6% of the 54 patients receiving asciminib who had gained an MMR at any time had gone on to lose their response, compared to 0% of the 14 patients receiving bosutinib who had gained a response at any time. At the updated data cut-off, these values were 3.2% and 5.6%, respectively.

At the time of primary analysis, 2.3% of the 44 patients receiving asciminib who had gained a CCyR at any time had gone on to lose their response, compared to 5.3% of the 19 patients receiving bosutinib who had gained a response at any time. At the updated data cut-off, these values were 2.0% and 4.5%, respectively.

Time to Response

At the time of primary analysis, the mean time to first MMR in the 54 patients receiving asciminib who had achieved an MMR at any time was 19.0 weeks (SD = 14.40) and 22.8 weeks (SD = 18.37) for the 14 patients receiving bosutinib that had gained a response at any time. At the updated data cut-off, these values were 24.7 weeks (SD = 21.71) and 31.1 weeks (SD = 25.81), respectively.

At the time of primary analysis, the mean time to first CCyR in the 44 patients receiving asciminib who had achieved an MMR at any time was 25.4 weeks (SD = 5.09) and 29.0 weeks (SD = 11.50) for the 19 patients receiving bosutinib who had gained a response at any time. At the updated data cut-off, these values were 29.1 weeks (SD = 13.47) and 31.6 weeks (SD = 12.60), respectively.

Harms Results

A summary of harms is included in Table 2. At the time of primary analysis almost all patients in both treatment groups had experienced at least 1 treatment-emergent adverse event; 89.7% in the asciminib group and 96.1% in the bosutinib group. The most common adverse events (AEs) in the asciminib group were thrombocytopenia (22.4% versus 13.2% in the bosutinib group), neutropenia (17.9% versus 17.1% in the bosutinib group), and headache (16.0% versus 13.2% in the bosutinib group). The most common AEs in the bosutinib group were diarrhea (71.1% versus 11.5% in the asciminib group), nausea (46.1% versus 11.5% in the asciminib group), and increased alanine aminotransferase (27.6% versus 3.8% in the asciminib group). Serious adverse events (SAEs) occurred in 13.5% of patients in the asciminib group and 18.4% of patients in the bosutinib group, with none, other than pyrexia, occurring in more than 1 patient. Deaths occurred in 2.6% of patients in the asciminib group and 1.3% of patients in the bosutinib group. The largest differences between the study treatments were in hepatotoxicity, in which 8.3% of patients in the asciminib group reported AEs compared to 30.3% of patients in the bosutinib group, and in gastrointestinal toxicity, in which 31.4% of patients in the asciminib group reported AEs compared to 78.9% of patients in the bosutinib group. Pancreatic toxicity was similar between the treatment groups, with 8.3% of patients in the asciminib group reporting AEs compared to 9.2% of patients in the bosutinib group.

Critical Appraisal

The primary end point of the ASCEMBL trial was stratified based on MCyR at baseline; however, there was an imbalance within the patients in MCyR at baseline and proportionally more patients in the asciminib group were in CCyR than in the bosutinib group, which may have biased the study results in favour of asciminib. Additionally, there was a substantial number of patients with missing MCyR data at baseline, resulting in 15.9% of patients receiving asciminib and 14.5% of patients receiving bosutinib assigned to the incorrect stratum. A sensitivity analysis was conducted to correct for this using BCR-ABL1 ratio as a proxy for cytogenetic response, the results of which are consistent with the primary analysis. Formal statistical testing was only conducted on the primary end point and none of the other analyses, aside from the primary end point analysis, were controlled for multiplicity (including MMR at 48 weeks). There were slight differences in baseline characteristics of important prognostic factors with proportionally more patients in the bosutinib group having received higher numbers of prior TKIs and having discontinued their prior TKI due to resistance, suggesting bias in favour of asciminib. However, logistic regression adjusting for these factors found similar results with the primary analysis.

According to clinical experts consulted by CADTH, the demographic and disease characteristics of the ASCEMBL population were reflective of the Canadian population with CP-CML after 2 or more prior TKIs; however, it should be noted that patients with the T315I or V299L mutations were excluded from the trial population, which impacted the generalizability to this group of patients. The dosage of asciminib in the ASCEMBL trial (40 mg twice daily) represents only one of the Health Canada–approved dosages (40 mg twice daily and 80 mg once daily). It is unclear if the ASCEMBL evidence is generalizable to an 80 mg once daily dose. All outcomes evaluated in the trial and considered in this review (i.e., MMR, CCyR, OS, PFS, HRQoL) were clinically relevant, important to patients, and are used in clinical practice. The duration of follow-up was sufficient for assessment of the primary outcome of MMR at 24 weeks, CCyR, and HRQoL; however, conclusions regarding longer-term outcomes of PFS and OS cannot be drawn given the immaturity of the data. Subgroup analysis was not powered to detect treatment differences in patients who experienced treatment failure on their most recent TKI compared to treatment intolerance, line of therapy, disease severity at baseline, or mutational status, and there was no test for subgroup differences. Nevertheless, the clinical experts consulted for this review felt that the results were generalizable across strata for all these subgroups.

Indirect Comparisons

Description of Studies

One matching adjusted indirect comparison (MAIC) report was submitted by the sponsor and included in this report. In the absence of direct comparative evidence from trials, the aim of each MAIC was to compare the efficacy (response rate [MMR and CCyR] and time to treatment discontinuation [TTD]) of asciminib versus ponatinib, nilotinib, and dasatinib in patients with CP-CML who have received at least 2 prior TKIs. To identify evidence for relevant comparators a systematic literature review (SLR) was conducted to identify evidence from interventional and observational studies. Given the availability of individual patient data from the ASCEMBL index trial, the sponsor aimed to adjust for between-study differences in the distribution of prognostic factors and treatment effect modifiers. The sponsor consulted with an expert clinician to identify which characteristics should be adjusted for in the analysis and their relative importance. For response comparisons, the ponatinib single-arm phase II study PACE⁹ (N = 203), nilotinib and dasatinib single-centre prospective cohort study¹⁰ (N = 26; 6 of whom received nilotinib), and dasatinib single-centre retrospective chart review¹¹ (N = 24) were used.

Efficacy Results

In the comparison of MMR rate and CCyR rate at both 6 and 12 months in the weighted sample of patients from the ASCEMBL trial compared with the PACE trial (ponatinib), ||||||||| ||| |||||||| |||| ||||||| || ||| || ||| | ||| || ||||| ||||||||||| |||| || |||| ||||| |||| || |||| |||| ||| |||| || ||||| ||| |||| |||| ||| |||| || |||||| ||||||||||||| ||| || |||| ||| ||| |||| || ||| ||||||| ||||||||| ||| |||| ||||| || ||||| ||| |||| ||||| || ||||| || ||| |||||||| |||||||||.

The comparison of efficacy end points was only available for CCyR at both 6 and 12 months in the weighted sample of patients from the ASCEMBL trial compared with patients treated with dasatinib or nilotinib. ||||||||| ||| |||||||| |||| ||||||| || |||| || ||| | ||| |||||||| ||||||||||| |||| || || || |||| |||| ||| |||| || |||||| ||| |||| |||| ||| |||| || |||||| ||||||||||||.

The comparison of efficacy end points was only available for MMR at 6 months in the weighted sample of patients from the ASCEMBL trial compared with patients treated with dasatinib. ||| || ||| ||| || |||||||| ||| |||| |||| ||| |||| || |||||.

Critical Appraisal

The sponsor submitted 1 MAIC report that included comparisons of interest for asciminib against ponatinib, dasatinib, and nilotinib. The choice to conduct an unanchored MAIC was justified considering the lack of a common comparator. There were important differences in the design of the comparator studies that limit the ability to draw conclusions about the efficacy of asciminib compared with the other treatments. ASCEMBL was a randomized phase III interventional trial, while comparator trials included observational trials. These are prone to unique biases (e.g., selection bias, confounding) compared with those collected from prospective interventional studies (like randomized controlled trials [RCTs] and single-arm trials) that cannot be controlled for using MAIC methods.

An important limitation, inherent to all MAIC analyses, is that all prognostic factors should ideally be adjusted between index and comparator trials to eliminate as much bias from the comparison as possible. This includes both measured and unmeasured characteristics and thus can never be fully accounted for. The list of characteristics provided by the sponsor that were adjusted for were not informed by a systematic review of literature or clinical expert identification; rather, they were chosen because they were included in the comparator trials and could be reliably calculated for patients in the ASCEMBL trial. This limitation was in addition to the fact that all identified prognostic factors could not be matched due to non-convergence and concerns for effective sample size (ESS).

The ESS for most comparisons was very small, resulting in very wide CIs that precluded the ability to draw conclusions from the data. For the comparison of nilotinib specifically, the only available trial that included response data was a retrospective trial of 26 patients, of whom only 6 received nilotinib while the other 20 received dasatinib, though the issue of small ESS is present in all comparisons. As such, there is very little that can be said regarding the comparative efficacy of asciminib versus the chosen comparators with regards to response.

Other Relevant Evidence

Description of Studies

The sponsor submitted a phase I, multicentre, open-label study. The primary objective was to determine the maximum tolerated dose and/or recommended dose for expansion of asciminib single drug or in combination with other drugs. Among the 317 enrolled patients, 30 patients without the T315I mutation were treated with the 40 mg twice daily dosage and 17 were treated with the 80 mg once daily dosage.

Efficacy Results

MMR results were consistent with the pivotal trial. Patients receiving asciminib 40 mg twice daily had an MMR rate of 16% at 24 weeks, while patients receiving asciminib at 80 mg daily had an MMR rate of 28.6% at 24 weeks.

Harms Results

All patients in the 40 mg twice daily group (n = 30) and 80 mg daily group (n = 17) had AEs. SAEs were found among 11 (36.7%) and 8 (47.1%) patients taking 40 mg twice daily and 80 mg daily, respectively. AEs leading to dose adjustment or interruption were observed among 14 (46.7%) and 10 (58.8%) patients taking 40 mg daily and 80 mg daily dosages, respectively. Among the notable harms were myelosuppression (36.7% and 41.2%), pancreatic toxicity (53.3% and 29.4%), hepatotoxicity (including laboratory terms) (16.7% and 17.6%), gastrointestinal AEs (70.0% and 52.9%), and cardiac failure (6.7% and 17.6%) for all grades in asciminib 40 mg twice daily and 80 mg once daily groups, respectively. The safety profile seen was similar to that in the pivotal trial.

Critical Appraisal

There are several internal validity concerns that limit the certainty of conclusions that can be drawn from this trial. The primary concern is that there was no control group and no adjustment for known prognostic factors or effect modifiers; thus, causal conclusions cannot be established, and the findings are at high risk of confounding. Since the trial was open label, there is a risk that common subjective harms may have been overreported. Though the inclusion and exclusion criteria are clear, some details of the participant disposition are limited (i.e., number screened versus randomized). There was no hypothesis testing in the trial. The small sample size may negatively impact the reliability of the findings. The patients were not randomized, and there is a possibility of selection bias because it is not clear whether the patients were consecutively enrolled.

Conclusions

The ASCEMBL trial showed a statistically significant benefit with asciminib 80 mg daily over bosutinib 500 mg daily in MMR at 24 weeks in patients who had received 2 or more TKIs and experienced treatment failure on or intolerance to the most recent TKI. In the opinion of the clinical experts consulted by CADTH, the MMR rate at 24 weeks represents a clinically significant benefit for asciminib over bosutinib. Secondary end points such as HRQoL, duration of response, and time to response favoured asciminib but were not statistically tested; therefore, few conclusions can be drawn. CCyR results were supportive of the MMR results, though the analysis was not adjusted for multiplicity. Data on OS and PFS were immature at the time of analysis. The submitted MAIC provided indirect evidence for relative efficacy for asciminib compared to ponatinib, dasatinib, and nilotinib, but the significant limitations with the analysis prohibit any conclusions from being drawn. Asciminib appears to be more tolerable than bosutinib, though comparative safety evidence against other relevant comparators is lacking.

Introduction

Disease Background

CML is a clonal BM stem cell disorder resulting in the unregulated growth of myeloid precursor cells and production of excessive neutrophils, eosinophils, and basophils in the BM.¹ Although up to 50% of patients are asymptomatic at diagnosis, common signs and symptoms (e.g., fatigue, weight loss, malaise, easy satiety, left lower quadrant fullness or pain) result from anemia and splenic enlargement. Blood and BM cells in patients with CML usually contain a characteristic chromosomal abnormality resulting from a balanced translocation between chromosomes 9 and 22 (Ph).² The gene product of this BCR-ABL translocation is a tyrosine kinase that is constitutively active, resulting in the continuous activation of other cell cycle regulatory proteins and unrestrained BM proliferation. This kinase is now the key therapeutic target in the treatment of CML, and the presence of cells bearing the t(9;22) translocation in the blood and BM form the basis of response monitoring in this disorder.² Initial signs of CML are identified through typical findings in the blood and BM and confirmed by identification of the Ph chromosome, BCR-ABL1 fusion gene, or BCR-ABL1 fusion mRNA using conventional cytogenetics, fluorescence in situ hybridization analysis, or reverse transcription polymerase chain reaction (RT-PCR).¹²

The incidence rate of CML across all ages and sexes in Canada, excluding Quebec, ranged from 510 cases in 2011 to 585 cases in 2018. This corresponds to an incidence rate of 2.0 per 100,000 population in 2018.³ The 20-year prevalence rate in 2015 was higher in males in Canada (15.8 per 100,000) than in females in Canada (11.7 per 100,000).³ The 20-year prevalence of CML across all ages and sexes in Canada, excluding Quebec, ranged from 3,110 cases in 2012 to 3,760 cases in 2015. This corresponds to a 20-year prevalence rate of 13.7 per 100,000 population in 2015.³ The 20-year prevalence rate in 2015 was higher in males in Canada (15.8 per 100,000) than in females in Canada(11.7 per 100,000).³ The average age at diagnosis is 64 years of age, as CML is rarely diagnosed in children.¹³

The majority of patients (greater than 95%) with CML are in CP at diagnosis.⁴ In the distant past, without treatment or with chemotherapy using busulfan or hydroxyurea, this was followed by progression to accelerated and blast phases, which was invariably fatal. OS before the use of modern treatments was approximately 3 to 5 years.¹⁴ Allogeneic stem cell transplant from a sibling or matched unrelated donor resulted in cure of 70% to 80% of patients treated in CP, but was limited to younger patients and those with available donors, representing less than 25% of the patient population. Hence, CML was previously fatal for 80% to 90% of patients before the introduction of specific inhibitors of the BCR-ABL kinase. For those who were not candidates for allogeneic stem cell transplant, or for whom a donor could not be found, interferon alpha was effective in producing hematologic and occasional cytogenetic responses, but side effects limited its use to those younger than 50 years of age.¹⁴ Following the development of the first TKIs in 2001, 10-year survival rates have improved from approximately 20% to approximately 80% to 90% today.²

Standards of Therapy

The use of oral TKIs targeting the BCR-ABL kinase represents the standard of care for patients with newly diagnosed CP-CML. Imatinib was the first drug in this class to be approved, and reports of improvements in population-based CML outcomes can largely be attributed to the use of this drug.⁵ Long-term follow-up of patients in the original phase III randomized trial comparing imatinib to interferon alpha plus cytarabine therapy showed that at 5 years, 87% of patients had a CCyR (no evidence of the Ph chromosome in the BM) and only 6% had progressed to AP or BP.¹⁵

Roughly one-third of patients treated with imatinib will discontinue therapy, due either to intolerance from side effects (e.g., diarrhea, fatigue, edema) or loss of previous molecular, cytogenetic, or hematologic response because of drug resistance. Mutations to the adenosine triphosphate (ATP) binding site of BCR-ABL, which is the site of contact of TKIs active in these diseases, are associated with drug resistance and a high risk of progression. While some binding site mutations may preserve the activity of alternative TKIs, the T315I mutation is associated with universal resistance to first- and second-generation drugs. The second-generation TKIs dasatinib, nilotinib, and bosutinib have a much smaller spectrum of resistance mutations, but none can overcome the T315I mutation. These drugs produce similar rates of MMR and have similar PFS and OS when used as second-line therapies.^6,7

Ponatinib is a third-generation TKI with activity against wild-type and mutant BCR-ABL. It was designed to fit into the ATP binding domain of mutant forms of BCR-ABL and is known to bind firmly even in the presence of mutations such as T315I that are associated with resistance to first and second-generation TKIs. Ponatinib is associated with serious toxicity including cardiovascular, cerebrovascular, and peripheral vascular as well as the elevation of pancreatic enzymes, pancreatitis, dermatitis and fatigue.^6,7

Patients with Ph+ CML whose disease becomes resistant or who become intolerant to imatinib in the first-line setting may receive second-line second-generation TKIs such as bosutinib, dasatinib, or nilotinib. Patients who received a second-generation TKI in the first line may receive an alternative second-generation TKI in the second-line setting. Rarely, they may be stepped back onto imatinib in the second line if the change is being made for intolerance. Treatment options for patients whose disease becomes resistant or who become intolerant to 2 prior lines of TKI therapy are ponatinib, hematopoietic stem cell transplant, or any second-generation TKI that has not already been used in a prior line of therapy.^6,7

As patients with CP-CML who have failed on 2 or more previous TKI therapies have an advanced disease, achievement of an MMR as soon as possible reduces the risk of disease progression and is an important treatment goal. Durability of this response is another important goal for continuous suppression of the leukemic clone. Patients who have failed on 2 or more previous TKI therapies have few options for treatment; therefore, tolerability of therapy is an important treatment goal as well.

Drug

Asciminib is a potent inhibitor of ABL/BCR-ABL1 tyrosine kinase with a novel mode of action. It inhibits the ABL1 kinase activity of the BCR-ABL1 fusion oncoprotein, by the mechanism known as STAMP. Asciminib received an NOC from Health Canada, indicated for the treatment of adult patients with Ph+ CP-CML who have been previously treated with 2 or more TKIs and has not previously been reviewed by CADTH for any indication. The sponsor is requesting reimbursement for the indication as reviewed by Health Canada. On October 29, 2021, asciminib was approved by the FDA for patients with Ph+ CP-CLM who have been previously treated with 2 or more prior TKIs.¹⁶ The FDA also gave approval for patients with Ph+ CP-CLM with the T315I with a recommended dosage of 200 mg twice daily. This dose is specifically for patients with the T315I mutation, a patient population that is not part of the requested reimbursement population.

Asciminib is administered as an oral tablet at a dosage of 80 mg daily. Key characteristics of asciminib and relevant comparators are shown in Table 3.

Table 3: Key Characteristics of Asciminib, Bosutinib, Nilotinib, Dasatinib, and Ponatinib

ALL = acute lymphoblastic leukemia; ATP = adenosine triphosphate; CML = chronic myeloid leukemia; CP = chronic phase; NA = not applicable; Ph+ = Philadelphia chromosome positive; TKI = tyrosine kinase inhibitor.

^aHealth Canada–approved indication.

Source: Asciminib draft product monograph,¹⁷ Bosutinib product monograph,¹⁸ Nilotinib product monograph,¹⁹ Dasatinib product monograph,²⁰ Ponatinib product monograph.²¹

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full patient group submissions can be found at the end of this report in the Stakeholder Feedback section.

Two patient group submissions were received: 1 from the Chronic Myelogenous Leukemia Society of Canada and 1 from the LLSC and the Canadian CML Network. The Chronic Myelogenous Leukemia Society of Canada gathered information from 10 patients with CML and their caregivers through remote surveys and interviews between January and February 2022. The LLSC and the Canadian CML Network conducted an anonymous online survey collaboratively for patients with CML between November 30, 2021, and January 3, 2022. Overall, 16 participants responded to this survey, of which 11 were patients with CML and 5 were a caregiver, friend, or family member of a patient with CML.

According to the submission from the Chronic Myelogenous Leukemia Society of Canada, most patients do not feel sick at the time they are diagnosed with CP-CML, but patients are overwhelmed and physically and emotionally drained due to the financial stress associated with the cost of treatment and frequent appointments and testing. Family members also suffer as the family routine changes significantly and caregivers and/or spouses become more responsible for household management. In both submissions, patients described numerous side effects to the various TKIs, such as fatigue, muscle cramps or pain, rash, joint pain, headaches, fluid retention, and serious cardiovascular problems. It was clear that side effects can seriously impact patients’ quality of life. Those who responded to the LLSC and Canadian CML Network survey indicated that daily life was impacted through moderate impacts on ability to exercise, ability to work, mental health, ability to concentrate, ability to travel, personal image, and ability to continue daily activities. Similarly, respondent indicated moderate impacts of stress, anxiety and/or worry, difficulty sleeping, loss of sexual desire, financial impacts, interruption of life goals and/or accomplishments, and depression.

Patients identified extended survival, improved quality of life, minimization of side effects, and a return to normal life as being important. The majority of patients treated with asciminib rated a positive impact of this treatment on their ability to perform daily activities. All of respondents who had experience with asciminib treatment agreed (11%) or strongly agreed (89%) that asciminib improved HRQoL, and all would recommend this treatment to other patients diagnosed with CML.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding 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 development of 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 CML.

Unmet Needs

The clinical experts commented that some patients do not respond to, lose response to, or experience intolerance to first- and second-line TKI therapy and have few options remaining for them in the third line and beyond setting. At this stage of treatment, intolerance and safety become strong considerations for selecting treatment for a patient. The third-generation therapy, ponatinib, has been shown to be effective but is associated with elevated cardiovascular complications. Patients with cardiovascular risk factors are contraindicated for ponatinib and have limited options available to them. Patients who have failed on the second- and/or third-generation TKIs are left with very low chance of long-term survival and their treatment options include allogeneic stem cell transplant or management with hydroxyurea and/or interferon and cytarabine.

Place in Therapy

The clinical experts highlighted that asciminib has a novel mechanism of action known as STAMP. As such, asciminib has been shown to maintain clinical activity even in patients whose disease has become resistant to other TKIs. Therefore, asciminib would likely be the preferred treatment in the third line for patients who have failed on or become intolerant to 2 or more previous TKIs.

Patient Population

The clinical experts confirmed that patients with CP-CML who have failed on or become intolerant to 2 or more TKIs are best suited for the drug under review. Diagnostic investigations to diagnose and monitor CML are now standard of care and readily available. Given that pregnant patients, as well as patients under 18 years of age, were not included in the trial, these patients would be less suitable for treatment with asciminib. One of the 2 experts consulted suggested that patients with AP-CML or BC-CML would not be suitable for treatment with asciminib, given that they were not included in the trial. It is also expected that patients who are intolerant (rather than resistant) to their previous TKI would have a better response because their disease is not yet resistant.

Assessing Response to Treatment

The clinical experts commented that patient response would be measured by the depth of molecular response, as measured by RT-PCR performed every 3 months, as was done in the clinical trial. Other blood tests are conducted as part of disease and side effect monitoring. BM aspiration is only conducted as needed in the case of investigation of disease resistance or progression. The primary end point of the trial, MMR at 24 weeks, is considered a clinically meaningful response indicative of successful CML treatment because of its association with superior long-term outcomes, including survival. Patients would also be monitored for how well they tolerate the therapy.

Discontinuing Treatment

The clinical experts commented that patients should discontinue therapy upon disease progression, as defined by the ELN guideline for failure to meet milestones, or the inability of the patient to tolerate asciminib.

Prescribing Conditions

The clinical experts commented that CML can be appropriately managed in both community and academic settings, with the majority of patients being managed as outpatients. Patients with CML should be managed by a practitioner with experience treating CML, commonly a hematologist or occasionally a medical oncologist.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full clinician group submissions can be found at the end of this report in the Stakeholder Feedback section.

Clinician group input on the review of asciminib for the treatment of adult patients with Ph+ CP-CML previously treated with 2 or more TKIs was received from 2 groups: Ontario Health – Cancer Care Ontario Hematology Drug Advisory Committee (2 clinicians) and a peer group of hematologists across Canada who are involved in treating patients with CML (14 clinicians). The clinician groups both highlighted that the least suitable patients for asciminib would be those in AP or BC, the second group emphasized that tolerance is important for treatment adherence, which affects suppression of the leukemic clone.

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 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

AP = accelerated phase; BC = blast crisis; CML = chronic myeloid leukemia; CP = chronic phase; ECLN = European LeukemiaNet; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; TKI = tyrosine kinase inhibitor.

Clinical Evidence

The clinical evidence included in the review of asciminib is presented in 3 sections. The first section, Systematic Review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of asciminib 40 mg oral tablets for the treatment of adult patients with Ph+ CML in CP previously treated with 2 or more TKIs.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; CP = chronic phase; CML = chronic myeloid leukemia; CyR = cytogenetic response; DOR = duration of response; HR = hematological response; HRQoL = health-related quality of life; MMR = major molecular response; MR = molecular response; OS = overall survival; Ph+ = Philadelphia chromosome positive; PFS = progression-free survival; RCT = randomized controlled trial; SAE = serious adverse event; TKI = tyrosine kinase inhibitor; TTR = time to response; WDAE = withdrawal due to adverse event.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.²²

Published literature was identified by searching the following bibliographic databases: Medline All (1946–) via Ovid and Embase (1974–) via Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Scemblix and asciminib. Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 1 for the detailed search strategies.

The initial search was completed on February 17, 2022. Regular alerts updated the search until the CADTH pERC meeting on June 8, 2022.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature resource.²³ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy. Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

A total of 3 reports^8,24,25 of 1 study were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Study

ASCEMBL is a phase III, open-label, randomized study of asciminib compared to bosutinib in patients with CP-CML who had received 2 or more TKIs and experienced treatment failure on or intolerance to the most recent TKI. Novartis funded the study. The primary objective of the ASCEMBL trial was to determine the efficacy of asciminib (40 mg twice daily) as compared to bosutinib (500 mg daily) in achieving MMR at the 24-week time point. Beginning October 26, 2017, a total of 233 patients with CP-CML who had previously received 2 or more TKIs were enrolled in ASCEMBL at 87 sites across North America (n = 5 patients from 1 site in Canada), South America, Europe, Australia, and Asia. Patients were randomized 2:1 to either asciminib or bosutinib; randomization was stratified by cytogenic response status at screening (i.e., yes or no).

Patients were screened for a period of up to 56 days before beginning study treatment. Patients were treated until treatment failure or intolerance. Patients in the bosutinib group were permitted to switch to asciminib if they experienced treatment failure. The end of study was defined as 96 weeks after the last patient received their first dose or up to 48 weeks after the last patient switched from bosutinib to asciminib. Patients who discontinued study treatment at any time were followed for survival and disease progression for up to 5 years from the date that the last patient randomized received their first dose. Study visits were conducted every 4 weeks during the treatment phase up to 96 weeks and every 12 weeks during survival follow-up.

The primary analysis was conducted based on the May 25, 2020, data cut-off date, when all patients randomized had been on study treatment for 24 weeks or discontinued earlier. A future planned updated analysis to conduct testing on the 96-week secondary end points was not presented. An unplanned updated data cut-off was provided based on a January 1, 2021, data cut, when all patients randomized had been on study treatment for 48 weeks or discontinued earlier.

There were 3 amendments made to the trial protocol, 2 of which were made after patients had been randomized. A July 2018 amendment was made to align the frequency of BM aspirate collection in patients having achieved MMR with the recommendations from ELN²⁶ and National Comprehensive Cancer Network.²⁷ The December 2018 amendment was made after 86 patients had been randomized, changing the inclusion requirement for baseline BCR-ABL1 ratio (International Standard [IS] percentage) from 1% or more to more than 0.1% specifically for patients who were intolerant to their most recent TKI. The reasoning given was that physicians would not wait for transcript level to increase before switching an intolerant patient to their next treatment option.²⁶ No more than 66 patients fitting these characteristics were to be enrolled in the study. Patients who failed on their most recent TKI were still required to meet the criteria defined by ELN.²⁶

Populations

Inclusion and Exclusion Criteria

Key inclusion and exclusion criteria are summarized in Table 6. Adult patients (age 18 years or older) with CML-CP that had received prior treatment with 2 or more ATP binding site TKIs and had experienced treatment failure or intolerance to their most recent TKI were eligible for inclusion. Treatment failure was defined according to the 2013 ELN guidelines. Intolerance was defined as patients with grade 3 or 4 nonhematological toxicity while on therapy, or with persistent grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction was not considered in the best interest of the patient if response is already suboptimal). The definition of intolerance also included patients with grade 3 or 4 hematological toxicity (absolute neutrophil count or platelets) while on therapy that was recurrent after dose reduction to the lowest doses recommended by the manufacturer. Evidence of BCR-ABL1 transcript was required at time of screening. Patients who were intolerant to their most recent TKI were required to have a BRC-ABL1 ratio of greater than 0.1%, in accordance with the protocol amendment. Eligible patients were required to have an European Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 2.

Patients were considered ineligible for inclusion in the ASCEMBL trial if there was known presence of a T315I or V299L mutation at any point before study entry as these mutations confer resistance to the efficacy of bosutinib. Excluded from the study population were patients for which this was their second-known CP of CML after previous progression to AP or BC, previous treatment with hematopoietic stem cell transplant, cardiac or cardiac repolarization abnormality, or previous treatment with or hypersensitivity to asciminib or bosutinib.

Baseline Characteristics

The baseline characteristics of patients randomized (i.e., full analysis set [FAS]) in the ASCEMBL trial are shown in Table 7. The mean age in both groups was 51.0 years with a slightly higher proportion of males in the asciminib group (52.2%) compared to the bosutinib group (40.8%). The proportion of patients who identified as Hispanic or Latino was higher in the bosutinib group (22.4%) than in the asciminib group (9.6%). All other baseline characteristics were broadly similar between the groups.

Table 7: Summary of Baseline Characteristics — FAS

ECOG PS = Eastern Cooperative Oncology Group Performance Status; SD = standard deviation.

Source: Asciminib Clinical Study Report.⁸

A summary of baseline disease characteristics for patients randomized is shown in Table 8. The mean time in years since initial diagnosis of CML was 6.2 (SD = 5.75) in the asciminib group and 7.0 (SD = 5.63) in the bosutinib group. There were 28.0% and 27.6% of patients in MCyR at baseline according to bone marrow aspirate (BMA) measurements in the asciminib and bosutinib groups, respectively. Of note, there were 22.3% and 11.8% of patients with missing BMA measurements at baseline in the asciminib and bosutinib groups, respectively. MCyR is classified as 0% to 35%, inclusive Ph+ metaphases in BM. In the asciminib group there was 12.1% of patients at 0% Ph+ metaphases in the BM and 15.9% at greater than 0% to 35% or less, while in the bosutinib group, these values were 6.6% and 21.1%, respectively. Patients with any mutation were balanced at baseline with 12.7% in the asciminib group and 13.2% in the bosutinib group. Patients were identified as T315I positive (1.9% in the asciminib group and 1.3% in the bosutinib group) and V299L positive (0% in the asciminib group and 1.3% in the bosutinib group) despite this being an exclusion criterion for the study. In the asciminib group, 1.9% of patients had multiple mutations while there were no patients with multiple mutations in the bosutinib group.

Table 8: Summary of Disease Characteristics — FAS

BM = bone marrow; BMA = bone marrow aspirate; CML = chronic myeloid leukemia; Ph+ = Philadelphia chromosome positive; SD = standard deviation

^aBased on BM aspirate results; results based on the randomization data collected in the Interactive Response Technology system were similar.

Source: Asciminib Clinical Study Report.⁸

Table 9 summarizes the prior antineoplastic therapy received by patients randomized in each treatment group. The most commonly received TKIs were dasatinib, imatinib, and nilotinib, all received by more than 65% of patients in each treatment group. Ponatinib had been received by 14.6% of patients in the asciminib group and 23.7% of patients in the bosutinib group. A similar number of patients had received between 2 and 3 lines of prior TKI therapy in each treatment group, though there was a higher proportion of patients who had received only 2 prior TKI therapies in the asciminib group (52.2%) compared to in the bosutinib group (39.5%). There was a higher number of patients who had discontinued their most recent TKI due to lack of efficacy (60.5% in the asciminib group and 71.1% in the bosutinib group) compared to patients who discontinued due to intolerance (37.5% in the asciminib group and 28.9% in the bosutinib group). The reasons for discontinuation of the previous TKI were imbalanced across the treatment groups.

Baseline BCR-ABL1 ratio (IS percentage) by reason for discontinuation of prior TKI for patients who were randomized is summarized in Table 10. There was 1 patient in the asciminib group with a BCR-ABL1 ratio greater than 0.1% to less than or equal to 1% who had entered the study after treatment failure of most recent TKI therapy, while 22.0% and 18.2% of the patients who were intolerant to their prior TKI therapy had a BCR-ABL1 ratio greater than 0.1% to less than or equal to 1% in the asciminib and bosutinib groups, respectively. Distribution among BCR-ABL1 ratio categories were broadly similar in both groups.

Interventions

Patients in the ASCEMBL trial were administered asciminib or bosutinib as oral tablets in accordance with 40 mg twice daily and 500 mg daily dosing regimens, respectively. Asciminib was to be taken in a fasted state, that is, food was to be avoided for 2 hours before dose administration and for 1 hour after, only water was permitted. Bosutinib was to be taken with food. Asciminib tablets were given in 20 mg and 40 mg forms, while bosutinib tablets were given in 100 mg and 500 mg forms. For patients who were unable to tolerate the protocol-specified dosing schedule, dose modifications and/or reductions were to follow the provided step-down rules. Asciminib, from the starting dose of 40 mg twice daily, was reduced to 20 mg twice daily at the first dose-reduction level and no further dose reductions were permitted. Bosutinib, from the starting dose of 500 mg daily, was reduced to 400 mg daily at the first dose-reduction level, and further to 300 mg daily at the second dose-reduction level. Dose escalation beyond the standard 40 mg twice daily dosage of asciminib was not permitted, but dose escalation to 600 mg daily bosutinib was allowed for patients who were taking 500 mg daily, did not have grade 3 or higher AEs, and who either did not reach complete hematological response by week 8 or did not reach CCyR by week 12. Any concomitant medication or therapies deemed necessary for the supportive care of the patient were permitted unless specifically prohibited. Prohibited concomitant therapies for asciminib included other anticancer drugs; strong CYP3A4, 5 inhibitors, inducers and strong UGT1A/2B inducers; drugs with known, possible, or conductional risk of Torsades de Pointes; and herbal medications. For bosutinib prohibited concomitant therapies included other anticancer drugs, strong or moderate CYP3A inhibitors or inducers, or pH altering medications. Patients could voluntarily withdraw for any reason at any time. A patient was considered withdrawn if they stated an intention to withdraw, failed to return for visits, or became lost for follow-up for any reason.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trial included in this review is provided in Table 11. These end points are further summarized in the following. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

HRQoL was measured using the EQ-5D 5-Levels (EQ-5D-5L) and indirectly measured using the MD Anderson Symptom Inventory (MDASI) and patients’ global impression of change (PGIC). All patient-reported outcome questionnaires were completed at scheduled visits before clinical assessments. The EQ-5D is a generic HRQoL instrument that may be applied to a wide range of health conditions and treatments.^28,29 The first of 2 parts of the EQ-5D is a descriptive system that classifies respondents (aged 12 years and older) based on the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D-5L has 5 possible levels for each domain representing “no problems,” “slight problems,” “moderate problems,” “severe problems,” and “extreme problems.” Respondents are asked to choose the level that reflects their health state for each of the 5 dimensions. The second part is a 20 cm VAS that has end points labelled 0 and 100, with respective anchors of “worst imaginable health state” and “best imaginable health state.” No assessments of minimally important difference (MID) were identified in patients with CML for the EQ-5D-5L.

The MDASI is a brief measure used to assess the severity and impact of cancer-related symptoms and its treatment. The MDASI-CML is a modified 26 item self-administered questionnaire suitable for adult patients with CML.³⁰ Twenty of the items in the MDASI-CML measure the severity of disease-related symptoms and are scored from 0 (not present) to 10 (as bad as you can imagine), whereas 6 items measure symptom interference with daily life scored from 0 (did not interfere) to 10 (interfered completely). Higher scores represent worse HRQoL. No assessments of MID were identified in patients with CML for the MDASI. The PGIC uses a 7-point scale where 1 indicates very much improved and 7 indicates very much worse. No assessments of MID were identified in patients with CML for the PGIC.

OS was defined as the time from the date of randomization to the date of death due to any cause, including the survival follow-up period. PFS was defined as the time from the date of randomization to the earliest occurrence of documented disease progression to AP or BC or the date of death from any cause, including progressions and deaths observed during the survival follow-up period.

MMR was defined as at least a 3.0 log reduction in BCR-ABL1 transcript compared to standardized baseline, which is equivalent to 0.1% or less BCR-ABL1/ABL percentage by IS as measured by RT-PCR. Treatment discontinuation for any reason (intolerance, treatment failure, death) within the first 24 weeks of treatment was considered a nonresponse. Molecular response is similar in that it is equivalent to 1% or less BCR-ABL1/ABL percentage by IS percentage. Molecular response was not a specific end point in the ASCEMBL trial. Hematological response (HR) was also not a reported end point in ASCEMBL.

Treatment failure events were based on the ELN criteria,²⁶ including:

• no complete hematologic response (CHR) or greater than 95% Ph+ metaphases at 3 months after randomization or thereafter

• BCR-ABL1 ratio greater than 10% IS and/or greater than 65% Ph+ metaphases at 6 months after randomization or thereafter

• BCR-ABL1 ratio greater than 10% IS and/or greater than 35% Ph+ metaphases at 12 months after randomization or thereafter

• loss of CHR, CCyR, or partial cytogenetic response (PCyR) at any time after randomization

• detection of new BCR-ABL1 mutations that potentially cause resistance to study treatment at any time after randomization

• confirmed loss of MMR in 2 consecutive tests

• new clonal chromosome abnormalities in Ph+ cells at any time after randomization

• discontinuation from randomized treatment for any reason.

Cytogenetic response was assessed locally as the percentage of Ph+ metaphases in BM according to the following categories:

• CCyR — 0% Ph+ metaphases

• PCyR — greater than 0 to 35% Ph+ metaphases

• MCyR — 0 to 35% Ph+ metaphases

• minor cytogenetic response — greater than 35% to 65% Ph+ metaphases

• minimal cytogenetic response — greater than 65% to 95% Ph+ metaphases

• no cytogenetic response — greater than 95% to 100% Ph+ metaphases.

Duration of response (MMR and CCyR) was defined as the time from the date of first documented MMR or CCyR to the earliest date of loss of MMR or CCyR, progression to AP or BC, or CML-related death. Time to response (MMR and CCyR) was defined as the time from the date of randomization to the date of the first documented MMR or CCyR.

Safety outcomes were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grades 1 to 5 were used to characterize severity of AEs.

Statistical Analysis

To test the null hypothesis that the primary end point of MMR rate at 24 weeks is equal in the 2 treatment groups, based on a 2-sided 5% level of significance and with 90% power, 222 patients were estimated to be needed in total (i.e., 148 patients in the asciminib group and 74 patients in the bosutinib group based on 2:1 randomization allocation).

The key secondary end point of MMR rate at 96 weeks was only to be tested if statistical significance was found in the primary end point of MMR rate at 24weeks. The data for this end point will be available in the future. The overall alpha is therefore controlled at the 5% 2-sided level using a gatekeeping strategy. This is the only secondary end point that was to be formally tested, and data were not analyzed at the latest available data cut-offs. No confirmatory statistical testing was undertaken for other end points, including secondary end points, patient-reported outcomes, and harms; however, nominal P values were presented in some cases.

Only patients with MMR at the 24-week visit were considered responders for the primary end point. In other words, any patient who achieved MMR before 24 weeks, but was no longer in MMR at 24 weeks, was considered a nonresponder in the primary analysis. Patients who discontinued the randomized treatment before 24 weeks due to any reason were considered nonresponders. One exception was if the 24-week PCR evaluation was missing, but both a PCR evaluation at 16 weeks and a PCR evaluation at 36 weeks indicated MMR, in which case the 24-week assessment was imputed as a “response.” If PCR evaluations were performed at unscheduled visits closer to the week 24 visit (before or after), these were used to impute the 24-week value.

Statistical analysis of the efficacy end points is summarized in Table 12. The primary analysis was conducted according to randomization stratum (MCyR versus no MCyR at baseline). Patients with missing BMA data at baseline were inferred to be in MCyR if baseline BCR-ABL1 ratio (IS%) was 10% or lower. The primary analysis included 46 patients receiving asciminib and 22 patients receiving bosutinib in MCyR at baseline. However, based upon the previously stated assumption, 15.9% of patients receiving asciminib and 14.5% of patients receiving bosutinib were assigned to the incorrect stratum. A sensitivity analysis was conducted to explore the impact of this. Concordance between randomization strata and strata as per the baseline case report form (CRF) data was 84.5%. The model used to test between-treatment group differences was the Cochran-Mantel-Haenszel chi-square test, stratified by cytogenetic response status (MCyR versus no MCyR) at screening, at a 2-sided 5% level of significance. Response rates were presented along with 95% CI based on the Clopper-Pearson method and treatment differences between groups were presented along with 95% CI based on the Wald method. Preplanned exploratory subgroup analyses for the primary efficacy end point that were relevant according to the CADTH protocol were those based on baseline MCyR status, baseline or week 1 on day 1 BCR-ABL1 ATP binding site mutation status, failure versus intolerance to prior TKIs, and line of therapy. P values for the subgroup analyses were not produced or presented.

Analysis Populations

• The FAS included all patients who were randomized, analyzed according to the treatment and stratum assigned at randomization. Unless otherwise specified, this analysis set was used for the primary and all secondary end points. The FAS was also used for the patient disposition, demographics, and baseline characteristics.

• The safety set included all patients who received at least 1 dose of study treatment. Patients were analyzed according to their treatment and stratum assigned at randomization. This analysis set was used for the analysis of safety outcomes.

• The MMR responder set was a subset of the FAS and included any patient that achieved an MMR at any time on treatment. This subset was used in the analysis of time to MMR and duration of MMR.

• The CCyR analysis set was a subset of the FAS, and included patients who were not already in CCyR at baseline. This subset was used in the analysis of time to CCyR and duration of CCyR.

• The CCyR responder set included all patients from the CCyR analysis set who achieved CCyR at any time on treatment. This subset was used in the analysis of time to CCyR and duration of CCyR.

• The switch analysis set was a subset of the FAS and included patients from the bosutinib treatment group who received asciminib following discontinuation of bosutinib.

Results

Patient Disposition

In the ASCEMBL trial, a total of 319 patients were screened, of which 233 (73%) were enrolled. Full patient disposition is summarized in Table 13. Of the 157 patients who were randomized to receive asciminib, 29.3% were placed in the MCyR stratum and 70.7% were placed in the no MCyR stratum. Of the 76 patients randomized to receive bosutinib, these values were 28.9% and 71.1%, respectively. At the time of primary analysis, 61.8% of patients in the asciminib group and 28.9% of patients in the bosutinib group were receiving ongoing treatment. The most common reason for treatment discontinuation in both treatment groups was lack of efficacy (21.0% in the asciminib group and 31.6% in the bosutinib group). A lower proportion of patients in the asciminib group discontinued treatment due to AEs compared to the bosutinib group (5.1% versus 21.2%). Patient disposition was similar based on the updated January 1, 2021, data cut-off. The FAS included all 157 patients randomized to asciminib and 76 patients randomized to bosutinib. One patient randomized to asciminib developed cytopenia, did not receive any study treatment, and was therefore excluded from the safety analysis set. The mean duration of follow-up for all patients randomized at the primary analysis was 15.6 months and 23.0 months at the updated data cut-off.

Table 13: Patient Disposition

CCyR = complete cytogenetic response; FAS = full analysis set; MCyR = major cytogenetic response; MMR = major molecular response; NA = not applicable; SD = standard deviation.

^aData from the January 1, 2021, data cut-off.

Source: Asciminib Clinical Study Report.⁸

Protocol deviations at the time of the primary analysis are summarized in Table 14. Overall, deviations were more common in the asciminib group, speculated by the sponsor to be possibly due to the longer duration of treatment exposure (median = 43.4 weeks in the asciminib group versus 29.2 weeks in the bosutinib group). The most common deviations were reported within the “other” category, including visits done outside of study site due to COVID-19 (20.4% in the asciminib group versus 14.5% in the bosutinib group), stratification to the wrong randomization stratum (15.3% in the asciminib group versus 13.2% in the bosutinib group), and study procedure noncompliance (15.3% in the asciminib group versus 9.2% in the bosutinib group). Study procedure noncompliance included BMA performed despite patient being in MMR (a stipulation added in a protocol amendment after patients had been randomized), key procedures to assess eligibility assessed on the basis of local laboratory instead of central laboratory, and routine pregnancy test not performed as per protocol. A larger proportion of patients in the asciminib than the bosutinib group were enrolled despite being ineligible (15.9% versus 5.3%, respectively). A respective 8.3% versus 2.6% did not meet the exclusion criteria and 7.6% versus 2.6% did not meet the inclusion criteria.

Exposure to Study Treatments

Treatment exposure in the ASCEMBL trial is shown in Table 15. At the time of primary analysis, the mean duration of exposure for patients in the asciminib group was 49.38 (SD = 31.49) weeks and 33.66 (SD = 26.41) weeks for patients in the bosutinib group. Patients received a mean relative dose intensity of 89.1% (SD = 18.17%) in the asciminib group and 85.9% (SD = 17.61%) in the bosutinib group. At the time of the updated data cut-off. The mean duration of exposure was 68.33 (SD = 42.49) weeks in the asciminib group and 42.02 (SD = 36.52) weeks in the bosutinib group. The relative dose intensity was similar to the primary analysis.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in the following. See Appendix 3 for detailed efficacy data.

Health-Related Quality of Life

Results for HRQoL measured using the EQ-5D-5L at baseline and up to week 48. EQ VAS results are shown in Table 16. Completion of the EQ-5D-5L questionnaire at week 24 was 83.1% in the asciminib group and 82.0% in the bosutinib group. Baseline mean EQ VAS was 71.3 (SD = 21.71) in the asciminib group and 74.2 (SD = 18.79) in the bosutinib group. Mean change from baseline at week 24 was 7.5 (SD = 23.36) in the asciminib group and 0.5 (SD = 17.87) in the bosutinib group. Between-treatment differences for asciminib versus bosutinib for the EQ VAS was 2.50 (95% CI, –2.31 to 7.30). The proportion of patients reporting no problems within EQ-5D-5L domains at 24 weeks in the asciminib versus the bosutinib group, respectively, was 55.4% versus 48.0% for mobility, 74.6% versus 68.0% for self-care, 56.2% versus 48.0% for usual activities, 48.5% versus 32.0% for pain/discomfort, and 51.5% versus 44.0% for anxiety/depression.

Other indirect measures of HRQoL (including the MDASI-CML and PGIC) are presented in Appendix 3. Compliance for completing the MCASI-CML at 24 weeks was 83.1% in the asciminib group and 82.0% in the bosutinib group. Between-treatment differences for the change in severity and interference scores were –0.65 (95% CI, –1.01 to –0.29) and –0.16 (95% CI, –0.67 to 0.36), respectively. Compliance for completing the PGIC at 24 weeks was 82.3% in the asciminib group and 82.0% in the bosutinib group. Seventeen percent of patients in the asciminib group and 8.0% of those in the bosutinib group rated their overall health as very much improved.

Overall Survival

The results for OS are summarized in Table 17. At the time of primary analysis, death had occurred in 2.5% of patients in the asciminib group and 1.3% of patients in the bosutinib group. The median OS had not been reached. The 1-year Kaplan–Meier (KM) estimate of OS was 97.5% (95% CI, 92.4% to 99.2%) in the asciminib group and 98.6% (95% CI, 90.2% to 99.8%) in the bosutinib group. The OS results at the updated data cut-off were consistent with the primary analysis.

Progression-Free Survival

The results for PFS are summarized in Table 18. At the time of primary analysis, a PFS event had occurred in 4.5% of patients in the asciminib group and 6.6% of patients in the bosutinib group. The median PFS had not been reached. The 1-year KM estimate of PFS was 95.1% (95% CI, 89.2% to 97.8%) in the asciminib group and 88.6% (95% CI, 72.8% to 95.5%) in the bosutinib group. The PFS results at the updated data cut-off were consistent with the primary analysis.

MMR and Molecular Response

The results for MMR at 24 and 48 weeks are presented in Table 19. At the primary analysis, the MMR rate at 24 weeks in the asciminib group was 25.48% (95% CI, 18.87% to 33.04%) and in the bosutinib group it was 13.16% (95% CI, 6.49% to 22.87%). The unstratified difference in response rate was 12.32% (95% CI, 2.11% to 22.53%). Based on a common risk stratification of MCyR versus no MCyR at baseline, the difference in response rate based on common risk difference was 12.24% (95% CI, 2.19% to 22.30; P = 0.029). At the updated data cut-off, the MMR rate at 48 weeks was 26.11% (95% CI, 19.44% to 33.72%) in the asciminib group and 11.84% (95% CI, 5.56%, 21.29%) in the bosutinib group. The unstratified difference in response rate was 16.14% (95% CI, 5.73% to 26.55%). The common risk difference in response rate based on MCyR stratification was 16.09% (95% CI, 5.69% to 26.49%). The difference was not tested statistically.

Sensitivity analyses were consistent with the primary analysis. The common risk difference when BMA data were stratified as reported in the CRF was 11.54% (95% CI, 1.73% to 21.34%); when dealing with missing PCR evaluations without the imputation rule, the common risk difference was 12.24% (95% CI, 2.19% to 22.30%); when removing patients with a planned 24-week visit after the start of the COVID-19 pandemic, the common risk difference was 16.1% (95% CI, 4.91% to 27.36%); and when excluding patients with T315I or V299L mutation at week 1, day 1, the common risk difference was 12.43% (95% CI, 2.15% to 22.71%). These results are presented in Appendix 3. The OR of the treatment effect adjusted for MCyR at randomization only (2.35; 95% CI, 1.08 to 5.12) was consistent with the treatment effect adjusted by sex, line of therapy, and reason for discontinuation from the last TKI in addition to MCyR at randomization (2.38; 95% CI, 1.06 to 5.35) or CRF data (2.37; 95% CI, 1.04 to 5.37).

Shown in Table 20 is the distribution of patients across BCR-ABL1 ratios (IS percentage) at 24 weeks at the primary analysis and at 48 weeks at the updated data cut-off. MMR is considered as a BCR-ABL1 ratio of 0.01% or less. Within this range, at 24 weeks 8.9% of patients in the asciminib group had a BCR-ABL1 ratio of 0.0032% or lower while 1.9% had a BCR-ABL1 ratio greater than 0.0032% to 0.01% or less. The corresponding values for patients in the bosutinib group were 1.3% and 3.9%, respectively. With regards to the patients with missing data, 2.5% in the asciminib group and 5.3% in the bosutinib group were receiving treatment without treatment failure. All other patients with missing data had either failed on treatment or discontinued. The proportions of patients with MMR in each treatment group at the time of the updated data cut-off were similar to those of the primary analysis.

Preplanned exploratory subgroup analyses were conducted on the primary end point of MMR at 24 weeks, and these are summarized in Table 21. For patients in with and without MCyR at baseline, the risk differences were 27.5% (95% CI, 5.9% to 49.1%) and 6.0% (95% CI, –4.9% to 16.9%), respectively. For patients with BCR-ABL1 transcript levels of 1% or greater and less than 1% at baseline, the risk differences were 12.8% (95% CI, 2.7% to 22.9%) and –10.0% (95% CI, –64.9% to 44.9%), respectively. For patients who discontinued their prior TKI due to failure and due to intolerance, the risk differences were 15.5% (95% CI, 5.3% to 25.7%) and 2.1% (–20.8% to 25.0%), respectively. For patients who had been treated with 2, 3, or 4 or more previous TKIs, the risk differences were 12.2% (95% CI, –4.1% to 28.4%), 10.5% (95% CI, –5.3% to 26.4%), and 6.7% (95% CI, –6.0% to 19.3%), respectively. For patients with and without a BCR-ABL1 mutation at baseline, the risk differences were 10.3% (95% CI, –27.3% to 47.9%) and 13.7% (85% CI, 2.8% to 24.5%), respectively.

Hematologic Response

Hematologic response was not reported in the ASCEMBL trial.

Cytogenic Response

CcyR among patients who were not already in CcyR at baseline is summarized in Table 22. At the primary analysis, the CcyR at 24 weeks in the asciminib group was 40.78% (95% CI, 31.20% to 50.90%) and in the bosutinib group it was 24.19% (95% CI, 14.22% to 36.74%). The unstratified difference in response rate was 16.58% (95% CI, 2.31% to 30.86%). Assessed by common risk stratification of McyR versus no McyR at baseline, the common risk difference was 17.30% (95% CI, 3.62% to 30.99%). At the updated data cut-off, the CcyR rate at 48 weeks was 39.81% (95% CI, 30.29% to 49.92%) in the asciminib group and 20.97% (95% CI, 11.66% to 33.18%) in the bosutinib group. The unstratified difference in response rate was 18.84% (95% CI, 4.98% to 32.70%). The common risk difference based on McyR stratification was 19.05% (95% CI, 4.87% to 33.24%).

Duration of Response

Duration of response among patients who achieved an MMR is summarized in Table 23. At the primary analysis, loss of response occurred in 5.6% patients of the 54 patients who had achieved MMR in the asciminib group, and no patient who achieved MMR in the bosutinib group lost response. At the updated data cut-off, loss of response had occurred in 3.2% of patients achieving response while receiving asciminib and 5.6% of patients achieving response while receiving bosutinib.

Duration of response among patients who achieved a CcyR is summarized in Table 24. At the primary analysis, loss of response occurred in 2.3% patients of the 44 patients who had achieved CcyR in the asciminib group, and 5.3% of the 19 patients who achieved CcyR in the bosutinib group lost response. At the updated data cut-off, loss of response had occurred in 2.0% of patients achieving response while receiving asciminib and 4.5% of patients achieving response while receiving bosutinib.

Time to Response

Time to first MMR among patients who achieved an MMR is summarized in Table 25. At the primary analysis the mean time to MMR was 19.0 (SD = 14.40) weeks in the asciminib group and 22.8 (SD = 18.37) weeks in the bosutinib group. At the updated data cut-off, the corresponding mean time to MMR values were 24.7 (SD = 21.71) weeks in the asciminib group and 31.1 (SD = 25.81) weeks in the bosutinib group.

Time to first CcyR among patients who achieved a CcyR is summarized in Table 26. At the primary analysis the mean time to CcyR was 25.4 (SD = 5.09) weeks in the asciminib group and 29.0 (SD = 11.50) weeks in the bosutinib group. At the updated data cut-off, the corresponding mean time to CcyR values were 29.1 (SD = 13.47) weeks in the asciminib group and 31.6 (SD = 12.60) weeks in the bosutinib group.

Harms

Only those harms identified in the review protocol are reported in the following. See Table 27 for detailed harms data.

Adverse Events

At the time of primary analysis almost all patients in both treatment groups experienced treatment-emergent AEs, 89.7% in the asciminib group and 96.1% in the bosutinib group. The most common AEs in the asciminib group were thrombocytopenia (22.4% versus 13.2% in the bosutinib group), neutropenia (17.9% versus 17.1% in the bosutinib group), and headache (16.0% versus 13.2% in the bosutinib group). The most common AEs in the bosutinib group were diarrhea (71.1% versus 11.5% in the asciminib group), nausea (46.1% versus 11.5% in the asciminib group), and increased alanine aminotransferase (27.6% versus 3.8% in the asciminib group).

Serious Adverse Events

SAEs occurred in 13.5% of patients in the asciminib group and 18.4% of patients in the bosutinib group. The only SAE that occurred in more than 1 patient was pyrexia, which occurred in 1.3% of patients in the asciminib group.

Withdrawals Due to AEs

Withdrawal from study treatment due to AEs occurred in 5.8% of patients in the asciminib group and 21.1% of patients in the bosutinib group. The AE that most commonly resulted in withdrawal in the asciminib group was thrombocytopenia (5.8% of patients) and in the bosutinib group it was increased alanine aminotransferase (5.3% of patients).

Mortality

Deaths occurred in 2.6% of patients in the asciminib group and 1.3% of patients in the bosutinib group. The causes of death were arterial embolism and ischemic stroke in the asciminib group and septic shock in the bosutinib group. Two of the 4 deaths reported in the asciminib group occurred during survival follow-up and were due to underlying disease.

Notable Harms

Notable harms specified in the CADTH review protocol are included in the Table 27 summary. The largest differences between the study treatments were in hepatotoxicity, in which 8.3% of patients in the asciminib group reported AEs compared to 30.3% of patients in the bosutinib group; and in gastrointestinal toxicity, in which 31.4% of patients in the asciminib group reported AEs compared to 78.9% of patients in the bosutinib group. Pancreatic toxicity was similar between the treatment groups with 8.3% of patients in the asciminib group reporting AEs compared to 9.2% of patients in the bosutinib group.

Table 27: Summary of Harms — Safety Analysis Set

AE = adverse event; CNS = central nervous system; QTc = corrected QT; SAE = serious adverse event.

NOTE: Numbers for patients with a Grade 3 or 4 AE are based on the maximum grade experienced.

^aAEs only presented if occurring in greater than 10% of patients in either treatment group.

^bAEs only presented if occurring in more than 1 patient in either treatment group.

Source: Asciminib Clinical Study Report.⁸

Critical Appraisal

Internal Validity

ASCEMBL was a phase III, open-label RCT that evaluated asciminib in comparison to bosutinib in patients with CP-CML who had failed on or become intolerant to 2 or more prior TKI therapies. The outcomes assessed in the ASCEMBL trial (MMR, CcyR, PFS, OS, HRQoL) are standard in CML and are considered clinically meaningful. Given that ASCEMBL is an open-label trial, there is possibility for bias in favour of asciminib in the patient-reported outcomes of HRQoL, AE reporting, and general discontinuation rates between the treatment groups. However, the primary end point of MMR and key secondary end point of CCyR are objective measures and are therefore less likely to be subject to bias. There were slight differences in baseline characteristics of important prognostic factors with proportionally more patients in the bosutinib group having received higher numbers of prior TKIs and having discontinued their prior TKI due to resistance, suggesting bias in favour of asciminib; however, the sponsor did provide a logistic regression adjusting for these factors and found similar results with the primary analysis.

The statistical analysis was appropriate, although given that only the primary end point was formally tested for statistical significance there are few conclusions beyond the primary end point that can be draw. For the HRQoL and related outcomes, the lack of responsiveness and MID studies conducted in patients with CML for the EQ-5D-5L and PGIC further impacts the certainty of the conclusions. Further, none of the analyses aside from the primary end point analysis were controlled for multiplicity, so there is an increased risk of false-positive conclusions. Of the 2 data cut-offs presented, both are interim analyses, only 1 of which was preplanned. Also, survival data are immature given that so few patients had progressed or died, impacting the conclusions that can be drawn for these OS and PFS. According to the clinical experts consulted, an important predictor of treatment success is the severity of disease upon study entry. The statistical plan for the ASCEMBL trial accounted for this fact through stratification of patients based on whether they were in MCyR at baseline to ensure a common risk difference when analyzing the primary end point of the trial. Although the binary categorization of in MCyR versus not in MCyR at baseline is a rough proxy for disease severity and patient risk, MCyR can further be classified into CCyR and PCyR and an imbalanced distribution within these 2 categories could indicate an imbalanced disease severity between treatment groups even with stratification. In the asciminib group, of the patients in MCyR at baseline, 43% were in CCyR, while in the bosutinib group, of the patients in MCyR at baseline, 24% were in CCyR. This imbalance introduces bias in favour of asciminib for all outcomes that use MCyR stratification to account for common risk difference.

Furthermore, there were 22.3% of patients in the asciminib group and 11.8% of patients in the bosutinib group who had missing MCyR data at baseline, leading to 15.9% of patient receiving asciminib and 14.5% of patients receiving bosutinib assigned to the incorrect stratum. Sensitivity analysis was conducted to correct for this using BCR-ABL1 ratio as a proxy for cytogenetic response, the results of which were consistent with the primary analysis. It should be noted, however, that additional testing is not adjusted for multiplicity and should be interpreted with caution.

Patients positive for T315I and V299L mutations were excluded from the ASCEMBL trial due those mutations conferring resistance to the comparator drug bosutinib. There were, however, 3 patients in the asciminib group and 2 patients in the bosutinib group who were identified as being positive for those mutations at the first study visit post-screening. Although these are a small number of patients in each group, there would be slight bias toward asciminib given the lack of efficacy of bosutinib in these patients, although the asciminib dose received by these patients is lower than the FDA-approved dose for patients with the T315I mutation. The sponsor provided a scenario analysis excluding these patients from the analysis and showed results consistent with the primary analysis. Predefined subgroup analyses were also provided; however, these end points were exploratory and the estimates were very imprecise due to small sample sizes leading to an inability to draw conclusions.

There were protocol amendments implemented after patients had been randomized and began treatment in the ASCEMBL trial. One specifically of note was an adjustment of inclusion criteria to allow patients who were intolerant of their most recent TKI to enrol if their BCR-ABL1 ratio was greater than 0.1%. While an amendment to inclusion criteria after patients have been randomized is always a concern for internal validity, the clinical experts consulted by CADTH agreed with the provided rationale that it was important to capture the third-line intolerant population and the study was unlikely to adequately enroll patients who were intolerant with a requirement for BCR-ABL1 ratio greater than 1%.

External Validity

According to clinical experts consulted by CADTH, the demographic and disease characteristics of the ASCEMBL trial population were reflective of the Canadian population with CP-CML after 2 or more prior TKIs. According to the clinical experts, and as in most oncology trials, the enrolment criteria likely selected for a healthier cross-section of the overall patient population who were most likely to benefit from and more able to tolerate protocol therapies. This is further evidenced from the proportion of screening failures (27%), indicating the patient population was indeed a select group. Patients with the T315I or V299L mutation were excluded from the trial given that they would be unlikely to respond to bosutinib treatment; therefore, there is an evidence gap for the efficacy of asciminib in patients with these mutations.

The dosage of asciminib in the ASCEMBL trial (40 mg twice daily) represents only one of the Health Canada–approved dosages (40 mg twice daily and 80 mg once daily).¹⁷ The FDA has approved both 40 mg twice daily and 80 mg once daily dosages for the corresponding indication.¹⁶ It is unclear if the ASCEMBL trial evidence is generalizable to an 80 mg once daily dosage. The study allowed for patients to receive treatment for up to 96 weeks after the last patient received their dose or up to 48 weeks after the last patient receiving bosutinib switched to asciminib. The mean duration of follow-up at the primary analysis was 15.6 months, and at the updated data cut-off it was 23.0 months. While this does represent a reasonably long follow-up, CML is a chronic disease and patients in the third-line setting are expected to be on treatment indefinitely so long as they are experiencing treatment benefit. Therefore, the trial may not be generalizable beyond the follow-up time reported; however, the clinical experts consulted for this review do not anticipate issues with extending treatment beyond the follow-up times in the trial.

All outcomes evaluated in the trial and considered in this review (i.e., MMR, CCyR, OS, PFS, time to response, duration of response, and HRQoL) were clinically relevant, important to patients, and are used in clinical practice. The duration of follow-up was sufficient for assessment of the primary outcome of MMR at 24 weeks, CCyR, and HRQoL; however, longer-term outcomes of PFS and OS are difficult to interpret given the immaturity of the data. Subgroup analysis was not powered to detect treatment differences in patients who experienced treatment failure on their most recent TKI compared to treatment intolerance, line of therapy, disease severity at baseline, or mutational status. Nevertheless, the clinical experts consulted for this review felt that the results were generalizable across strata for all these subgroups.

Since administration of asciminib would occur mainly in the outpatient setting, background care (e.g., hematologist or oncologist visits, monitoring) would be expected to be similar for patients in Canada compared with those participating in the ASCEMBL trial.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

The objective of this section is to provide a summary and appraisal of the indirect evidence submitted by the sponsor, which included MAICs,³¹ comparing asciminib to other treatments used for patients with CP-CML who have received at least 2 prior TKI therapies.

A focused literature search for network meta-analyses that included asciminib as a comparator was run in Medline All (1946-) on February 15, 2022. No limits were applied. The literature search identified a total of 29 citations, none of which met the eligibility criteria.

Description of MAICs

The sponsor submitted a MAIC report aiming to demonstrate the efficacy of asciminib compared to relevant treatments for CP-CML following the use of at least 2 prior TKIs. The analysis used individual patient data (IPD) from the phase III trial ASCEMBL and aggregate data from published interventional and observational studies to compare efficacy outcomes for asciminib, ponatinib, nilotinib, dasatinib, and omacetaxine. Note that omacetaxine was not a comparator of interest for the current review.

Methods of the MAIC

Objectives

In the absence of direct comparative evidence from trials, the aim of each analysis was to compare the efficacy (response rate [MMR and CCyR] and TTD) of asciminib in patients with CP-CML who have received at least 2 prior TKIs versus ponatinib, nilotinib, dasatinib, and omacetaxine.

Study Selection Methods

The index trial was based on the asciminib group’s IPD from the phase III ASCEMBL trial (n = 157). To identify evidence for relevant comparators a SLR was conducted to identify evidence from interventional and observational studies. The studies identified from the SLR were further refined to fit the purposes. The refined selection criteria for inclusion in the indirect treatment comparison are summarized in Table 28. Of note, the selection criteria included interventions imatinib, omacetaxine, and hydroxycarbamide, which are not of interest to the current review and will not be commented on. Furthermore, the efficacy outcome of TTD was not of interest to the current review and will not be commented on.

A total of 2,728 citations were screened and 7 studies of interest were included for analysis in the MAIC. Presented in Table 29 are the 4 studies that were available for response rate analysis (MMR and CCyR at 6 and 12 months) along with key population characteristics.

The ASCEMBL trial was rated as having high risk for detection bias and unclear risk for performance bias according to the Cochrane Collaboration’s Risk of Bias assessment. According to the Newcastle-Ottawa quality assessment tool, the PACE trial scored a 6-star rating, Ibrahim et al. (2010) scored a 3-star rating, and Tan et al. (2019) scored a 4-star rating. Higher scores indicate lower risk of bias.

MAIC Analysis Methods

In the absence of direct trial evidence for relevant comparators or RCTs to form a connected network, an unanchored MAIC was deemed to be the only means by which to estimate relative treatment effects between asciminib and the identified relevant comparators.

Given the availability of IPD from the index trial ASCEMBL, the sponsor aimed to adjust for between-study differences in the distribution of prognostic factors and treatment effect modifiers. The sponsor extracted all characteristics reported in the included studies and consulted with an expert clinician who ranked these in priority order based on their impact on the outcomes.

Specifically for the comparison between asciminib and ponatinib, patients needed to be removed from ASCEMBL to address the difference in inclusion criteria between the studies. In ASCEMBL patients in CCyR at baseline were permitted to enrol in the study whereas in PACE, these patients were excluded. To account for this, the sponsor created 3 scenarios. Scenario 1 removed all 54 patients from ASCEMBL that were either in CCyR at baseline, or for whom CCyR data was not available at baseline. Scenario 2 removed only the 19 patients from ASCEMBL that were in CCyR at baseline. Scenario 3 removed the 24 patients from ASCEMBL that were either in CCyR at baseline or had BCR-ABL1 ratio ≤ 1% (a proxy for CCyR) at baseline. Additionally, due to PACE including patients with the T315I mutation, only the subgroup of 203 patients that were not positive for T315I were included in the analyses.

The list of factors is presented in Table 30. Of note, data on best cytogenetic response to the last TKI were not available within the ASCEMBL IPD. Furthermore, patients harbouring the T315I mutation were excluded from ASCEMBL and, therefore, adjustments were not possible for this prognostic factor. Logistic propensity score models were used to estimate weights for the IPD from ASCEMBL so that the weighted mean baseline characteristics would match those observed for the comparator trials. The remaining variables were examined to ensure that there was sufficient overlap between the populations, and to ensure that the propensity score models were numerically stable. Patient weights were analyzed to ensure that no patients were too heavily weighted, for example, although number of mutations factor was originally categorized into 0, 1, and ≥ 2, due to extreme weights in the model, this was reduced to 0 and ≥ 1. Finally, if the propensity score model did not converge using the full set of characteristics, characteristics were removed from the model in a stepwise fashion until convergence was achieved. Characteristics that were least clinically relevant or that were already well balanced between studies were removed first. Once the model had achieved convergence a further reduction of characteristics from the model was possible to achieve a balance between a large ESS and the highest number of characteristics that could be balanced in the model.

Results of MAIC

Asciminib Versus Ponatinib

The model could not converge when all prognostic factors and effect modifiers were included. To balance the largest number of matched factors, the model that was selected included age, ECOG PS, no mutation, PCyR, and 2 prior TKIs. The ESS of this selected model was 53.

Patient characteristics from the PACE trial and the ASCEMBL trial before and after applying the matching methodology are summarized in Table 31. As the characteristics of race and sex were not included in the propensity scoring model, there remained imbalances in these characteristics. The other characteristics included in the propensity score model were well matched post-weighting.

The comparison of efficacy end points MMR and CCyR at both 6 and 12 months in the patients post-MAIC from the ASCEMBL trial compared with the PACE trial is shown in Table 32. Following the MAIC, ||||||||| ||| |||||||| |||| ||||||| || ||| || ||| | ||| |||||||| ||||||||||| |||| || |||| ||| || |||| |||||| ||||| ||| |||| |||||| |||||| ||||||||||||| ||| || |||| ||| ||| |||| || ||| ||||||| ||||||||| ||| |||| |||||| ||||| ||| |||| |||||| ||||| || ||| |||||||| |||||||||.

Asciminib Versus Nilotinib and Dasatinib

For this comparison, the comparator trial Ibrahim et al. (2010) was a cohort trial of 26 patients, 20 of whom received dasatinib, 6 of whom received nilotinib. Analysis was conducted on the full cohort of combined patients. The model could not converge when all prognostic factors and effect modifiers were included. To balance the largest number of matched factors, the model that was selected included prior intolerance, prior resistance, and 2 prior TKIs. The ESS of this selected model was 35.

Patient characteristics from the Ibrahim et al. (2010) prospective cohort and the ASCEMBL trial before and after applying the matching methodology are summarized in Table 33. As the characteristics of race, sex, and proportion of patients with no mutation were not included in the propensity scoring model, there remained imbalanced in these characteristics. The other characteristics included in the propensity score model were well matched post-weighting.

The comparison of efficacy end points was only available for CCyR at both 6 and 12 months in patients post-MAIC from the ASCEMBL trial compared with the Ibrahim et al. (2010) trial. The results are shown in Table 34. Following the MAIC, ||||||||| ||| |||||||| |||| ||||||| || |||| || ||| | ||| || ||||| ||||||||||| |||| || |||| ||| || |||| |||||| |||||| ||| |||| |||||| |||||| ||||||||||||.

Asciminib Versus Dasatinib

The model could not converge when all prognostic factors and effect modifiers were included. To balance the largest number of matched factors, the model that was selected included sex, age, no mutation, nilotinib resistance, nilotinib intolerance, and 2 prior TKIs. The ESS of this selected model was 23.

Patient characteristics from the Tan et al. (2010) retrospective chart review and the ASCEMBL trial before and after applying the matching methodology are summarized in Table 35. The presented characteristics are the factors that were matched in the model; factors that could not be matched due to lack of reporting in the comparator trial are not shown. The characteristics that changed the most from pre-MAIC to post-MAIC in patients in the ASCEMBL trial ||| ||||| ||| ||||| || | |||| || |||||.

The comparison of efficacy end points was only available for MMR at 6 months in patients post-MAIC from the ASCEMBL trial compared with the Tan et al. (2019) retrospective chart review. The results are shown in Table 36. Following the MAIC, the OR for MMR at the 6-month time point was 1.40 (95% CI, 0.49 to 3.98).

Critical Appraisal of the Sponsor-Submitted MAICs

The sponsor submitted 1 MAIC report that included comparisons of interest for asciminib against ponatinib, dasatinib, and nilotinib. The choice to conduct an unanchored MAIC was justified considering the lack of a common comparator. In all cases, the ASCEMBL trial was used as the index trial. The comparator trials were identified via an SLR that identified publications that were further refined for the purposes of the MAIC analysis. Given the use of a systematic approach to identify publications, there is a low risk of selection bias.

There were important differences in the design of the comparator studies that limit the ability to draw strong conclusions about the efficacy of asciminib compared with the other treatments. ASCEMBL was a randomized phase III interventional trial, while comparator trials included observational trials such as Ibrahim et al. (2010) and Tan et al. (2019). Data analyzed in an observational fashion are prone to unique biases (e.g., selection bias, confounding) compared with those collected from prospective interventional studies (like RCTs and single-arm trials) that cannot be controlled for using MAIC methods.

The data collection period and setting of the included studies varied, with enrolment as far back as 2005, whereas the ASCEMBL trial began in 2017. Some studies recruited internationally, whereas others recruited from single nations (UK or China). There may be differences in clinical practice by region at varying time points, though the direction of potential bias is unclear.

An important limitation, inherent to all MAIC analyses, is that all prognostic factors should ideally be matched between index and comparator trials to eliminate as much bias from the comparison as possible. This includes both measured and unmeasured characteristics and thus can never be fully accounted for. The list of characteristics provided by the sponsor that were adjusted for were not informed by a systematic review of literature or clinical expert identification, rather they were chosen because they were included in the comparator trials and could be reliably calculated for patients in the ASCEMBL trial. The consulted clinical expert provided input on the ranking of the relative importance of the chosen clinical characteristics. This introduces bias and uncertainty into the results due to the potential for important prognostic factors that went unadjusted in the analysis. Furthermore, due to the instability in the propensity score model for some comparisons, as well as a lack of reporting in the comparator trials, clinical characteristics were either removed from the model to achieve convergence or could not be included in the model. Notably, these factors that could not be adjusted included the proportion of patients with T315I mutation, prior resistance or intolerance, and baseline cytogenetic response, introducing uncertainty given the lack of adjustment of these important prognostic factors. The results of the propensity score model resulted in ESS in the index trial that were significantly reduced compared to the original sample size of the ASCEMBL trial and included some patients with a weighting greater than 5, further introducing uncertainty into the reliability of the results.

There were differences in the trial inclusion criteria specifically for the asciminib versus ponatinib comparison. Because the ASCEMBL trial enrolled patients who were already in CCyR at baseline and the PACE trial did not, the ASCEMBL population was adjusted to account for difference through the removal of patients that were in CCyR at baseline as well as patients who had missing CCyR data at baseline. The sponsor provided a scenario analysis with the removal of only patients who were in CCyR at baseline; however, this analysis was conducted on the full PACE population, including patients positive for the T315I mutation, which has been acknowledged as an important prognostic factor. No scenario analysis was provided for the third scenario that excluded the patients in CCyR at baseline as well as the patients with missing CCyR data provided they showed BCR-ABL1 ratio less than1%. Given the strength of the relationship between BCR-ABL1 ratio and CCyR, this was potentially a very informative scenario analysis that was not provided, further increasing the uncertainty of the MAIC results.

The ESS for most comparisons was very small, resulted in very wide CIs and precluding the ability to draw conclusions from the data. For the comparison of nilotinib specifically, the only available trial that included response data was a retrospective trial of 26 patients, of which only 6 received nilotinib while the other 20 received dasatinib, though the issue of small ESS is present in all comparisons. As such, there is very little that can be said regarding the comparative efficacy of asciminib versus the chosen comparators with regards to response. Reporting bias may have further impacted the results given that Giles et al. (2010) does report CCyR data at the 12-month time point according to the sponsor-submitted SLR. It is unclear why this data was not considered in the submitted MAIC. Given that MAIC methodology adjusts the index trial to be more similar to the comparator trials, consideration must be given to the external validity with the target population of the index trial for which the reimbursement request is based on. Additionally, there are various outcomes such as HRQoL, PFS, and OS that could not be analyzed despite being important to patients.

Other Relevant Evidence

This section includes 2 reports of 1 submitted phase I, multicentre, open-label study provided within the sponsor’s submission to CADTH that wase considered to supplement evidence included in the systematic review. The multi-arm, dose-finding phase I trial provides long-term evidence on the safety and tolerability of asciminib as well as some preliminary evidence of long-term efficacy of asciminib in patients with CML or Ph+ acute lymphoblastic leukemia, given as single drug or in combination with either nilotinib, imatinib, or dasatinib. Though it is a multi-arm trial, CADTH will only review patients with CP-CML without the T315I mutation who received asciminib as a single drug (40 mg twice daily and 80 mg daily dosages) for the purpose of this report.³⁴

Sponsor-Submitted Phase I, Multicentre, Open-Label Study^34,35

Description of Study

The primary objective of the study was to determine the maximum tolerated dose and/or recommended dose for expansion of asciminib as a single drug or in combination with other drugs. There were 5 arms; however, for the present review CADTH will only include patients with CP-CML without the T315I mutation who received asciminib as a single drug (40 mg twice daily and 80 mg once daily dosages). Patients needed an ECOG PS of 2 or greater to be enrolled.

Patients had to be adults with CP-CML and an ECOG PS of 2 or greater and had to be previously treated with 2 or more TKIs and have relapsed, been refractory to, or intolerant of TKIs to be enrolled in the study. Among the 317 enrolled patients, 115 patients with CP-CML without the T315I mutation were treated with asciminib as a single drug. Of these, 30 patients were treated with the 40 mg twice daily dosage and 17 were treated with the 80 mg once daily dosage. Patients were treated until progression or unacceptable toxicity. The median ages of patients taking 40 mg twice daily and 80 mg once daily were 53.0 (range = 27 to 75) and 59.0 (range = 30 to 86) years, respectively. Table 37 shows the baseline characteristics and Table 38 presents the patient disposition and exposure to study treatment for these patients. The study enrolled patients who received at least 2 prior TKIs. Full details of prior treatment with TKIs and BCR-ABL1 ratio (IS percentage) categories for patients with CP-CML without the T315I mutation treated with asciminib single drug are also shown in Table 37 along with the baseline characteristics.

Outcomes of interest to this review included MMR and AEs, SAEs, withdrawals due to AEs, mortality, and notable harms up to 30 days after the last dose of asciminib. The definition of MMR was the same as in the pivotal trial.

Table 37: Baseline Characteristics of Patients in Phase I Study for Single-Drug Asciminib in CP-CML Without the T315I Mutation at Screening (FAS)

b.i.d. = twice daily; CML = chronic myeloid leukemia CP = chronic phase; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FAS = full analysis set; q.d. = once daily; SD = standard deviation; TKI = tyrosine kinase inhibitor.

Source: CABL001X2101 Clinical Study Report.³⁴

Table 38: Patient Disposition in Phase I Study for Single-Drug Asciminib in CP-CML Without the T315I Mutation at Screening (FAS)

b.i.d. = twice daily; CML = chronic myeloid leukemia CP = chronic phase; FAS = full analysis set; q.d. = once daily.

^aPatients ongoing at the time of the cut-off April 2, 2020.

Source: CABL001X2101 Clinical Study Report.³⁴

Results

Details of MMR by time point are shown in Table 40. In the 40 mg twice daily and 80 mg once daily groups, 60% and 50% patients achieved MMR, respectively. Clinically meaningful MMR rates were achieved by patients with CP-CML without the T315I mutation across all lines of therapy. The results were similar to those observed in the pivotal trial. An overview of AEs is presented in Table 49. All patients in the 40 mg twice daily (n = 30) and 80 mg once daily (n = 17) groups had AEs. SAEs were experienced among 11 (36.7%) and 8 (47.1%) patients taking 40 mg twice daily and 80 mg once daily dosages, respectively. AEs leading to dose adjustments or interruptions were observed among 14 (46.7%) and 10 (58.8%) patients taking 40 mg twice daily and 80 mg daily dosages, respectively.

Table 41 shows a summary of harms. The most common AEs observed in 40 mg twice daily dosage group were increased lipase (46.7%), fatigue (43.3%), abdominal pain (33.3%), diarrhea (30.0%), rash (30.0%), headache (26.7%), hypertension (26.7%), and arthralgia (26.7%). In 80 mg daily dosage group the most common AEs were upper respiratory tract infection (47.1%), fatigue (41.2%), headache (29.4%), hypertension (29.4%), and thrombocytopenia (29.4%). Four patients in each group (13.3% in the 40 mg twice daily dosage group and 23.5% in the 80 mg daily dosage group) stopped treatment due to AEs. Increase of lipase and amylase, pancreatitis and pancreatitis acute (1 each for asciminib 40 mg twice daily group), acute kidney injury, cardiac arrest, leukocytosis, and thrombocytosis (1 each for asciminib 80 mg daily group) were the 8 AEs for which patients stopped treatment. There was 1 death in the 80 mg daily dosage group due to cardiac arrest. Among the notable harms were myelosuppression (36.7% and 41.2%), pancreatic toxicity (53.3% and 29.4%), hepatotoxicity (including laboratory terms) (16.7% and 17.6%), gastrointestinal issues (70.0% and 52.9%), and cardiac failure (6.7% and 17.6%) for all grades in the asciminib 40 mg twice daily and 80 mg once daily groups, respectively.³⁴

Table 39: Exposure to Study Treatment — Single-Drug Asciminib in CP-CML Without the T315I Mutation at Screening (SS)

b.i.d. = twice daily; CML = chronic myeloid leukemia CP = chronic phase; q.d. = once daily; SD = standard deviation; SS = safety set.

Source: CABL001X2101 Clinical Study Report.³⁴

Table 40: MMR by Time Point — Single-Drug Asciminib in CP-CML Without the T315I Mutation and Not in MMR at Screening, MMR Evaluable (FAS)

b.i.d. = twice daily; CML = chronic myeloid leukemia CP = chronic phase; FAS = full analysis set; MMR = major molecular response; q.d. = once daily.

Source: CABL001X2101 Clinical Study Report.³⁴

Table 41: Summary of Harms

AE = adverse event; b.i.d. = twice daily; q.d. = once daily; SAE = serious adverse event.

^aReported in ≥ 10% in at least one group.

^bMyelosuppression includes erythropenia, leucopenia, thrombocytopenia, and cytopenias affecting more than 1 lineage.

Source: CABL001X2101 Clinical Study Report.³⁴

Critical Appraisal

There are several internal validity concerns that limit the certainty of conclusions that can be drawn. The primary concern is that there was no control group and no adjustment for known prognostic factors or effect modifiers; thus, causal conclusions cannot be established, and the findings are at high risk of confounding. Since the trial was open label, there is a risk that common subjective harms may have been overreported. Though the inclusion and exclusion criteria are clear, some details of the participant disposition are limited (i.e., number screened versus randomized). There was no hypothesis testing in the trial. The small sample size may negatively impact the reliability of the findings. The patients were not randomized, and there is a possibility of selection bias since it is not clear whether the patients were consecutively enrolled.

Despite some differences in setting (study sites were located in the US, Europe, Australia, Asia) than would be seen in clinical practice, the clinical experts consulted by CADTH did not express concern in generalizing the evidence to patients with CP-CML living in Canada.

Discussion

Summary of Available Evidence

The pivotal trial submitted for this review, ASCEMBL (N = 233), is a phase III, open-label, randomized study of asciminib compared to bosutinib in patients with CP-CML who had received 2 or more TKIs and experienced treatment failure on or intolerance to the most recent TKI. The primary objective of the ASCEMBL trial was to determine the efficacy of asciminib (80 mg daily) as compared to bosutinib (500 mg daily) in achieving MMR at the 24-week time point. The average age was 51 years, with 28% of patients in MCyR at baseline. Patients with the T315I and V299L mutations were excluded given the inactivity of bosutinib in that population.

The sponsor submitted a MAIC report aiming to demonstrate the efficacy of asciminib compared to relevant treatments for CP-CML following the use of 2 or more prior TKIs. The report compared IPD from the phase III ASCEMBL trial to published interventional and observational studies reporting efficacy outcomes for ponatinib, nilotinib, dasatinib, and omacetaxine. Note that omacetaxine was not a comparator of interest for the current review. To identify evidence for relevant comparators an SLR was conducted. In the absence of identified head-to-head trial evidence for relevant comparators or RCTs to form a connected network, an unanchored indirect comparison was justified as the only means by which to estimate relative treatment effects between asciminib and the identified relevant comparators. The MAICs evaluated MMR and CCyR at 6 and 12 months. The ponatinib single-arm phase II study PACE⁹ (N = 203), a nilotinib or dasatinib single-centre prospective cohort study¹⁰ (N = 26; 6 of which received nilotinib), and a dasatinib single-centre retrospective chart review¹¹ (N = 24) were used for comparisons.

The sponsor submitted a phase I, multicentre, open-label study, which provided additional evidence for the long-term safety and efficacy of asciminib in patients with CP-CML without the T315I mutation. The primary objective was to determine the maximum tolerated dose and/or recommended dose for expansion of asciminib as a single drug or in combination with other drugs.

Interpretation of Results

Efficacy

In the pivotal trial ASCEMBL, the primary end point was MMR at 24 weeks. Patients receiving asciminib had an MMR rate of 25.48%, while patients receiving bosutinib had a 13.16% response rate. This corresponds to an unstratified difference in response rate of 12.32% (95% CI, 2.11% to 33.04%). In accordance with the statistical analysis plan, the primary end point was tested with patients stratified according to baseline MCyR to account for common risk difference. The stratified difference in response was 12.24% (95% CI, 2.19% to 22.30%) with a P value of 0.029. This represents a statistically significant improvement in MMR compared to bosutinib and was noted by the clinical experts to be a clinically meaningful response. The depth of response also favoured asciminib with patients who achieved MMR in general achieving a deeper response than patients who received bosutinib. Preplanned subgroup analyses across key groups were exploratory and conclusions could not be drawn from these data. Secondary end points such as HRQoL, duration of response, and time to response favoured asciminib but were not statistically tested. CCyR results were supportive of the MMR results, though the analysis was not adjusted for multiplicity and conclusions cannot be drawn. Furthermore, we are unable to draw conclusions from immature outcomes such as OS and PFS that are nonetheless important to patients.

While there were internal validity concerns with potential bias in favour of asciminib, namely the number of patients at baseline with missing stratification data, imbalance of patients within the MCyR category across treatment groups, number of prior TKIs, and reason for discontinuation of a prior TKI, it should be noted that multiple scenario analyses were presented to address most of the internal validity concerns. These scenario analyses were not adjusted for multiplicity so conclusions should be drawn with caution; however, they do suggest that the clinically significant benefit seen with asciminib is consistent across various scenarios.

Although the pivotal trial provided a head-to-head comparison against bosutinib, to determine relative efficacy compared to other relevant comparators, indirect comparisons by way of MAICs were submitted. The uncertainty in efficacy of asciminib versus these comparators is much higher relative to the head-to-head evidence against bosutinib. There were differences in study design and differences in inclusion criteria that lead to the removal of patients from the ASCEMBL index trial, potentially introducing bias as well as reducing the generalizability of the results. An uncertain method of selecting prognostic factors to adjust for and inability to match on all factors suggests that important characteristics between trials may have impacted results, while a very small ESS introduced further uncertainty into the results through very wide CIs. Asciminib was favoured with regards to response rates against ponatinib and a population that received nilotinib or dasatinib; however, there is very high uncertainty associated with these results given the small ESS, wide CIs, and between-study differences that could not be adjusted for.

Given the stated need from clinician groups and patient groups for additional treatment options in the third line and onward for patients with CMP-CP whose disease has become resistant or who have become intolerant to previous TKI therapies, particularly with respect to the varying safety profiles of the available therapies, asciminib appears to provide a more effective option compared to bosutinib. The efficacy of asciminib versus ponatinib, dasatinib, and nilotinib, the other relevant comparators in this setting, is unclear.

Harms

In the ASCEMBL trial, asciminib appeared to be more tolerable than bosutinib. A greater proportion of patients receiving bosutinib discontinued due to an AE (21.1%) than those receiving asciminib (5.8%). Thrombocytopenia was elevated with asciminib compared to bosutinib (22% versus 13%) and gastrointestinal toxicity and hepatotoxicity were less common with asciminib versus bosutinib. The longer-term safety results from the phase I trial were consistent with the reported harms in the ASCEMBL trial. The heterogeneity in safety profiles among the TKIs used in this disease space highlight the need for options, given that certain patients may be intolerant to certain TKIs or contraindicated based on risk factors. However, there is no comparative safety evidence for asciminib against comparators other than bosutinib. The clinical experts consulted for this review felt the safety profile of asciminib in patients with CP-CML is acceptable and could be managed with appropriate supportive care, and this aligned with the perspectives of patients gathered from patient groups, which felt the side effects of asciminib were manageable and worth the potential benefit.

Conclusions

The ASCEMBL trial showed a statistically significant benefit with asciminib 80 mg daily over bosutinib 500 mg daily in MMR at 24 weeks in patients who had received 2 or more TKIs and experienced treatment failure or intolerance to the most recent TKI. In the opinion of the clinical experts consulted by CADTH, the MMR rate at 24 weeks represents a clinically significant benefit for asciminib over bosutinib. Secondary end points, such as HRQoL, duration of response, and time to response, favoured asciminib but were not statistically tested; therefore, few conclusions can be drawn. CCyR results were supportive of the MMR results, though the analysis was not adjusted for multiplicity. Data on OS and PFS were immature at the time of analysis. The submitted MAIC provided indirect evidence for relative efficacy for asciminib compared to ponatinib, dasatinib, and nilotinib, but the significant limitations with the analysis prohibit any conclusions from being drawn. Asciminib appears to be more tolerable than bosutinib, though comparative safety evidence against other relevant comparators is lacking.

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