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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
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.
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.
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.
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.
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.
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.
Reimbursement Conditions and Reasons.
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:
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.
Responses to Questions From the Drug Programs.
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).
Summary of Findings for Trifluridine-Tipiracil Plus Bevacizumab Versus Trifluridine-Tipiracil Alone for Patients With Metastatic Colorectal Cancer.
Cost and Cost-Effectiveness.
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.
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About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
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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
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