Indication: In combination with bevacizumab, for the treatment of adult patients with metastatic colorectal cancer who have previously been treated with, or are not candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF biological agents, and, if RAS wild-type, anti-EGFR agents
Sponsor: Taiho Pharma Canada, Inc.
Final recommendation: Reimburse with conditions
Summary
What Is the CADTH Reimbursement Recommendation for Lonsurf?
CADTH recommends that Lonsurf be reimbursed by public drug plans in combination with bevacizumab for the treatment of metastatic colorectal cancer (mCRC) in adults who have been previously treated with or are not candidates for available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti–vascular endothelial growth factor (anti-VEGF) biological agents, and, if positive for RAS wild-type disease, anti–epidermal growth factor receptor (anti-EGFR) agents if certain conditions are met.
Which Patients Are Eligible for Coverage?
Lonsurf should be covered for use in adults with histologically confirmed adenocarcinoma that cannot be surgically removed or has spread to other parts of the body and if the patient’s disease progressed or the patient experienced intolerance to a maximum of 2 prior chemotherapy regimens. Eligible patients should have good overall health (performance status) and no unstable neurologic issues related to the central nervous system (CNS) or need increasing doses of steroids to control CNS disease.
What Are the Conditions for Reimbursement?
Lonsurf should be reimbursed in combination with bevacizumab. It should be prescribed by doctors who specialize in diagnosing and treating patients with mCRC. Lonsurf plus bevacizumab should be stopped if the disease worsens or the patient has severe side effects. The cost of Lonsurf should be reduced.
Why Did CADTH Make This Recommendation?
Evidence from a clinical trial demonstrated that Lonsurf plus bevacizumab compared with Lonsurf alone resulted in a clinically meaningful and statistically significant improvement in overall survival (OS) and progression-free survival (PFS).
The results from an indirect treatment comparison suggested that Lonsurf plus bevacizumab was better than the best supportive care in improving OS and PFS. However, the clinical benefit of the evidence is uncertain.
Lonsurf plus bevacizumab met some needs identified by patients, including extending life with manageable treatment side effects.
The CADTH economic assessment found that Lonsurf plus bevacizumab does not provide good value for the health care system at the public list price. Therefore, a price reduction is required for both Lonsurf and bevacizumab.
Based on public list prices, the estimated cost of Lonsurf plus bevacizumab for the public drug plans over the next 3 years is approximately $111 million. However, the actual budget impact is uncertain.
Additional Information
What Is Colorectal Cancer?
Colorectal cancer (CRC) is a type of cancer that begins in the lining of the rectum or colon as abnormal growths called polyps, which can eventually turn cancerous. When the cancer spreads to other parts of the body, such as the liver, lungs, and lymph nodes, it is called mCRC. Symptoms of CRC vary based on where the tumour is located and may include pain, rectal bleeding, and bowel problems.
Unmet Needs in mCRC
Currently, patients with mCRC who do not respond well to treatment or whose disease becomes worse after second-line anticancer therapy do not have many treatment options. New treatments for these patients that work effectively while causing minimal side effects are needed.
How Much Does Lonsurf Cost?
Treatment with Lonsurf plus bevacizumab is expected to cost approximately $7,488 per 28-day cycle.
The CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that trifluridine-tipiracil plus bevacizumab be reimbursed for the treatment of mCRC in adults who have been previously treated with, or are not candidates for, available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF biological agents, and, if positive for RAS wild-type disease, anti-EGFR agents, only if the conditions listed in Table 1 are met.
One phase III, open-label, multicentre trial (SUNLIGHT; N = 492) demonstrated that treatment with trifluridine-tipiracil plus bevacizumab resulted in longer survival in adults with advanced mCRC who had received up to 2 previous chemotherapy regimens and demonstrated progressive disease or intolerance to their last regimen compared with trifluridine-tipiracil alone. Specifically, trifluridine-tipiracil plus bevacizumab led to a clinically meaningful and statistically significant improvement in OS and PFS benefit compared with trifluridine-tipiracil alone. After a median follow-up of 14.2 months (interquartile range, 12.6 to 16.4), the median OS in patients treated with trifluridine-tipiracil plus bevacizumab was 10.78 months (95% confidence interval [CI], 9.36 to 11.83) versus 7.46 months (95% CI, 6.34 to 8.57) in patients treated with trifluridine-tipiracil alone, hazard ratio (HR) = 0.61 (95% CI, 0.49 to 0.77; P < 0.001). The median PFS was 5.55 months (95% CI, 4.50 to 5.88) versus 2.4 months (95% CI, 2.07 to 3.22) in the groups treated with trifluridine-tipiracil plus bevacizumab versus trifluridine-tipiracil alone, respectively, HR = 0.44 (95% CI, 0.36 to 0.54; P < 0. 001). In addition, the safety profile of trifluridine-tipiracil plus bevacizumab was consistent with the known safety profile of trifluridine-tipiracil alone and was considered manageable.
pERC noted a lack of relevant direct comparative evidence given that the comparator in the SUNLIGHT trial (trifluridine-tipiracil alone) is not publicly funded in Canada. Therefore, the committee considered the results of a sponsor-submitted indirect treatment comparison (ITC) comparing trifluridine-tipiracil plus bevacizumab with best supportive care (BSC). pERC determined that notwithstanding the limitations of the ITC (mainly due to the heterogeneity of the included studies), the results suggest that OS and PFS outcomes with trifluridine-tipiracil plus bevacizumab were better than with BSC, recognizing the uncertainty of the magnitude of the clinical benefit when comparing with BSC.
pERC concluded that trifluridine-tipiracil plus bevacizumab met some of the needs identified by patients who have exhausted other publicly funded therapies, such as prolonging life while having manageable treatment side effects.
The committee considered the cost-effectiveness of trifluridine-tipiracil plus bevacizumab relative to BSC based on data from a sponsor-submitted ITC. Using the sponsor-submitted price for trifluridine-tipiracil plus bevacizumab and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio for trifluridine-tipiracil plus bevacizumab was estimated to be $195,000 per quality-adjusted life-year compared with BSC. Given the cost of the combination treatment ($7,488 per 28 days), the duration of treatment with trifluridine-tipiracil plus bevacizumab in the CADTH reanalysis, and the lack of robust evidence to support a postprogression survival benefit, there are no price reductions for trifluridine-tipiracil where a $50,000 per quality-adjusted life-year gained threshold could be achieved for the combination regimen.
Table 1: Reimbursement Conditions and Reasons
Reimbursement condition | Reason | Implementation guidance |
|---|---|---|
Initiation | ||
1. Adults with all of the following: 1.1. histologically confirmed adenocarcinoma with either unresectable or metastatic disease 1.2. disease progression or demonstrated intolerance to a maximum of 2 prior chemotherapy regimens for the treatment of advanced colorectal cancer. 1.2.1. Prior treatment must include fluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody and/or an anti-EGFR monoclonal antibody for RAS wild-type disease. 1.2.2. Patients who had received adjuvant/neoadjuvant chemotherapy and had recurrence during or within 6 months of completion could count the adjuvant/neoadjuvant therapy as 1 of the maximum of 2 required prior chemotherapy regimens to qualify. | Evidence from the pivotal SUNLIGHT trial showed that treatment with trifluridine-tipiracil plus bevacizumab resulted in OS and PFS benefits in patients with these characteristics. Prior treatment defined in this condition reflects patients’ experience in the SUNLIGHT trial and is aligned with how patients are treated in clinical practice in Canada. | For condition 1.2, pERC acknowledged that clinicians and patients may want access to trifluridine-tipiracil plus bevacizumab for use in the third-line setting and beyond. For condition 1.2.1, patients would be eligible for trifluridine-tipiracil plus bevacizumab regardless of prior bevacizumab exposure. |
2. Patients should have good performance status. | Patients with an ECOG Performance Status of 0 or 1 were included in the SUNLIGHT trial. | Treating patients with an ECOG Performance Status greater than 1 may be at the discretion of the treating clinician. |
3. Treatment with trifluridine-tipiracil plus bevacizumab should not be reimbursed in patients: 3.1. with symptomatic CNS metastases that are neurologically unstable, and/or 3.2. those requiring increasing doses of steroids to control CNS disease. | Patients with these conditions were excluded from the pivotal SUNLIGHT trial. Therefore, no evidence was reviewed regarding the safety and efficacy of trifluridine-tipiracil plus bevacizumab in these patients. | — |
Discontinuation | ||
4. Treatment with trifluridine-tipiracil plus bevacizumab should be discontinued upon the occurrence of any of the following: 4.1. disease progression (clinical or radiological) 4.2. intolerable toxicity. | In the SUNLIGHT trial, treatment was discontinued in patients who exhibited radiologic progressive disease, clinical progression, or unacceptable toxicity, whichever occurred first. Based on input from clinical experts, this is aligned with clinical practice. | — |
Prescribing | ||
5. The trifluridine-tipiracil plus bevacizumab regimen should only be prescribed by a clinician with expertise in the diagnosis and management of patients with mCRC. | This is intended to ensure that the treatment is prescribed only for appropriate patients and adverse effects are managed in an optimized and timely manner. | — |
6. Trifluridine-tipiracil plus bevacizumab should not be used with other systemic therapy. | No evidence was reviewed to demonstrate that trifluridine-tipiracil plus bevacizumab would result in additional benefits when used in addition to other systemic cancer therapy. | — |
Pricing | ||
7. A reduction in price | The ICER for trifluridine-tipiracil plus bevacizumab is $195,000 when compared with BSC. Given the cost ($7,488 per 28 days) and the duration of treatment for the combination regimen, and the lack of robust evidence to support a postprogression survival benefit, the CADTH reanalysis showed that there are no price reductions for trifluridine-tipiracil where a $50,000 per QALY gained threshold could be achieved for the combination regimen. If a price reduction is applied to both drugs within the combination regimen, a price reduction of at least 77% (i.e., a price reduction of at least 77% for trifluridine-tipiracil and a price reduction of at least 77% for bevacizumab) would be required to achieve an ICER of $50,000 per QALY gained compared to BSC. | — |
Feasibility of adoption | ||
8. The feasibility of adoption of trifluridine-tipiracil plus bevacizumab must be addressed. | At the submitted price, the incremental budget impact of trifluridine-tipiracil plus bevacizumab is expected to be greater than $40 million in year 3. At the submitted price, the magnitude of uncertainty in the budget impact must be addressed to ensure the feasibility of adoption, as CADTH reanalysis was not possible. | — |
BSC = best supportive care; CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; ICER = incremental cost-effectiveness ratio; mCRC = metastatic colorectal cancer; OS = overall survival; PFS = progression-free survival; QALY = quality-adjusted life-year; VEGF = vascular endothelial growth factor.
pERC acknowledged the need for a new treatment option for patients with mCRC who experience disease progression after second-line therapy. pERC noted that currently available treatment options are limited for this patient population and that these therapies have limited efficacy with considerable toxicity. Based on the evidence reviewed, trifluridine-tipiracil plus bevacizumab fills a current treatment gap.
pERC deliberated health-related quality of life (HRQoL) outcomes from the SUNLIGHT trial, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and 5-Level EQ-5D (EQ-5D-5L) scales. The committee noted that the uncertainty in the outcomes of some of the assessed domains precludes a definitive conclusion about the HRQoL benefit with trifluridine-tipiracil plus bevacizumab compared with trifluridine-tipiracil alone.
pERC noted that in the SUNLIGHT trial, some patients (29% of patients in the combination group and 20% in the trifluridine-tipiracil alone group) received concomitant granulocyte-colony stimulating factor as prophylaxis and to manage neutropenia. The committee discussed the existing variability in provincial funding of growth factors in the palliative setting and suggested that public plans consider making granulocyte-colony stimulating factor available to support all patients eligible for trifluridine-tipiracil plus bevacizumab.
pERC discussed the potential size of the budget impact associated with the introduction of trifluridine-tipiracil plus bevacizumab. The committee noted that the sponsor’s estimated 3-year budget impact of $110,993,278 was associated with uncertainty. Inputs such as duration of treatment, market size, and the proportion of the population eligible for public coverage affect the estimated budget impact. pERC noted that price negotiations and implementation of discontinuation criteria could assist in reducing the budget impact.
CRC collectively refers to malignant tumours that develop in the epithelial lining of the rectum or colon from polyps that progress into cancer. CRC is the third most prevalent cancer and the second leading cause of cancer-related death (11% of all cancer deaths) in Canada. It was estimated that, in 2018, the Canadian (excluding Quebec) 10-year prevalence of CRC in both sexes of all ages is 343.5 cases per 100,000 (or 97,755 cases). mCRC indicates that the cancer has spread beyond the primary tumour site to other organs of the body (i.e., stage IV disease), where the most common location of metastases are the liver, lung, peritoneum, and distant lymph nodes. The stage of CRC at diagnosis is strongly associated with survival. Patients with early CRC are usually asymptomatic, whereas patients with advanced disease experience varying symptoms depending on the location of metastasis, including upper-right quadrant pain, abdominal distention, early satiety, supraclavicular adenopathy, and periumbilical nodules. Right-sided (proximal) tumours rarely present with obvious rectal bleeding as the blood becomes admixed with the stool. Left-sided (distal) tumours are more likely to present with bright red rectal bleeding and symptoms of bowel obstruction. The majority of patients with mCRC have unresectable (inoperable) disease for which the mainstay of treatment is systemic multidrug chemotherapy. Choice of treatment is dependent on a number of factors, including a patient’s fitness (e.g., performance status), organ function, and comorbidities, in addition to the tumour(s) characteristics (e.g., tumour location [right versus left], presence of primary tumour, mutation status for RAS and BRAF, presence of deficient mismatch repair [dMMR]/microsatellite instability-high [MSI-H]), type and timing of prior therapy, and toxicity profiles of constituent drugs. Trifluridine-tipiracil (Lonsurf) and regorafenib (Stivarga) are approved in Canada for the treatment of patients who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF biological agents, and, if positive for RAS wild-type disease, anti-EGFR agents; however, these treatments are not publicly funded in Canada (except in Quebec). Following treatment with standard cytotoxic chemotherapy backbone regimens, patients are usually treated with BSC.
Trifluridine-tipiracil plus bevacizumab for the treatment of mCRC in adults who have been previously treated with, or are not candidates for, available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF biological agents, and, if positive for RAS wild-type disease, anti-EGFR agents, is an unlabelled indication. It is available as a 35 mg/m2 dose oral tablet and the dosage recommended in the product monograph is twice daily on days 1 to 5 and days 8 to 12 of each 28-day cycle, repeated every 4 weeks, plus bevacizumab.
To make its recommendation, the committee considered the following information:
a review of 1 randomized controlled trial (RCT) in adults with mCRC who have been previously treated with, or are not candidates for, available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF biological agents, and, if positive for RAS wild-type disease, anti-EGFR agents
patients’ perspectives gathered by 2 patient groups, Colorectal Cancer Resource & Action Network (CCRAN) and Colorectal Cancer Canada
input from the public drug plans and cancer agencies that participate in the CADTH review process
input from 2 clinical specialists with expertise diagnosing and treating patients with mCRC
input from 2 clinician groups, the Canadian Gastrointestinal Oncology Evidence Network (CGOEN) with the Medical Advisory Board of Colorectal Cancer Canada (and other Colorectal Cancer Canada–treating physicians) and Ontario Health (Cancer Care Ontario) Gastrointestinal Cancer Drug Advisory Committee (OH-CCO)
a review of the pharmacoeconomic model and report and ITC submitted by the sponsor.
The information in this section is a summary of input provided by the patient and clinician groups that responded to CADTH’s call for input and from the clinical experts consulted by CADTH for the purpose of this review.
CADTH received 2 patient group submissions from CCRAN and Colorectal Cancer Canada. CCRAN used a multifaceted outreach approach by emailing clinicians who treat advanced colorectal cancer to help recruit patients or caregivers with experience with Lonsurf (plus bevacizumab) and via an online survey of patients’ experience of mCRC and prior drug therapies, which resulted in 77 survey respondents (including 60 patients, 13 caregivers, and 4 patients who were also caregivers). Colorectal Cancer Canada conducted an online survey of 23 respondents (22 patients and 1 caregiver). Most patients reported that fatigue and weakness; bloody stools; diarrhea; and abdominal cramping, gas, and feeling bloated; and abdominal pain are common symptoms they experienced and that they felt were important to control. Symptoms of CRC affected the quality of life for patients and their families, limiting the patients’ ability to work, exercise, participate in social activities, and perform daily tasks. According to both patient groups, it is very important for a new therapy to bring about improvements to patients’ physical condition (e.g., tumour shrinkage, tumour stability, reduced pain, and improved breathing) and quality of life (e.g., improved mobility, improved sense of wellness, relief from side effects). Patients would take a new therapy to bring about improvement in their quality of life even if it does not extend OS (e.g., at a modest 3 months to 4 months of survival, 53% of respondents were willing to tolerate significant side effects, including nausea, anemia, and neutropenia). Moreover, patients prefer a drug therapy that is convenient (e.g., orally administered, either at home or with a short infusion duration and/or chair time at a cancer centre). CCRAN believes that if publicly funded, trifluridine-tipiracil plus bevacizumab would be an extremely important third-line and beyond therapy for patients whose disease has been deemed to be refractory or ineligible for standard of care therapies. Colorectal Cancer Canada noted that given that Lonsurf alone is currently reimbursed only in Quebec, there is a strong need for equity of access for patients located elsewhere in Canada. Both patient groups strongly agreed that trifluridine-tipiracil aligns well with the identified patient and caregiver need for a new, effective treatment option that is capable of prolonging life and maintaining quality of life.
Two clinical experts with expertise in the diagnosis and management of mCRC reported that the cornerstone of treatment for patients with mCRC involves sequential use of the best available systemic therapies. Standard of care (SOC) first-line treatment in Canada includes pembrolizumab immunotherapy (for patients with dMMR/MSI-H mCRC); chemotherapy with a regimen of infusional 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) or a regimen of infusional 5-fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus an EGFR inhibitor (for patients with left-sided, extended RAS wild-type CRC); and, chemotherapy with FOLFOX or FOLFIRI plus bevacizumab (for patients with right-sided or extended RAS mCRC). Patients who progress on or within 6 months of adjuvant therapy (e.g., cancer growth while on adjuvant therapy or within 6 months of adjuvant FOLFOX) would be considered to experience progression on first-line treatment. Following disease progression on first-line therapy, the clinical experts consulted by CADTH indicated that SOC second-line systemic treatment in Canada includes encorafenib plus cetuximab (for patients with BRAF V600E mutations) or switching of the backbone chemotherapeutic regimen (for patients without BRAF V600E mutation) such that patients who were initially treated with FOLFOX would then be switched to FOLFIRI, for example. Antiangiogenic therapies added to the chemotherapy backbone (e.g., bevacizumab, aflibercept, ramucirumab) for patients without BRAF V600E mutation or dual immunotherapy (e.g., nivolumab plus ipilimumab) for patients with the MMR deficient and MSI-high molecular marker, are routinely offered to patients with colorectal cancer and recommended in guidelines for CRC, according to the clinical experts consulted by CADTH. The clinical experts consulted by CADTH noted that following disease progression on 2 lines of prior therapy, a single-agent EGFR inhibitor (cetuximab or panitumumab) or cetuximab plus irinotecan as SOC treatment in Canada is an option for patients with the extended RAS wild-type marker, whereas regorafenib monotherapy or trifluridine-tipiracil is SOC in Canada for patients without the extended RAS wild-type marker (among patients with access through private insurance or out-of-pocket payment). Importantly, there exists a significant unmet need for effective treatment options for patients with mCRC who experience disease progression following 2 lines of anticancer therapy, according to the clinical experts consulted by CADTH.
The clinical experts consulted by CADTH considered trifluridine-tipiracil plus bevacizumab to represent a new SOC treatment for patients with unresectable CRC after progression on 2 prior lines of anticancer therapy. According to the clinical experts consulted by CADTH, eligible patients should be able to tolerate both trifluridine-tipiracil (i.e., able to safely swallow pills; have normal bowel transit; have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1; and have adequate hematologic, hepatic, and renal function) and bevacizumab (i.e., without absolute contraindication to use of a VEGF inhibitor, included but not limited to uncontrolled hypertension, in situ colonic stent, recent surgery, high risk for bleeding, risk for or presence of fistula or gastrointestinal tract perforation). The clinical experts consulted by CADTH outlined the following hierarchy for determining treatment response: first, patient-reported symptoms or side effects, as determined by clinician assessment of patient treatment history; second, examination and selective use of clinical instruments to evaluate symptoms (e.g., Edmonton Symptoms Assessment System, EQ-5D); and third, cross-sectional imaging (e.g., CT scan, MRI) and tumour markers (e.g., CEA and CA 19-9). Patients should be assessed after every 2 to 3 cycles of treatment (and more frequently with bothersome symptoms or adverse events [AEs]), with tumour markers completed at least once every 4 weeks and CT scans conducted every 2 to 3 months, according to the clinical experts consulted by CADTH. These experts highlighted OS, symptom control, and quality of life as clinically meaningful end points. Side effects or toxicity were key determinants for discontinuing treatment with trifluridine-tipiracil plus bevacizumab, according to the clinical experts consulted by CADTH, particularly for discontinuing bevacizumab in the event of development of an absolute contraindication to further therapy with a VEGF inhibitor. The clinical experts consulted by CADTH highlighted the importance of shared and fully informed decision-making with patients that includes discussions regarding treatment effectiveness and symptoms or AEs that significantly impact quality of life.
CADTH received 2 clinician group submissions from CGOEN with the Medical Advisory Board of Colorectal Cancer Canada (and other CCC-treating physicians) and OH-CCO. CGOEN gathered data and information based on personal experience in treating patients with mCRC and expert evidence-based reviews by gastrointestinal cancer specialists in Canada of the following information presented at international oncology meetings, and subsequently published in the New England Journal of Medicine, and OH-CCO’s Drug Advisory Committees gathered information through videoconferencing and email communication. Both clinician groups highlighted that trifluridine-tipiracil would be placed as a further line of therapy and would be used in patients who received current SOC options and have experienced disease progression or intolerance, or chose to stop for personal reasons. This combination would also be used for those with medical contraindications to earlier line SOC therapies. CGOEN stated that trifluridine-tipiracil is currently Health Canada–approved but received a do not reimburse recommendation from CADTH in August 2019 because the magnitude of benefit was felt to be too small to warrant approval, despite being recognized as addressing the needs of a population with unmet need. It is currently funded in Quebec, having received a reimburse recommendation from Institut national d'excellence en santé et services sociaux (INESSS). Outside of Quebec, patients have been able to apply to the manufacturer for access to the drug under review through private insurance or direct user pay. Therefore, the majority of patients with mCRC in Canada do not have access to publicly funded trifluridine-tipiracil according to CGOEN. OH-CCO’s Drug Advisory Committees also echoed this concern highlighted by CGOEN; therefore, CGOEN felt that findings from the original trial of trifluridine-tipiracil alone compared to BSC should be considered in the current review of trifluridine-tipiracil plus bevacizumab given the current landscape in Canada.
The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug programs.
Table 2: Responses to Questions From the Drug Programs
Drug program implementation questions | Response |
|---|---|
Relevant comparators | |
The SUNLIGHT trial compared trifluridine-tipiracil plus bevacizumab against trifluridine-tipiracil, which is not funded. The comparator of trifluridine-tipiracil received a do not reimburse recommendation from pCODR in 2018 and 2019 in which PAG input noted the trifluridine-tipiracil had very modest overall survival (1.8 months), short PFS (incremental 0.3 months PFS), low objective response rates, and occurrence of serious side effects. Regorafenib is indicated in the same group of patients and pERC did not recommend funding regorafenib as it had only a very modest PFS and overall survival benefit, moderate but not insignificant toxicities, and a similar decline in the quality of life. | The clinical experts consulted by CADTH acknowledged that if trifluridine-tipiracil plus bevacizumab were to be recommended for reimbursement, it would replace trifluridine-tipiracil as well as regorafenib. pERC agreed with the clinical experts that if trifluridine-tipiracil plus bevacizumab were to be reimbursed, it would replace trifluridine-tipiracil as well as regorafenib, which are not currently publicly reimbursed. Regorafenib may still be available through private payers. pERC noted that for trifluridine-tipiracil plus bevacizumab to be successfully implemented, it is recommended that the drug plans consider aligning the timing of access to both the oral and IV components of the regimen. |
Generalizability | |
Should trifluridine-tipiracil bevacizumab be used in patients with
| The clinical experts consulted by CADTH anticipated that trifluridine-tipiracil plus bevacizumab would be used in patients with small bowel or appendiceal adenocarcinoma based on extrapolation of findings from the SUNLIGHT trial, as they represent a very small number of patients, and therefore precludes a randomized trial exclusively in this subpopulation. The clinical experts consulted by CADTH commented that the ECOG is subjective, and for patients who have exhausted all previous lines of therapy and are highly motivated, their oncologist would likely advocate for them to access trifluridine-tipiracil plus bevacizumab, as long as they are otherwise eligible (e.g., criteria for laboratory assessments are met). For patients with MSI-H/dMMR or with BRAF V600E mutation, the clinical experts reiterated that they would be considered eligible for treatment with trifluridine-tipiracil plus bevacizumab if all other lines of therapy have been exhausted. In the SUNLIGHT enrolled population (N = 492), there were 21 (6.8%) patients with MSI-H/dMMR and 19 (5.6%) patients with a BRAF mutation. pERC agreed with the clinical experts that patients with small bowel or appendiceal adenocarcinoma, ECOG PS > 1, MSI-H/dMMR, and BRAF V600E mutation would be considered eligible for treatment with trifluridine-tipiracil plus bevacizumab if all other lines of therapy have been exhausted. |
Funding algorithm | |
Trifluridine-tipiracil plus bevacizumab may change place in therapy of drugs reimbursed in subsequent lines. | The clinical experts consulted by CADTH reported that patients with advanced metastatic colorectal have limited treatment options after they have exhausted all prior lines of therapy. For patients who currently have access to trifluridine-tipiracil (alone) or regorafenib, the clinical experts consulted by CADTH remarked that trifluridine-tipiracil plus bevacizumab may replace either drug as the last line of therapy. The clinical experts consulted by CADTH agreed with the sponsor’s proposed place in therapy for trifluridine-tipiracil plus bevacizumab to replace BSC as a new treatment option. pERC agreed with the clinical experts that if trifluridine-tipiracil plus bevacizumab were to be reimbursed, it would replace trifluridine-tipiracil as well as regorafenib, which would remain available privately. pERC acknowledged that clinicians and patients may want access to trifluridine-tipiracil plus bevacizumab for use in the third-line setting and beyond. |
Care provision issues | |
If bevacizumab is discontinued for reasons other than disease progression, can trifluridine-tipiracil be continued as monotherapy and vice-versa? This is a key question as trifluridine-tipiracil alone received 2 do not reimburse pCODR recommendations on July 6, 2018, and August 29, 2019. | pERC agreed with the clinical experts that trifluridine-tipiracil alone (without bevacizumab) could be continued in patients who develop contraindication to bevacizumab. pERC would not recommend using bevacizumab alone if trifluridine-tipiracil is discontinued. |
System and economic issues | |
There are confidential negotiated prices for panitumumab, bevacizumab, pembrolizumab, and encorafenib. | This is a comment from the drug plans to inform pERC deliberations. |
In Canada, bevacizumab is available as a biosimilar. Therefore, for this indication, bevacizumab plus trifluridine-tipiracil will be using a biosimilar bevacizumab as well. | pERC acknowledged the drug plan’s intentions to use biosimilar bevacizumab. |
BSC = best supportive care; dMMR = deficient mismatch repair; ECOG PS = Eastern Cooperative Oncology Group Performance Status; MSI-H = microsatellite instability-high; PAG = Provincial Advisory Group; pCODR = pan-Canadian Oncology Drug Review; PFS = progression-free survival.
One randomized, phase III, open-label, multicentre study (SUNLIGHT) evaluated the efficacy and safety of trifluridine-tipiracil plus bevacizumab versus trifluridine-tipiracil alone. The SUNLIGHT trial enrolled 492 adults with advanced mCRC who had received up to 2 previous chemotherapy regimens and demonstrated progressive disease or intolerance to their last regimen, and randomized patients to each group with stratification by geographic region (North America, European Union, rest of the world), time since first metastasis diagnosis (< 18 months and ≥ 18 months), and RAS status (wild type or mutant). The primary objective of the SUNLIGHT trial was to demonstrate superiority of OS and the key secondary objective was to estimate investigator-assessed PFS. Additional secondary end points included HRQoL (assessed with the EORTC QLQ-C30 and EQ-5D-5L) and treatment-emergent adverse events (TEAEs).
Patients had a mean age of 61.7 years (standard deviation [SD] = 11.1) and most were enrolled from the European Union (64.0%). Most patients had a primary diagnosis of colon cancer (73%), stage IV disease (66%), and primary tumour located on the left side (72%). The time from the diagnosis of the first metastasis until randomization was 18 months or longer in 57.5% of the patients, and 30.7% had RAS wild-type disease. Most patients (92.1%) had received 2 previous treatment regimens for metastatic disease, 2.6% had more than 2 prior regimens, and 5.3% had received 1 previous treatment regimen. All patients had received previous fluoropyrimidine-based therapy, 72.0% had received previous anti-VEGF therapy (47.8% had received bevacizumab as part of their first regimen, 43.9% as part of their second regimen, and 20.3% as part of both their first and second regimens), and 93.7% of the patients with RAS wild-type disease had received previous anti-EGFR therapy. Demographic characteristics were generally similar between trifluridine-tipiracil plus bevacizumab and trifluridine-tipiracil alone, with notable (> 5%) between-group differences for patients aged 65 years and older (41% versus 48%, respectively), primary tumour located on the right side (25% versus 31%, respectively), and primary tumour located on the left side (75% versus 69%, respectively).
The key efficacy results from the SUNLIGHT trial are summarized, based on the data cut-off date of July 5, 2022, for clinical (nonsurvival) data and July 19, 2022, for survival data.
At the survival cut-off date of July 19, 2022, the median follow-up was 14.2 months (interquartile range, 12.6 to 16.4) in the trifluridine-tipiracil plus bevacizumab group and 13.6 months (interquartile range, 12.7 to 15.9) in the trifluridine-tipiracil alone group. OS at 6 months among patients in the full analysis set (FAS) population was 0.77 (95% CI, 0.72 to 0.82) and 0.61 (95% CI, 0.55 to 0.67) for trifluridine-tipiracil plus bevacizumab and trifluridine-tipiracil alone, respectively. OS at 12 months was 0.43 (95% CI, 0.36 to 0.49) and 0.30 (95% CI, 0.24 to 0.36) for trifluridine-tipiracil plus bevacizumab and trifluridine-tipiracil alone, respectively. The median OS was 10.78 months (95% CI, 9.36 to 11.83) in the trifluridine-tipiracil plus bevacizumab group and 7.46 months (95% CI, 6.34 to 8.57) in the trifluridine-tipiracil alone group. The HR in the FAS population was 0.61 (95% CI, 0.49 to 0.77; P < 0.001) for trifluridine-tipiracil plus bevacizumab when compared with trifluridine-tipiracil alone.
The PFS at 3 months among patients in the FAS population was 0.73 (95% CI, 0.67 to 0.78) in the trifluridine-tipiracil plus bevacizumab group versus 0.45 (95% CI, 0.39 to 0.51) in the trifluridine-tipiracil alone group. PFS at 6 months was 0.43 (95% CI, 0.37 to 0.49) and 0.16 (95% CI, 0.11 to 0.21) for trifluridine-tipiracil plus bevacizumab and trifluridine-tipiracil alone, respectively. Median PFS was 5.6 months (95% CI, 4.50 to 5.88) in the trifluridine-tipiracil plus bevacizumab group and 2.4 months (95% CI, 2.07 to 3.22) in the trifluridine-tipiracil alone group. The HR for PFS was 0.44 (95% CI, 0.36 to 0.54; P < 0.001) for trifluridine-tipiracil plus bevacizumab when compared with trifluridine-tipiracil alone.
In the SUNLIGHT trial, analyses for the EORTC QLQ-C30 and EQ-5D-5L were performed in patients from the FAS with at least 1 questionnaire item at baseline and during the study period. Higher scores in the EORTC QLQ-C30 Global Health Status and EQ-5D- 5L utility and EQ visual analogue scale (VAS) indicated better HRQoL, with positive change from baseline indicating benefit and negative change from baseline indicating deterioration.
In the EORTC QLQ-C30 Global Health Status score, the least squares mean (LSM) change from baseline was –2.85 (95% CI, –5.92 to 0.22) for trifluridine-tipiracil plus bevacizumab and –6.62 (95% CI, –10.36 to –2.88) for trifluridine-tipiracil alone. The LSM difference in change from baseline for Global Health Status was 3.77 (95% CI, 0.22 to 7.32; P = 0.038) in favour of trifluridine-tipiracil plus bevacizumab. The number of patients in the FAS population with 10 points or greater definitive deterioration were 62 (25.2%) and 72 (29.3%) in the trifluridine-tipiracil plus bevacizumab and trifluridine-tipiracil alone group, respectively. Median time until definitive deterioration in the Global Health Status was 8.54 months (95% CI, 7.49 to 10.94) in the trifluridine-tipiracil plus bevacizumab group and 4.70 (95% CI, 4.01 to 5.78) in the trifluridine-tipiracil alone group (P < 0.001).
In the EQ-5D-5L utility, the LSM change from baseline was –0.01 (95% CI, –0.03 to 0.01) for trifluridine-tipiracil plus bevacizumab and –0.03 (95% CI, –0.06 to –0.01) for trifluridine-tipiracil alone. The LSM difference in change from baseline for EQ-5D-5L utility was 0.02 (95% CI, 0.00 to 0.05; P = 0.070). In the EQ VAS, the LSM change from baseline was –0.87 (95% CI, –3.74 to 2.00) for trifluridine-tipiracil plus bevacizumab and –5.34 (95% CI, –8.75 to –1.92) for trifluridine-tipiracil alone. The LSM difference in change from baseline for EQ VAS was 4.46 (95% CI, 1.11 to 7.81; P = 0.009).
The analysis population for harms included all patients who received at least 1 dose of trifluridine-tipiracil, with patients grouped according to the treatment received. Safety data were performed using the clinical data cut-off of July 5, 2022.
In the SUNLIGHT trial, the number of patients reporting any TEAEs was 98.0% for trifluridine-tipiracil plus bevacizumab and 98.0% for trifluridine-tipiracil alone. The most common TEAEs occurring in at least 20% of patients in either treatment group were neutropenia (62.2% versus 51.2%), nausea (37.0% versus 27.2%), anemia (28.9% versus 31.7%), asthenia (24.4% versus 22.4%), fatigue (21.5% versus 16.3%), diarrhea (20.7% versus 18.7%), and decreased appetite (20.3% versus 15.4%).
The proportion of patients who experienced at least 1 serious AE was 24.8% in the trifluridine-tipiracil plus bevacizumab group and 31.3% in the trifluridine-tipiracil alone group. Serious AEs occurring in at least 2% of patients in either treatment group were intestinal obstruction (2.8% versus 2.0%), malignant neoplasm progression (2.4% versus 4.5%), COVID-19 (2.0% versus 2.4%), anemia (0.4% versus 3.3%), febrile neutropenia (0.4% versus 2.4%), jaundice (0.8% versus 2.0%), and hepatic failure (0 versus 2.0%). The proportion of patients who experienced AEs of grade 3 or greater were 72.4% in the trifluridine-tipiracil plus bevacizumab group and 69.5% in the trifluridine-tipiracil alone group. The most common AEs of grade 3 or greater occurring in at least 5% of patients in either treatment group were neutropenia (43.1% versus 32.1%), anemia (6.1% versus 11.0%), decreased neutrophil count (8.9% versus 5.3%), and hypertension (5.7% versus 1.2%).
A total of 12.6% of patients experienced TEAEs that led to treatment withdrawal in each treatment group. Withdrawals due to AEs occurring in at least 1 patient in either treatment group were asthenia (3.3% versus 0.4%), jaundice (0.8% versus 0.8%), decreased appetite (0.8% versus 0.4%), fatigue (0.4% versus 0.8%), anemia (0.4% versus 0.8%), intestinal obstruction (0.4% versus 0.8%), malignant neoplasm progression (0.4% versus 0.8%), biliary dilation (0.8% versus 0), increased blood bilirubin (0.8% versus 0), pain (0.8% versus 0), and metastases to CNS (0 versus 0.8%).
At the clinical cut-off date, a total of 323 patients had died, including 59.4% of patients in the trifluridine-tipiracil plus bevacizumab group and 72.0% of patients in the trifluridine-tipiracil alone group. A total of 37 deaths during the treatment period occurred in 13 (5.3%) patients in the trifluridine-tipiracil plus bevacizumab and 24 (9.8%) patients in the trifluridine-tipiracil alone group. Deaths that occurred during the follow-up period (54.1% and 62.2%, respectively) were mostly due to progressive disease in the trifluridine-tipiracil plus bevacizumab and trifluridine-tipiracil alone group.
Notable harms in the SUNLIGHT trial were conducted post hoc using lists of predefined preferred terms with similar medical concepts to define the overall terms. The proportion of patients who experienced bone marrow suppression was 80.9% in the trifluridine-tipiracil plus bevacizumab group and 73.2% in the trifluridine-tipiracil alone group, including neutropenia (62.2% versus 51.2%), anemia (28.9% versus 31.7%), thrombocytopenia (17.1% versus 11.4%), and leukopenia (6.5% versus 8.5%). The proportion of patients who experienced at least 1 TEAE related to infections was 30.9% in the trifluridine-tipiracil plus bevacizumab group and 23.2% in the trifluridine-tipiracil alone group. Infections of grade 3 or higher were reported for 7.7% of patients and 7.3% of patients in the trifluridine-tipiracil plus bevacizumab group and trifluridine-tipiracil alone group, respectively. The proportion of patients who experienced gastrointestinal symptoms was 48.4% in the trifluridine-tipiracil plus bevacizumab group and 41.1% in the trifluridine-tipiracil alone group, including nausea (37.0% versus 27.2%), diarrhea (20.7% versus 18.7%), and vomiting (18.7% versus 14.6%). Gastrointestinal symptoms of grade 3 or higher were reported for 2.0% of patients and 4.9% of patients in the trifluridine-tipiracil plus bevacizumab group and trifluridine-tipiracil alone group, respectively, including nausea (1.6% versus 1.6%), diarrhea (0.8% versus 2.4%), and vomiting (0.8% versus 1.6%). The proportion of patients who experienced hypertension was 10.2% in the trifluridine-tipiracil plus bevacizumab group and 2.0% in the trifluridine-tipiracil alone group. Hypertension events of grade 3 or higher were reported for 5.7% of patients and 1.2% of patients in the trifluridine-tipiracil plus bevacizumab group and trifluridine-tipiracil (alone) group, respectively.
The SUNLIGHT trial was a phase III, open-label RCT that used stratified randomization that appeared to be appropriate as patients were generally balanced between treatment groups for key prognostic factors, disease characteristics, and prior chemotherapy regimens. The open-label study design has the potential to impact HRQoL as knowledge of the assigned treatment may bias reporting in favour of the intervention (i.e., trifluridine-tipiracil plus bevacizumab) group. Trifluridine-tipiracil alone was the comparator used in the SUNLIGHT trial. Trifluridine-tipiracil is approved and available in Canada but is not publicly funded so patients may only gain access via private drug coverage or out-of-pocket costs. OS as primary and PFS as key secondary end points were included in statistical hierarchical testing and were appropriate key end points according to treatment guidelines and outcomes identified important by patients and clinicians. The findings for OS and PFS demonstrated a benefit for patients treated with trifluridine-tipiracil plus bevacizumab; the proportional hazards assumption was likely valid based on Schoenfeld residuals testing and visual inspection of the Kaplan-Meier and log(-log) curves showing crossover early during treatment but clear separation thereafter. For HRQoL, minimal important differences were identified in the literature among patients with cancer and with mCRC for the cancer-specific EORTC QLQ-C30 tool, and among patients with cancer for the generic preference-based EQ-5D-5L tool. It was unclear whether significant missing data for HRQoL by cycle 3 to 4 may have impacted the findings. Longer treatment duration and higher mean dose of trifluridine-tipiracil in the trifluridine-tipiracil plus bevacizumab group may not be fully explained by the relatively small difference in treatment discontinuations between groups and it is unknown whether the open-label study design may have impacted patients’ adherence to assigned treatment.
The enrolled population in the SUNLIGHT trial was generally aligned with patients seen in clinical practice, according to the clinical experts consulted by CADTH, despite there being no patients in Canada enrolled in the trial. The patients who were not eligible (i.e., those with more than 2 prior chemotherapy regimens, those who had prior treatment with trifluridine-tipiracil, those with an ECOG PS greater than 1) were considered by the clinical experts consulted by CADTH to be eligible for treatment with trifluridine-tipiracil plus bevacizumab. These experts also considered patients with small bowel or appendiceal adenocarcinoma as eligible for treatment with trifluridine-tipiracil plus bevacizumab based on the small number of patients, which precludes a trial enrolling patients exclusively in this subpopulation. While the clinical experts consulted by CADTH noted a higher proportion of patients with RAS status–expressing mutations (compared with the wild-type marker), the key prognostic indicators (i.e., age, number of metastatic sites, number of prior chemotherapy regimens, sidedness of tumour, and ECOG PS) appeared to be reflective of patients in clinical practice. The intervention in the SUNLIGHT trial is for an unlabelled indication, as trifluridine-tipiracil alone was approved by Health Canada for adults with mCRC but is not publicly funded. Acknowledging that this treatment is only available to a small patient population with access (via private insurance or self-funding) among other treatment options (including BSC and regorafenib, the latter available via compassionate access), the clinical experts consulted by CADTH emphasized that trifluridine-tipiracil alone is the most relevant comparator for trifluridine-tipiracil plus bevacizumab. The outcomes included in the SUNLIGHT trial were identified as important to patients and clinicians, including survival, HRQoL, and TEAEs. OS at 6 months and 12 months was highlighted by the clinical experts consulted by CADTH as important for assessing effects of treatment. Furthermore, PFS (at 3 months and 6 months) was an appropriate end point as supportive evidence for OS. The findings may be limited in generalizability to patients with mCRC in Canada for the EQ-5D-5L health utility values derived using a French value set and in the absence of patients enrolled from sites in Canada. A higher proportion of patients who discontinued treatment in the trifluridine-tipiracil alone group was not concerning to the clinical experts consulted by CADTH as they noted that the proportions were low, with similar between-group rates for discontinuations due to AEs and deaths.
No long-term extension studies were submitted in the systematic review evidence.
The sponsor submitted a systematic review and ITC comparing trifluridine-tipiracil plus bevacizumab to BSC, regorafenib, and trifluridine-tipiracil alone among patients with mCRC who have been previously treated with, or are not considered candidates for, available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF agents, and anti-EGFR agents.
In this ITC, OS, PFS, and treatment-related AEs were assessed. The network meta-analyses were conducted within a Bayesian framework.
In total, 10 RCTs were included and contributed evidence. These studies were conducted in Asia, North America, South America, and Europe. There was no information as to whether patients from Canada were enrolled. The mean age of patients ranged from 55.5 years to 67 years. The proportion of male patients ranged from 48.5% to 64.8%. These studies were published between 2007 and 2023. The included RCTs evaluated the efficacy and safety of the following therapies that are relevant to this review: trifluridine-tipiracil plus bevacizumab in 2 studies, BSC alone in 7 studies, regorafenib in 2 studies, and trifluridine-tipiracil alone in 6 studies.
Based on the results of the sponsor-submitted ITC, treatment with trifluridine-tipiracil plus bevacizumab may be associated with prolonged OS and PFS in patients with mCRC compared to other treatments such as BSC, regorafenib, or trifluridine-tipiracil alone.
Treatment of trifluridine-tipiracil plus bevacizumab may be associated with increased risk of treatment-related AEs in patients with mCRC compared to other treatments such as BSC, regorafenib, or trifluridine-tipiracil alone. However, the results of the network meta-analyses for treatment-related AEs were imprecise with wide credible intervals.
In the sponsor-submitted ITC, based on the data presented, potential sources of heterogeneity with respect to the patients’ characteristics were identified, such as ECOG PS (the proportion of patients with ECOG PS of 0 ranged from 22% to 64%) and RAS status (the proportion of patients with a positive RAS status ranged from 27% to 70%) at baseline. Heterogeneities in trial characteristics were observed in the study design (such as blinding, definition of BSC across trials, and prior lines of therapies). Despite various statistical models being employed to lessen the impact of potential clinical heterogeneity on the estimated comparative treatment effect of trifluridine-tipiracil plus bevacizumab, there remains significant uncertainty in the ITC results. In addition, given the lack of closed loops in any of the networks, consistency in the ITC analyses could not be tested. All comparisons are therefore informed only by indirect evidence, which increases the level of uncertainty.
Some important patient characteristics in the included trials were not reported in this ITC, such as treatment duration, timing of study end point evaluation, use of subsequent therapies after disease progression, and the length of follow-up. Therefore, adjustments for their potential treatment effect modification were not feasible, and it is likely that the transitivity assumption (the assumption that if treatment A is preferred to treatment B and treatment B is preferred to treatment C then treatment A is preferred to treatment C) was not met. Furthermore, it is unclear whether the results can provide insight into the long-term effect of the study drug for patients with mCRC due to a lack of data regarding the length of trial follow-up.
Outcomes other than OS and PFS that are important to the patients and clinicians (e.g., HRQoL) were not analyzed in the ITC. A more comprehensive assessment of trifluridine-tipiracil plus bevacizumab's safety profile is desired.
No additional studies addressing important gaps in the systematic review evidence were submitted.
For the pivotal studies and RCTs identified in the sponsor’s systematic review, Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group. Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.
The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: survival (OS and PFS), HRQoL (measured as LSM change from baseline and the proportion of patients with a 10-point or greater deterioration from baseline in the EORTC QLQ-C30 Global Health Status and LSM change from baseline in the EQ-5D-5L utility score and EQ VAS), and harms (bone marrow suppression, infections, gastrointestinal symptoms, and hypertension).
When possible, the certainty was rated in the context of the presence or absence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The target of the certainty of evidence assessment was the presence or absence of an important effect based on thresholds for survival informed by the clinical experts consulted for this review (OS and PFS), HRQoL (EORTC QLQ-C30 and EQ-5D-5L), and harms (bone marrow suppression, infections, gastrointestinal symptoms, and hypertension).
Table 3: Summary of Findings for Trifluridine-Tipiracil Plus Bevacizumab Versus Trifluridine-Tipiracil Alone for Patients With Metastatic Colorectal Cancer
Outcome and follow-up | Patients (studies), N | Relative effect, (95% CI) | Trifluridine- tipiracil | Absolute effects | Certainty | What happens | |
|---|---|---|---|---|---|---|---|
Trifluridine-tipiracil plus bevacizumab, (95% CI) | Difference, (95% CI) | ||||||
Survival | |||||||
Overall survival | |||||||
Probability of overall survival at 6 months Median follow-up: 14.1 months | 492 (1 RCT) | RR = 1.26 (1.17 to 1.36) | 610 per 1,000 | 770 per 1,000 (720 to 820 per 1,000) | 160 more per 1,000 (80 to 240 more per 1,000) | Moderatea | Trifluridine-tipiracil plus bevacizumab likely results in a clinically important increase in the probability of overall survival at 6 months when compared with trifluridine-tipiracil alone. |
Probability of overall survival at 12 months Median follow-up: 14.1 months | 492 (1 RCT) | RR = 1.43 (1.31 to 1.57) | 300 per 1,000 | 430 per 1,000 (360 to 490 per 1,000) | 130 more per 1,000 (40 to 220 more per 1,000) | Moderateb | Trifluridine-tipiracil plus bevacizumab likely results in a clinically important increase in the probability of overall survival at 12 months when compared with trifluridine-tipiracil alone. |
Progression-free survival | |||||||
Probability of progression-free survival at 3 months Median follow-up: 14.1 months | 492 (1 RCT) | RR = 1.62 (1.50 to 1.76) | 450 per 1,000 | 730 per 1,000 (670 to 780 per 1,000) | 280 more per 1,000 (200 to 360 more per 1,000) | Highc | Trifluridine-tipiracil plus bevacizumab results in a clinically important increase in the probability of progression-free survival at 3 months when compared with trifluridine-tipiracil alone. |
Probability of progression-free survival at 6 months Median follow-up: 14.1 months | 492 (1 RCT) | RR = 2.69 (2.49 to 2.91) | 160 per 1,000 | 430 per 1,000 (370 to 490 per 1,000) | 270 more per 1,000 (190 to 350 more per 1,000) | Moderated | Trifluridine-tipiracil plus bevacizumab likely results in a clinically important increase in the probability of progression-free survival at 6 months when compared with trifluridine-tipiracil alone. |
Health-related quality of life | |||||||
EORTC QLQ-C30 (0 [worse health-related quality of life] to 100 [best health-related quality of life]) | |||||||
Global Health Status, LSM change from baseline Follow-up: cycle 1 to cycle 10e | 450 (1 RCT) | NA | –6.62 points | –2.85 points (–5.92 to 0.22) | 3.77 points (0.22 to 7.32) | Very lowf | The evidence is very uncertain about the effect of trifluridine-tipiracil plus bevacizumab on the LSM change from baseline in Global Health Status score when compared with trifluridine-tipiracil alone. |
Global Health Status, patients with at least a 10-point deterioration from baseline Follow-up: median 8.54 months vs. 4.70 months | 492 (1 RCT) | RR = 0.86 (0.64 to 1.15) | 293 per 1,000 | 252 per 1,000 (NR) | 40 fewer per 1,000 (120 fewer to 40 more per 1,000) | Very lowg | The evidence is very uncertain about the effect of trifluridine-tipiracil plus bevacizumab on the proportion of patients with at least a 10-point deterioration from baseline in Global Health Status score when compared with trifluridine-tipiracil alone. |
EQ-5D-5L utility score (0 [death] to 1 [full health]) | |||||||
EQ-5D-5L utility score, LSM change from baseline Follow-up: cycle 1 to cycle 10e | 448 (1 RCT) | NA | –0.03 points | –0.01 points (–0.03 to 0.01) | 0.02 points (0.00 to 0.05) | Very lowh | The evidence is very uncertain about the effect of trifluridine-tipiracil plus bevacizumab on the LSM change from baseline in EQ-5D-5L utility score when compared with trifluridine-tipiracil alone. |
EQ VAS (0 [worst health imaginable] to 100 [best health imaginable]) | |||||||
EQ VAS, LSM change from baseline Follow-up: cycle 1 to cycle 10e | 448 (1 RCT) | NA | –5.34 points | –0.87 points (–3.74 to 2.00) | 4.46 points (1.11 to 7.81) | Lowi | Trifluridine-tipiracil plus bevacizumab may result in little to no clinically important difference in the LSM change from baseline in EQ VAS score when compared with trifluridine-tipiracil alone. |
Caregiver burden | |||||||
Caregiver burden | Not assessed | No data available | No data available | No data available | No data available | Not assessed | There is no evidence for the effect of trifluridine-tipiracil plus bevacizumab on caregiver burden when compared with trifluridine-tipiracil alone. |
Notable harms | |||||||
Proportion of patients with bone marrow suppression Follow-up: median 5.0 months vs. 2.1 months | 492 (1 RCT) | NA | 732 per 1,000 | 809 per 1,000 (NR) | 80 more per 1,000 (0 to 150 more per 1,000) | Lowj | Trifluridine-tipiracil plus bevacizumab may result in little to no clinically important difference in the proportion of patients who experience bone marrow suppression when compared with trifluridine-tipiracil alone. |
Proportion of patients with infections Follow-up: median 5.0 months vs. 2.1 months | 492 (1 RCT) | NA | 232 per 1,000 | 309 per 1,000 (NR) | 80 more per 1,000 (0 to 160 more per 1,000) | Lowk | Trifluridine-tipiracil plus bevacizumab may result in little to no clinically important difference in the proportion of patients who experience infections when compared with trifluridine-tipiracil alone. |
Proportion of patients with gastrointestinal symptoms Follow-up: median 5.0 months vs. 2.1 months | 492 (1 RCT) | NA | 411 per 1,000 | 484 per 1,000 (NR) | 70 more per 1,000 (10 fewer to 160 more per 1,000) | Lowl | Trifluridine-tipiracil plus bevacizumab may result in little to no clinically important difference in the proportion of patients who experience gastrointestinal symptoms when compared with trifluridine-tipiracil alone. |
Proportion of patients with hypertension Follow-up: median 5.0 months vs. 2.1 months | 492 (1 RCT) | RR = 5.00 (1.95 to 12.85) | 20 per 1,000 | 102 per 1,000 (NR) | 80 more per 1,000 (40 to 120 more per 1,000) | Lowm | Trifluridine-tipiracil plus bevacizumab may result in little to no clinically important difference in the proportion of patients who experience hypertension when compared with trifluridine-tipiracil alone. |
CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L = 5-Level EQ-5D; LSM = least squares mean; NA = not applicable; NR = nor reported; RCT = randomized controlled trial; RR = risk ratio; VAS = visual analogue scale; vs. = versus.
Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the following footnotes.
aRated down 1 level for serious imprecision. There is no established minimal important difference (MID). The clinical experts consulted by CADTH indicated that a between-group difference of 10% to 20% was clinically important. The lower bound of the 95% CI for difference between groups did not reach the identified threshold.
bRated down 1 level for serious imprecision. There is no established MID. The clinical experts consulted by CADTH indicated that a between-group difference of 10% to 20% was clinically important. The lower bound of the 95% CI for difference between groups did not reach the identified threshold.
cThere is no established MID. The clinical experts consulted by CADTH indicated that a between-group difference of 20% was clinically important.
dRated down 1 level for serious imprecision. There is no established MID. The clinical experts consulted by CADTH indicated that a between-group difference of 20% was clinically important. The lower bound of the 95% CI for difference between groups did not reach the identified threshold.
eA repeated measures mixed effects model that included terms for treatment, baseline stratification factors, baseline score, time to visit before any procedure (at each cycle, including the withdrawal visit), and treatment groups by time to visit interaction was used to compare change from baseline subscales scores longitudinally (cycle 1 to cycle 10) over time between treatment groups.
fRated down 2 levels for very serious study limitations. The open-label study design and patients’ and caregivers’ knowledge of the assigned treatment may have biased reporting of health-related quality of life (HRQoL) questionnaires. There were substantial missing data from treatment cycle 1 to cycle 10 that may impact the prognostic balance of the treatment groups. Rated down 1 level for serious imprecision. An MID of 5.53 to 6.36 (weighted to 5.86) for improvement and –9.21 to –6.81 (weighted to –8.13) for deterioration were identified in the literature. The point estimate suggests little to no difference and the 95% CI included the possibility of important benefit. Statistical testing for the EORTC QLQ-C30 were not conducted; therefore, results are considered as supportive evidence.
gRated down 2 levels for very serious study limitations. The open-label design and patients’ and caregivers’ knowledge of assigned treatment may have biased reporting of HRQoL questionnaires. There was substantial missing data from cycle 1 to cycle 10 that may impact the prognostic balance of treatment groups. Rated down 1 level for serious imprecision. The clinical experts consulted by CADTH indicated that a between-group difference of 10% was clinically important. The lower bound of the 95% CI for difference between groups included possible important benefit. Statistical testing for EORTIC QLQ-C30 were not conducted; therefore, results are considered as supportive evidence.
hRated down 2 levels for very serious study limitations. The open-label study design and patients’ and caregivers’ knowledge of the assigned treatment may have biased reporting of HRQoL questionnaires. There were substantial missing data across and up to treatment cycle 10 that may impact the prognostic balance of the treatment groups. Rated down 1 level for serious indirectness due to utility values that were derived from a French population set. No MID was identified in the literature for patients with metastatic colorectal cancer. An MID of 0.08 based on literature for patients with cancer was identified by the clinical experts consulted by CADTH. Statistical testing for the EQ-5D-5L were not conducted; therefore, the results are considered as supportive evidence.
iRated down 2 levels for serious study limitations. The open-label study design and patients’ and caregivers’ knowledge of the assigned treatment may have biased reporting of HRQoL questionnaires. There were substantial missing data across and up to treatment cycle 10 that may impact the prognostic balance of the treatment groups. No MID was identified in the literature for patients with metastatic colorectal cancer. An MID of greater than 7 points to 10 points was identified by the clinical experts consulted by CADTH, based on literature for patients with cancer. Statistical testing for the EQ-5D-5L were not conducted; therefore, the results are considered as supportive evidence.
jRated down 1 level for post hoc analyses of adverse events of risk of bias in the selection of outcomes reported in the results. Rated down 1 level for serious imprecision. The clinical experts consulted by CADTH indicated that a between-group difference of 10% was clinically important. The point estimate suggests little to no difference and the 95% CI included the possibility of important harm.
kRated down 1 level for post hoc analyses of adverse events of risk of bias in the selection of outcomes reported in the results. Rated down 1 level for serious imprecision. The clinical experts consulted by CADTH indicated that a between-group difference of 10% was clinically important. The point estimate suggests little to no difference and the 95% CI included the possibility of important harm.
lRated down 1 level for post hoc analyses of adverse events of risk of bias in the selection of outcomes reported in the results. Rated down 1 level for serious imprecision. The clinical experts consulted by CADTH indicated that a between-group difference of 10% was clinically important. The point estimate suggests little to no difference and the 95% CI included the possibility of important harm.
mRated down 1 level for post hoc analyses of adverse events of risk of bias in the selection of outcomes reported in the results. Rated down 1 level for serious imprecision. The clinical experts consulted by CADTH indicated that a between-group difference of 10% was clinically important. The point estimate suggests little to no difference and the 95% CI included the possibility of important harm.
Source: SUNLIGHT Clinical Study Report. Details included in the table were provided from the sponsor in response to an additional data request.
Table 4: Cost and Cost-Effectiveness
Component | Description |
|---|---|
Type of economic evaluation | Cost-utility analysis PSM |
Target population | Adults with metastatic colorectal cancer who have been previously treated with, or are not candidates for, available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF biological agents, and, if positive for RAS wild-type disease, anti-EGFR agents. |
Treatment | Trifluridine-tipiracil with bevacizumab |
Dose regimen | The recommended dose is 35 mg/m2 of trifluridine-tipiracil (to a maximum of 80 mg/dose based on the trifluridine component) twice daily on days 1 to 5 and days 8 to 12 every 28 days as long as benefit is observed or until unacceptable toxicity occurs, plus 5 mg/kg of bevacizumab every 14 days. |
Submitted price | Trifluridine 15 mg/tipiracil 6.14 mg: $76.25 per tablet Trifluridine 20 mg/tipiracil 8.19 mg: $78.54 per tablet |
Treatment cost | The 28-day cost of trifluridine-tipiracil plus bevacizumab is $8,191. The 28-day cost of trifluridine-tipiracil alone and bevacizumab alone is $5,405 and $2,786, respectively. |
Comparator | BSC (interventions required to provide palliation of symptoms and improve quality of life as needed) |
Perspective | Canadian publicly funded health care payer |
Outcomes | QALYs, Lys |
Time horizon | Lifetime (28.3 years) |
Key data sources | The SUNLIGHT trial, the RECOURSE trial, and network meta-analyses |
Key limitations |
|
CADTH reanalysis results |
|
BSC = best supportive care; EGFR = epidermal growth factor receptor; ICER = incremental cost-effectiveness ratio; LY = life-year; NMA = network meta-analysis; QALY = quality-adjusted life-year; OS = overall survival; PFS = progression-free survival; PSM = partitioned survival model; VEGF = vascular endothelial growth factor.
CADTH identified the following key limitations with the sponsor’s analysis: the number of eligible patients is uncertain, the treatment duration for trifluridine-tipiracil plus bevacizumab is uncertain, the estimated proportion of patients that would be eligible for public coverage is uncertain, and market uptake is uncertain.
In the absence of more reliable input values to estimate the eligible population size and the proportion of patients eligible for public coverage, the sponsor’s base case was maintained. The net budget impact of reimbursing trifluridine-tipiracil plus bevacizumab for the treatment of adults with metastatic colorectal cancer who have been previously treated with, or are not candidates for, available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapies, anti-VEGF biological agents, and, if positive for RAS wild-type disease, anti-EGFR agents, was estimated to be $31,235,958 in year 1, $37,485,914 in year 2, and $42,271,406 in year 3. The net budget impact over the 3-year time horizon was $110,993,278.
Dr. Maureen Trudeau (Chair), Mr. Daryl Bell, Dr. Phillip Blanchette, Dr. Kelvin Chan, Dr. Matthew Cheung, Dr. Michael Crump, Dr. Jennifer Fishman, Mr. Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Christian Kollmannsberger, Dr. Catherine Moltzan, Ms. Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Marianne Taylor, and Dr. W. Dominika Wranik
Meeting date: January 10, 2024
Regrets: One expert committee member did not attend.
Conflicts of interest: One expert committee member did not participate due to considerations of conflict of interest.
ISSN: 2563-6596
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