Reimbursement Recommendation

Fruquintinib (Fruzaqla)

Indication: For the treatment of adult patients with metastatic colorectal cancer who have been previously treated with or are not considered candidates for available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF agent; an anti-EGFR agent (if RAS wild-type); and either trifluridine-tipiracil or regorafenib

Sponsor: Takeda Canada Inc.

Final recommendation: Reimburse with conditions

What Is the Reimbursement Recommendation for Fruzaqla?

Canada’s Drug Agency (CDA-AMC) recommends that Fruzaqla should be reimbursed by public drug plans for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with or are not considered candidates for available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti–vascular endothelial growth factor (anti-VEGF) agent; an anti–epidermal growth factor receptor (anti-EGFR) agent (if RAS wild-type); and either trifluridine-tipiracil or regorafenib if certain conditions are met.

Which Patients Are Eligible for Coverage?

Fruzaqla should be covered for use in adult patients with a confirmed diagnosis of colorectal adenocarcinoma that has spread to other parts of the body and who have been previously treated with, or are not candidates for, currently available standard treatments. Patients should have good overall health (performance status) and no unstable neurologic issues related to the central nervous system or need for increasing doses of steroids to control central nervous system disease.

What Are the Conditions for Reimbursement?

Fruzaqla should be prescribed by clinicians who specialize in diagnosing and treating patients with mCRC. Fruzaqla should be stopped if the disease worsens or the patient has severe side effects. The cost of Fruzaqla should be reduced.

Why Did CDA-AMC Make This Recommendation?

• Evidence from a clinical trial demonstrated that Fruzaqla, when used in addition to best supportive care (BSC), resulted in a clinically meaningful and statistically significant improvement in overall survival and progression-free survival compared with placebo. The side effects of fruquintinib appeared to be consistent with other drugs in the same class.

• Fruzaqla met some needs identified by patients, including extending life with manageable side effects and being convenient to administer orally.

• Based on the CDA-AMC assessment of the health economic evidence, Fruzaqla does not represent good value to the health care system at the public list price. A price reduction is therefore required.

• Based on public list prices, Fruzaqla is estimated to cost the public drug plans approximately $27 million over the next 3 years for the third-line and later-line population. CDA-AMC was unable to assess the budget impact of Fruzaqla as a fourth-line treatment in Canada.

Additional Information

What Is mCRC?

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. In 2022, the 5-year prevalence of CRC in Canada was estimated to be 79,009 people.

Unmet Needs in mCRC

There is currently no approved treatment for patients with mCRC that progressed on available standard chemotherapy and trifluridine-tipiracil–based therapy; BSC is the only option for these patients in clinical practice. New treatments that work effectively while causing minimal side effects are needed.

How Much Does Fruzaqla Cost?

Treatment with Fruzaqla is expected to cost approximately $6,321 per 28-day cycle.

Recommendation

The pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends that fruquintinib be reimbursed for the treatment of adult patients with metastatic colorectal cancer (mCRC) who have been previously treated with or are not considered candidates for available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti–vascular endothelial growth factor (anti-VEGF) agent; an anti–epidermal growth factor receptor (anti-EGFR) agent (if RAS wild-type); and either trifluridine-tipiracil or regorafenib only if the conditions listed in Table 1 are met.

Rationale for the Recommendation

One phase III, double-blind, randomized controlled trial (RCT) (FRESCO-2; N = 691) demonstrated that treatment with fruquintinib plus best supportive care (BSC) resulted in statistically significant and clinically meaningful improvements in overall survival (OS) and progression-free survival (PFS) compared with placebo plus BSC in adults patients with mCRC who were previously treated with standard chemotherapy, an anti-VEGF agent, and an anti-EGFR agent (if RAS wild-type), and had progressed on or been intolerant to treatment with trifluridine-tipiracil or regorafenib. Median OS was 7.4 months (95% confidence interval [CI], 6.7 to 8.2 months) in the fruquintinib plus BSC group and 4.8 months (95% CI, 4.0 to 5.8 months) in the placebo plus BSC group, with a hazard ratio (HR) of 0.66 (95% CI, 0.55 to 0.80; P < 0.001). Median PFS was 3.7 months (95% CI, 3.5 to 3.8 months) in the fruquintinib plus BSC group and 1.8 months (95% CI, 1.8 to 1.9 months) in the placebo plus BSC, with an HR of 0.32 (95% CI, 0.27 to 0.39; P < 0.001). Fruquintinib plus BSC was associated with a higher frequency of grade 3 or greater side effects (including hand-foot syndrome and hypertension) compared with placebo plus BSC. Nevertheless, pERC considered the safety profile of fruquintinib to be consistent with the known safety of VEGF receptor inhibitors.

Patients identified a need for accessible and effective treatment options that can be administered orally, prolong survival, improve quality of life (QoL), and have fewer side effects. pERC concluded that fruquintinib met some of the needs identified by patients because it offers ease of oral administration, provides improvements in OS and PFS, and has manageable side effects. The evidence suggested that fruquintinib may result in in little or no deterioration in health-related quality of life (HRQoL); however, pERC noted that this was uncertain due to a notable amount of missing data.

Using the sponsor-submitted price for fruquintinib and publicly listed prices for all other drug costs, the incremental cost-effectiveness ratio (ICER) for fruquintinib was $325,989 per quality-adjusted life-year (QALY) compared with BSC. At this ICER, fruquintinib is not cost-effective at a willingness-to-pay threshold of $50,000 per QALY for adults with mCRC who have been previously treated with or are not considered candidates for available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF agent; an anti-EGFR agent (if RAS wild-type); and either trifluridine-tipiracil or regorafenib. A price reduction for fruquintinib is therefore required.

Table 1: Reimbursement Conditions and Reasons

BSC = best supportive care; CDA-AMC = Canada’s Drug Agency; CNS = central nervous system; dMMR = deficient mismatch repair; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ICER = incremental cost-effectiveness ratio; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; QALY = quality-adjusted life-year.

Discussion Points

• Aligned with the input from patient and clinicians, pERC acknowledged that there is an unmet need for effective and safe therapy options for patients with mCRC who experience disease progression after third-line therapy. pERC noted that there is currently no approved treatment for these patients. BSC alone is typically offered to provide palliation of symptoms in this patient population and to maintain or improve patients’ QoL. Based on the evidence reviewed, pERC noted that fruquintinib could address a current treatment gap by improving OS and PFS in the fourth-line or later-line setting.

• pERC deliberated on the results of the phase III FRESCO-2 trial that demonstrated statistically significant improvements in OS and PFS with fruquintinib treatment plus BSC compared to placebo plus BSC in the patient population under review. pERC discussed the improvement in median OS (7.4 months in the fruquintinib group versus 4.8 months in the placebo group) was modest but considered it to be clinically meaningful in this population of patients who were heavily pretreated.

• Considering that trifluridine-tipiracil was recently recommended by pERC for reimbursement in the third or later line of treatment, when used in combination with bevacizumab, the clinical experts consulted for this review anticipated that most patients would receive fruquintinib in the fourth or later lines of treatment subsequent to disease progression on trifluridine-tipiracil plus bevacizumab if this combination therapy becomes publicly funded. In the FRESCO-2 trial, all patients received prior treatment with trifluridine-tipiracil and/or regorafenib (including 52.2% receiving trifluridine-tipiracil alone and 39.4% receiving both trifluridine-tipiracil and regorafenib). However, the proportion of patients who had previously received trifluridine-tipiracil plus bevacizumab was unknown. pERC noted that this could introduce uncertainty to the generalizability of the study results. Nonetheless, pERC agreed with the clinical experts that patients who have experienced disease progression or demonstrated intolerance to trifluridine-tipiracil in combination bevacizumab would be eligible for fruquintinib treatment. The committee further discussed the eligibility of patients who might have missed the window of opportunity to receive trifluridine-tipiracil plus bevacizumab (e.g., those with more than 2 prior cytotoxic chemotherapy regimens) and agreed that those patients would be eligible to receive fruquintinib treatment.

• pERC discussed the question from the public drug programs regarding the generalizability of the evidence reviewed to patients with small bowel or appendiceal adenocarcinoma. pERC acknowledged that the rarity of small bowel or appendiceal adenocarcinomas may preclude an RCT exclusively in this patient population, and agreed with the clinical experts that these patients would be considered eligible for treatment with fruquintinib if all other lines of therapy have been exhausted. pERC further noted that this would be consistent with the reimbursement recommendation for trifluridine-tipiracil plus bevacizumab.

• pERC discussed the HRQoL outcomes from the FRESCO-2 trial, as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) scale. The evidence suggested that fruquintinib plus BSC may result in little to no difference in HRQoL compared with placebo plus BSC; however, it was noted that the results were uncertain due to a notable amount of missing data. The committee was unable to draw definitive conclusions on the effect of fruquintinib on HRQoL based on the submitted evidence.

• Caregiver burden was identified as important outcome as per input from patient group and clinical experts. pERC noted that this outcome was not assessed in the submitted trials thus the effect of fruquintinib on that is unknown. pERC acknowledged that fruquintinib treatment is administered orally, which aligns with patient preference.

• pERC noted that the sponsor’s budget impact analysis was not designed to assess the reimbursement of fruquintinib as a fourth-line therapy, and the assumptions regarding subsequent treatment use in the sponsor’s analysis were associated with uncertainty. As a result, Canada’s Drug Agency (CDA-AMC) was unable to adequately assess the budget impact of fruquintinib in the fourth-line treatment setting after trifluridine-tipiracil plus bevacizumab in Canada.

Background

Colorectal cancer (CRC) refers to malignant tumour(s) that develop in the epithelial lining of the rectum or colon, originating from polyps that progress into cancer. In 2022, the 5-year prevalence of CRC in Canada was estimated to be 79,009 people. mCRC results when CRC cells become invasive and travel to other parts of the body, most commonly the liver, lungs, and bones. The most common symptoms of mCRC include altered bowel habits, such as diarrhea or constipation, blood in stool, fatigue, nausea, abdominal pain, loss of appetite, and unintentional weight loss. Prognosis is typically worse for patients who have progressed on multiple lines of therapy. Clinical trials in patients with mCRC receiving third-line or later-line treatment reported median OS ranging from 6.4 months to 7.1 months. First-line and second-line treatments for mCRC consist of chemotherapy (including fluoropyrimidine, oxaliplatin, irinotecan), which may be combined with molecular targeted therapies. In patients who have progressed on available chemotherapy, trifluridine-tipiracil and regorafenib have been studied as single-agent treatments; their benefits are modest, and they are currently not publicly funded in Canada. Trifluridine-tipiracil plus bevacizumab combination therapy is currently under consideration for public funding as a third-line or later-line treatment. There is currently no approved treatment for patients with disease that progressed on available standard chemotherapy and either trifluridine-tipiracil or regorafenib (i.e., fourth-line or later-line setting); BSC is available to these patients in clinical practice.

The proposed indication was revised during the review process. At the time of the review submission, the proposed indication of fruquintinib was for the treatment of adult patients with mCRC who have been previously treated with or are not considered candidates for available therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF therapy; and an anti-EGFR therapy. Subsequently, fruquintinib was approved by Health Canada for the treatment of adult patients with mCRC who have been previously treated with or are not considered candidates for available standard therapies, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF agent; an anti-EGFR agent (if RAS wild-type); and either trifluridine-tipiracil or regorafenib. Fruquintinib is a VEGF receptor inhibitor. It is available as 1 mg and 5 mg oral capsules; the dosage recommended in the product monograph is 5 mg orally once daily for 21 consecutive days followed by a 7-day rest period to comprise a complete cycle of 28 days. Treatment with fruquintinib should be continued until disease progression or unacceptable toxicity occurs.

Sources of Information Used by the Committee

To make its recommendation, the committee considered the following information:

• a review of 2 RCTs in adults with mCRC

• patients’ perspectives gathered by 2 patient groups, including the Colorectal Cancer Resource & Action Network (CCRAN) and Colorectal Cancer Canada

• input from public drug plans and cancer agencies that participate in the CDA-AMC review process

• input from 2 clinical specialists with expertise diagnosing and treating patients with mCRC

• input from 1 clinician group, the Canadian GI Oncology Evidence Network (CGOEN)

• a review of the pharmacoeconomic model and report submitted by the sponsor.

Stakeholder Perspectives

Patient Input

CDA-AMC received 2 patient group submissions from CCRAN and Colorectal Cancer Canada. CCRAN is a national, not-for-profit patient advocacy group championing the health and wellbeing of Canadians affected by CRC and those at risk of developing the disease by providing support, education, and advocacy to help improve patient outcomes by way of longevity and QoL. Colorectal Cancer Canada is a not-for-profit organization for patients with CRC dedicated to CRC awareness and education, supporting patients and their caregivers and advocating on their behalf.

CCRAN employed a multifaceted outreach approach. This resulted in 3 patient interviews and a survey of patients with mCRC from March 21 to April 17, 2024, which had 119 respondents, including 115 patients who resided in Canada and the remaining 4 patients who were from the US. Data were gathered by Colorectal Cancer Canada via 4 online patient interviews between April 1 and May 15, 2024, and 1 online survey with patients in the US and Canada in August 2023, to which 15 patients and 1 caregiver responded.

Most patients reported that abdominal cramps, gas, bloating, pain, fatigue, weakness, bloody stools, and diarrhea are common impacts of the disease that affect QoL, resulting in inability to work, exercise, concentrate, participate in social activities, and fulfill family obligations. Caregivers also noted significant difficulties caring for patients with mCRC. Fluorouracil-based chemotherapy, capecitabine, bevacizumab, and panitumumab were cited to be the most frequently used treatments by the respondents, with the most common side effects being fatigue, hair loss, nausea, peripheral neuropathy, and diarrhea. Both patient groups noted that it is very important for a new therapy to improve their physical condition (e.g., tumour shrinkage, tumour stability, reduction of pain, and improved breathing) and QoL. Four respondents to CCRAN’s survey and 3 respondents to Colorectal Cancer Canada’s survey had experience with fruquintinib treatment; the patients’ main access to fruquintinib was through a clinical trial centre in US. Patients reported that fruquintinib treatment helped stabilize their disease and was easy to administer as an oral therapy. Most patients experienced hand-foot syndrome with fruquintinib treatment but noted that it was manageable. Both groups believed that access to fruquintinib for patients in the refractory mCRC setting is of utmost importance because it could provide these patients with an effective treatment option to stabilize their disease and improve their QoL.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

The clinical experts noted there is a need for effective mCRC treatments that provide more durable disease control and OS benefit, have fewer adverse effects, and could delay decline in QoL from the underlying cancer. The clinical experts also noted that comprehensive biomarker profiling and adaptive treatment strategies are required to personalize therapy more effectively. According to the input from the clinical experts, equitable access to novel treatments remains a key barrier for many patients with mCRC.

The clinical experts expect fruquintinib to be used in patients with mCRC in the fourth-line or later-line setting (i.e., have disease refractory to or intolerable toxicity to at least 2 lines of standard chemotherapy [including fluoropyrimidine, irinotecan, and oxaliplatin] and to trifluridine-tipiracil plus bevacizumab).

The clinical experts noted that fruquintinib would be most appropriate for patients with mCRC who have disease that progressed on or have intolerable toxicity to all standard approved cytotoxic treatment (fluoropyrimidine, irinotecan, and oxaliplatin), an anti-VEGF, anti-EGFR, as well as trifluridine-tipiracil plus bevacizumab or regorafenib. Patients should also have received prior immune checkpoint inhibitors and BRAF inhibitor–targeted therapy, if indicated, as per the clinical experts. The clinical experts noted that patients with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 are suitable treatment candidates, although patients with a ECOG PS score of 2 may be eligible for treatment at the treating physician’s discretion. However, for patients with an ECOG PS score higher than 2, the clinical experts felt it was inappropriate to prescribe fruquintinib because of the absence of evidence and that the harms would likely outweigh the benefits in these patients. The clinical experts noted that patients with untreated or unstable central nervous system metastases would not be suitable candidates for fruquintinib treatment.

According to the clinical experts, a clinically meaningful response includes improved survival, significant reduction in the frequency and severity of disease-related symptoms, enhanced ability to perform daily activities, and noticeable improvements in QoL. The clinical experts noted that patients are generally seen in each cycle (28 days in the case of fruquintinib), with blood work and a CT scan of the chest, abdomen, and pelvis performed every 2 to 3 cycles (8 to 12 weeks). The clinical experts noted that treatment discontinuation would be considered upon disease progression and/or intolerable toxicity. The clinical experts noted that fruquintinib should be prescribed by an oncologist with expertise in assessing and monitoring patients with mCRC.

Clinician Group Input

CDA-AMC received 1 clinician group submission from CGOEN, which was represented by 16 clinicians across Canada.

In general, CGOEN shared a consistent view on management of mCRC with the clinicians consulted by CDA-AMC. The clinician group stated that the main goals of treatment for mCRC are improvements in OS and QoL while minimizing toxicities from treatment. In terms of unmet need, the clinician group noted that there are currently no publicly funded treatment options for patients with mCRC who have been previously treated with, or are intolerant to, standard chemotherapy. However, with a recent positive reimbursement recommendation for trifluridine-tipiracil in combination with bevacizumab for treatment-refractory CRC, the clinician group indicated that fruquintinib could be considered in patients who would not be eligible for trifluridine-tipiracil plus bevacizumab or in patients who previously received trifluridine-tipiracil plus bevacizumab, which could provide clinical flexibility required in this specific later-line setting.

The clinician group also indicated that fruquintinib would be used in patients with mCRC who have been treated with or are intolerant of fluoropyrimidine, irinotecan, and oxaliplatin. Furthermore, fruquintinib would be considered after encorafenib-based therapy in patients with BRAF-mutant tumours, immunotherapy in patients with dMMR tumours, anti-EGFR therapies in patients with KRAS wild-type tumours, and anti-VEGF therapies as well as in patients who have not received previous anti-VEGF therapy. The clinician group further commented that patients would undergo clinical evaluations on a regular basis for clinical response and toxicity, and a meaningful response would be patient preference, tolerability of treatment, QoL, and response on imaging. Moreover, fruquintinib should be discontinued upon disease progression (i.e., radiologic or clinical), toxicity, clinician discretion, or patient’s request. The clinician group also mentioned that fruquintinib could be reasonably given in any centre and by any specialist who is currently treating mCRC patients with systemic therapy.

Drug Program Input

Table 2: Responses to Questions From the Drug Programs

AE = adverse event; BSC = best supportive care; CDA-AMC = Canada’s Drug Agency; dMMR = deficient mismatch repair; ECOG PS = Eastern Cooperative Oncology Group Performance Status; MSI-H = microsatellite instability-high; pERC = pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

Systematic Review

Description of Studies

Two studies, FRESCO (N = 416) and FRESCO-2 (N = 691), met the inclusion criteria for the systematic review conducted by the sponsor. FRESCO and FRESCO-2 were multicentre, randomized, double-blind, placebo-controlled phase III trials assessing the efficacy and safety of fruquintinib plus BSC compared with placebo plus BSC in adult patients with mCRC. The FRESCO trial enrolled patients from 28 sites (all in China) who had progressed on, or had intolerable toxicity to, at least 2 lines of standard chemotherapy. The FRESCO-2 trial enrolled patients from 124 sites (North America, Europe, Asia Pacific; none from Canada) who were previously treated with all standard chemotherapy, anti-VEGF therapy, and if RAS wild-type, an anti-EGFR therapy, and had progressed on, or been intolerant to, treatment with trifluridine-tipiracil or regorafenib. Patients in FRESCO-2 also had received immune checkpoint inhibitors and/or BRAF inhibitors if indicated.

In both trials, patients were randomized in a 2:1 ratio to receive fruquintinib (5 mg orally once daily for 3 weeks then 1 week off for a 28-day cycle) plus BSC or placebo plus BSC until disease progression or intolerable toxicity. The efficacy outcomes of interest to this review included OS (primary end point), PFS (secondary end point in FRESCO; key secondary end point in FRESCO-2), EORTC QLQ-C30 global health status and QoL score (FRESCO-2 only, secondary end point).

In FRESCO, at baseline, the majority of patients had received 3 or fewer lines of prior anticancer treatment for metastatic disease (78.8%); 30.0% of patients received prior anti-VEGF treatment and 14.2% of patients received prior anti-EGFR treatment. The proportion of patients who had previously received immune checkpoint inhibitors, BRAF inhibitors, trifluridine-tipiracil, and regorafenib, was not reported. In FRESCO-2, at baseline, most patients had received more than 3 lines of prior anticancer treatment for metastatic disease (72.6%) and prior anti-VEGF treatment (96.4%). All patients received prior treatment with trifluridine-tipiracil and/or regorafenib (including 52.2% who received trifluridine-tipiracil alone; 39.4% received both trifluridine-tipiracil and regorafenib). Approximately one-third of patients had prior anti-EGFR treatment. In both trials, the proportion of patients who received prior trifluridine-tipiracil plus bevacizumab combination therapy was unknown.

Efficacy Results

Results presented subsequently represent the final efficacy analysis at the data cut-off on January 17, 2017 (FRESCO) and June 24, 2022 (FRESCO-2).

Overall Survival

FRESCO

The median duration of follow-up was 13.3 months (95% CI, 12.1 to 14.7 months) in the fruquintinib plus BSC group and 13.2 months (95% CI, 10.6 to 19.6 months) in the placebo plus BSC group when a total of 297 deaths occurred (fruquintinib plus BSC: 188 deaths; placebo plus BSC: 109 deaths). The Kaplan-Meier (KM) estimate for the median OS (primary end point) was 9.30 months (95% CI, 8.18 to 10.45 months) in the fruquintinib plus BSC group and 6.57 months (95% CI, 5.88 to 8.11 months) in the placebo plus BSC group, with a stratified HR of 0.65 (95% CI, 0.51 to 0.83; P < 0.001). The between-group difference in the probability of survival at 6 months, 12 months, and 18 months was █████ ████ ███ ████ ██ ███████ █████ ████ ███ ████ ██ ███████ ███ ████ ████ ███ █████ ██ ██████, respectively. Results of the sensitivity analysis and the subgroup analyses of interest were in general consistent with the primary analysis.

FRESCO-2

The median duration of follow-up was 11.3 months (95% CI, 10.6 to 12.4 months) in the fruquintinib plus BSC group and 11.2 months (95% CI, 9.9 to 12.0 months) in the placebo plus BSC group when a total of 490 deaths occurred (fruquintinib plus BSC: 317 deaths; placebo plus BSC: 173 deaths). The KM estimate for the median OS (primary end point) was 7.4 months (95% CI, 6.7 to 8.2 months) in the fruquintinib plus BSC group and 4.8 months (95% CI, 4.0 to 5.8 months) in the placebo plus BSC group, with a stratified HR of 0.66 (95% CI, 0.55 to 0.80; P < 0.001). The between-group difference in the probability of survival at 6 months, 12 months, and 18 months was █████ ████ ███ █████ ██ ███████ ████ ████ ███ █████ ██ ███████ ███ █████ ████ ███ █████ ██ ██████, respectively. Results of the sensitivity analysis and the subgroup analyses of interest were generally consistent with the primary analysis. However, no effect was observed in the subgroup of patients with 3 or fewer prior lines (not specific to the stage of disease in which they were given) of chemotherapy treatment (HR = 0.94; 95% CI, 0.56 to 1.53), whereas treatment effect was consistently observed across subgroups by the number of prior lines of chemotherapies specific to the metastatic setting.

Progression-Free Survival

FRESCO

The KM estimate for the median PFS (secondary end point) was 3.71 months (95% CI, 3.65 to 4.63 months) in the fruquintinib plus BSC group and 1.84 months (1.81 to 1.84 months) in the placebo plus BSC group, with a stratified HR of 0.26 (95% CI, 0.21 to 0.34; P < 0.001). The majority of PFS event in both treatment groups were attributed to disease progression. The between-group difference in the probability of surviving progression-free at 3 months, 6 months, and 9 months was █████ ████ ███ ██████ ██████ ███ █████ ████ ███ ███████ ███████ ███ █████ ████ ███ ████ ██ ███████ respectively. None of these end points were adjusted for multiplicity. Results of the subgroup analysis were consistent with the primary analysis.

FRESCO-2

The KM estimate for the median PFS (key secondary end point) was 3.7 months (95% CI, 3.5 to 3.8 months) in the fruquintinib plus BSC group and 1.8 months (95% CI, 1.8 to 1.9 months) in the placebo plus BSC group, with a stratified HR of 0.32 (95% CI, 0.27 to 0.39; P < 0.001); this end point was adjusted for multiplicity. The majority of PFS events in both treatment groups were attributed to disease progression. The between-group difference in the probability of survival at 3 months, 6 months, and 9 months was █████ ████ ███ █████ ██ ███████ █████ ████ ███ █████ ██ ███████ ███ █████ ████ ███ ████ ██ ██████, respectively. Results of the subgroup analysis were consistent with the primary analysis.

EORTC QLQ-C30

FRESCO

This outcome was not assessed in this trial.

FRESCO-2

EORTC QLQ-C30 questionnaire-based outcomes were secondary end points and were not adjusted for multiplicity in the FRESCO-2 trial.

█████ ███████ ██ ██ ███ ███████ randomized patients in the fruquintinib plus BSC group and ███ ██ ███ ███████ randomized patients in the placebo plus BSC group were included in the analysis of proportion of patients with minimally important deterioration (i.e., at least a 6.38-point reduction) from baseline in EORTC QLQ-C30 global health status and QoL scores at the last on-treatment visit. Of the patients analyzed, █████ in the fruquintinib plus BSC group and █████ in the placebo plus BSC group achieved this end point; the between-group difference was ████ ████ ███ █████ ██ ██████.

Caregiver Burden

This outcome was not assessed in the trials.

Harms Results

Treatment-Emergent Adverse Events

The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was higher in the fruquintinib plus BSC group compared with the placebo plus BSC group in both the FRESCO (98.6% versus 88.3%) and the FRESCO-2 (98.9% versus 92.6%) trials. The most commonly reported TEAEs in the fruquintinib plus BSC group of the trials (reported in at least 30% of patients in at least 1 of the trials) were hand-foot syndrome, hypertension, dysphonia, proteinuria, and asthenia, all of which were reported more frequently than in the placebo plus BSC group.

Grade 3 or higher TEAEs were more commonly reported in the fruquintinib plus BSC group than the placebo plus BSC group in both the FRESCO (61.2% versus 19.7%) and the FRESCO-2 (62.7% versus 50.4%) trials. The most commonly reported grade 3 or higher TEAEs in the fruquintinib plus BSC groups were hypertension, asthenia, and hand-foot syndrome. The frequency of grade 3 or higher hypertension and hand-foot syndrome were consistently higher in the fruquintinib plus BSC group compared with the placebo BSC group in both trials (hypertension: 21.6% versus 2.2% in FRESCO and 13.6% versus 0.9% in FRESCO-2; hand-foot syndrome: 10.8% versus none in FRESCO and 6.4% versus none in FRESCO-2).

Serious Adverse Events

Serious adverse events (SAEs) were more commonly reported in the fruquintinib plus BSC group (15.5%) compared with the placebo plus BSC group (5.8%) in the FRESCO trial but were similar between the treatment groups in FRESCO-2 (fruquintinib plus BSC: 37.5%; placebo plus BSC: 38.3%). SAEs were not attributed to any specific TEAE in either trial.

Withdrawals Due to Adverse Events

Withdrawals due to adverse events (WDAEs) were more commonly reported in the fruquintinib plus BSC group (15.1%) compared with the placebo plus BSC group (5.8%) in the FRESCO trial but were similar between the treatment groups in the FRESCO-2 trial (fruquintinib plus BSC: 20.4%; placebo plus BSC: 21.3%). WDAEs were not attributed to any specific TEAE in either trials.

Mortality

Deaths were less commonly reported in the fruquintinib plus BSC group compared with the placebo plus BSC group in both the FRESCO (67.6% versus 78.8%) and the FRESCO-2 (68.9% versus 75.2%) trials.

Notable Harms

The incidence of thromboembolic events and gastrointestinal perforations were similarly low between the fruquintinib plus BSC group and the placebo plus BSC group in both trials (thromboembolic events: 0.7% in both treatment groups in FRESCO and 4.6% versus 2.2% in FRESCO-2; gastrointestinal perforations: 2.2% versus 1.7% in FRESCO and 3.5% versus 0.4% in FRESCO-2). The proportion of patients with hand-foot syndrome, hemorrhage, hypertension, and proteinuria in the fruquintinib plus BSC group were reported to be between 43.2% and 57.2% in the FRESCO trial, and between 14.3% and 36.8% in the FRESCO-2 trial; these harms were notably more common in the fruquintinib plus BSC group than the placebo plus BSC group.

Critical Appraisal

The trials used adequate methods of randomization and allocation concealment. Baseline patient characteristics were generally balanced between treatment groups, except for gender, although this was not expected to impact study results. The trials were adequately blinded; however, there is a risk of bias in measurement of subjective outcomes based on the inferred judgment by patients and investigators regarding treatment assignment due to adverse events (AEs) associated with the interventions (e.g., hypertension, hand-foot syndrome). This could potentially lead to results in favour of fruquintinib plus BSC for HRQoL outcomes and in favour of placebo plus BSC for subjective harms outcomes. No multiplicity adjustment was in place for the HRQoL outcomes in the FRESCO-2 trial and for PFS in the FRESCO trial, so statistically significant results were at an increased risk of type I error (false-positive results). In FRESCO-2, data were missing from a total of █████ ██ ████████ ████ ████ █████████ ████ █████ █████ ██ █████ █████████ ████, fruquintinib plus BSC and placebo plus BSC, respectively) in the analysis of proportion of patients with minimally important deterioration from baseline EORTC QLQ-C30 global health status and QoL scores. Missing data could have biased the validity and interpretability of HRQoL results. Sensitivity analyses for the change from baseline in score analysis using the mixed model for repeated measures were conducted to assess the impact of missing data; however, the underlying assumption that data were missing at random may not hold when, for example, missing data were more likely to occur in patients with end-stage disease and poor health status. There is the potential that the impact of the missing data ███████ could not be negligible in the analysis of proportion of patients with minimally important deterioration from baseline EORTC QLQ-C30 global health status and QoL scores, particularly when the between-group difference was small █████ ████ ███ █████ ██ ███████.

In the FRESCO-2 trial, treatment exposure, as measured by mean duration (4.0 months versus 2.0 months) and total number of treatment cycles received (4.3 versus 2.3), was almost doubled in the fruquintinib plus BSC group than the placebo plus BSC group. Patients discontinued the treatment largely due to disease progression, AEs, investigator decision, and so on, yet the proportion of patients who discontinued treatment due to disease progression was not substantially different (59% versus 64%) between the 2 groups. According to the protocol, patients in the FRESCO-2 study were allowed to continue the study treatment following disease progression as determined by the Response Evaluation Criteria for Solid Tumours Version 1.1 (RECIST 1.1) if deemed to be deriving clinical benefit by the investigator. Of the 461 patients randomized to the fruquintinib group, 301 experienced disease progression; among these, 99 patients (32.9%) received at least 1 dose of fruquintinib after disease progression. It is unclear what proportion of patients in the control group was allowed to continue treatment beyond radiographic progression. The decision to continue treatment beyond disease progression was made by the investigator in a blinded manner, and thus was unlikely to have introduced bias. Subsequent anticancer treatments were lower in the fruquintinib plus BSC group (29.4%) than in the placebo plus BSC group (34.3%), which could have introduced bias to the OS results in favour of the control group.

For the prespecified OS and PFS subgroup analyses, there was a lack of sample size consideration, control for multiplicity, and treatment by subgroup interaction analysis, which precludes any firm conclusions on subgroup effects.

In terms of external validity, the clinical experts consulted on this review anticipated that patients would have also received anti-VEGF and, if indicated, an anti-EGFR, BRAF inhibitor, and immune checkpoint inhibitor (in addition to 2 lines of standard chemotherapy) before receiving fruquintinib treatment, as per current treatment approach in Canada. As well, the clinical experts noted that if trifluridine-tipiracil became publicly funded, fruquintinib would be used subsequently in the fourth-line or later-line setting in most patients. The FRESCO trial was designed for patients who had failed at least 2 lines of chemotherapy; hence, by inclusion criteria, the aforementioned prior therapies were not required. By baseline characteristics, the proportion of patients who had received these treatments was either small or unknown. This does not align with the clinical expert input that, in clinical practice, most patients eligible for fruquintinib treatment would have received these prior therapies. FRESCO-2 included patients who had been heavily pretreated and received all standard chemotherapy, anti-VEGF, anti-EGFR, immune checkpoint inhibitor, and BRAF inhibitor, as indicated. Of note, patients were not required to have experienced disease progression on these treatments. This may increase uncertainty on the generalizability of study results to the fourth- or later-line setting. However, in the clinical experts’ opinion, the concern was minor because in clinical practice, treatments are typically switched upon disease progression or poor tolerance. As well, most patients were expected to receive trifluridine-tipiracil plus bevacizumab combination therapy before fruquintinib treatment in clinical practice as per clinical expert input. Although the majority of patients in the FRESCO-2 trial previously received trifluridine-tipiracil (91.6%), the sponsor was unable to provide data on the proportion of patients who received trifluridine-tipiracil in combination with bevacizumab in both trials, which could introduce uncertainty to the generalizability of the study results. The sponsor noted that the trials were completed during a time when there was limited clinical evidence for trifluridine-tipiracil plus bevacizumab therapy and no approved indications for the use of such combination therapy, which limits the ability to accurately characterize the proportion of patients who received trifluridine-tipiracil in combination with bevacizumab. In consultation with the clinical experts, the CDA-AMC review team considered that, compared to patients in the FRESCO trial, patients in the FRESCO-2 trial were more reflective of the patient population eligible for fruquintinib treatment based on the inclusion criteria and baseline characteristics, albeit subject to the aforementioned generalizability concerns. In addition, the clinical experts noted that the use of chemotherapy as a common subsequent treatment in the trials did not align with the clinical practice in Canada given that the trial populations were chemorefractory at baseline. As well, the FRESCO trial was conducted in China; therefore, there is potential for differences in the standard of care and availability of BSC across countries.

GRADE Summary of Findings and Certainty of the Evidence

For 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 the 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:

• OS (probability of OS at 6, 12, and 18 months)

• PFS (probability of PFS at 3, 6, and 12 months)

• HRQoL (EORTC QLQ-C30 global health status and QoL scores responder analysis)

• harms (SAEs).

Table 3 presents the GRADE summary of findings for fruquintinib plus BSC versus placebo plus BSC in patients with mCRC who had progressed on or intolerant to at least 2 lines of standard chemotherapy.

Table 4 presents the GRADE summary of findings for fruquintinib plus BSC versus placebo plus BSC in patients with mCRC who had previously received standard chemotherapy, an anti-VEGF, and an anti-EGFR (if RAS wild-type), and had progressed on or been intolerant to trifluridine-tipiracil or regorafenib.

Table 3: Summary of Findings for Fruquintinib Plus BSC Versus Placebo Plus BSC for Patients With mCRC Who Had Progressed on or Were Intolerant to at Least 2 Lines of Standard Chemotherapy

BSC = best supportive care; CI = confidence interval; mCRC = metastatic colorectal cancer; NA = not applicable; NR = not reported; RCT = randomized controlled trial.

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 table footnotes.

^aRated down 2 levels for very serious indirectness related to trial population and subsequent anticancer treatment use. The clinical experts consulted for this review anticipated that patients would have also received anti-VEGF and, if indicated, an anti-EGFR, BRAF inhibitor, and immune checkpoint inhibitor (in addition to 2 lines of standard chemotherapy) before receiving fruquintinib treatment, as per current treatment approach in Canada. As well, the clinical experts noted that if trifluridine-tipiracil became publicly funded, fruquintinib would be used subsequently in the fourth-line or later-line setting in most patients. The inclusion criteria in the FRESCO trial did not require these prior treatments. By baseline characteristics, the proportion of patients who had received these treatments was either small or unknown. The clinical experts also noted that, in the trial, the use of chemotherapy subsequent to treatment failure of fruquintinib did not align with the current treatment approach in the target population (i.e., chemorefractory) in Canada.

^bRated down 1 level for serious imprecision. Based on clinical expert input, 50 more per 1,000 to 100 more per 1,000 patients surviving could be considered clinically important. The 95% CI included the possibility of benefit and little to no difference.

^cAs per clinical expert input, the findings at later time points (i.e., at 18 months for OS and at 9 months for PFS) were less relevant because survival is generally limited for patients in later-line settings and most patients were expected to have experienced disease progression or died at those time points.

^dRated down 1 level for serious imprecision. Based on clinical expert input, 50 more per 1,000 to 100 more per 1,000 patients with serious adverse events could be considered clinically important. The 95% CI included the possibility of important harm and no difference. Rated down 1 level for indirectness. Clinical expert input indicated that patients eligible for fruquintinib treatment in clinical practice were expected to be more treatment experienced (i.e., received more prior anticancer treatments) than the trial population of FRESCO and that the trial was conducted in a single country with all patients from China; both factors could limit the generalizability of the harms results to the patient population in Canada.

Source: FRESCO Clinical Study Report.¹⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹⁷

Table 4: Summary of Findings for Fruquintinib Plus BSC Versus Placebo Plus BSC for Patients With mCRC Who Had Previously Received Standard Chemotherapy, an Anti-VEGF, and an Anti-EGFR (if RAS Wild-Type), and Had Progressed on or Been Intolerant to Trifluridine-Tipiracil or Regorafenib

BSC = best supportive care; CI = confidence interval; EGFR = epidermal growth factor receptor; EORTC = European Organisation for Research and Treatment of Cancer; mCRC = metastatic colorectal cancer; NR = not reported; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; VEGF = vascular endothelial growth factor.

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 table footnotes.

^aRated down 1 level for serious indirectness related to trial population and subsequent anticancer treatment use. The clinical experts consulted for this review anticipated that, in most patients, fruquintinib would be used in the fourth-line or later-line setting, subsequent to failure of trifluridine-tipiracil plus bevacizumab combination therapy if this combination therapy becomes publicly funded. The proportion of patients who had previously received trifluridine-tipiracil plus bevacizumab was unknown in the FRESCO-2 trial. The clinical experts also noted that in the trial, the use of chemotherapy subsequent to treatment failure of fruquintinib did not align with the current treatment approach in the target population (i.e., chemorefractory) in Canada.

^bRated down 1 level for serious imprecision. Based on clinical expert input, 50 more per 1,000 to 100 more per 1,000 patients surviving could be considered clinically important. The 95% CI included the possibility of benefit and little to no difference.

^cRated down 1 level for serious imprecision. Based on clinical expert input, 50 more per 1,000 to 100 more per 1,000 patients surviving could be considered clinically important. The 95% CI included the possibility of benefit and no difference. Did not rate down further even though the lower bound of the 95% CI indicated the possibility for harm given that it was marginally crossing the threshold of 50 fewer per 1,000 patients.

^dAs per clinical expert input, the findings at later time points (i.e., at 18 months for OS and at 9 months for PFS) were less relevant because survival is generally limited for patients in later-line settings and most patients were expected to have experienced disease progression or died at those time points.

^eRated down 1 level for a serious study limitation. There was substantial missing data (18.2%) in the treatment groups that may impact the prognostic balance of the groups. Did not rate down for imprecision. The lower limit of the 95% CI marginally crossed the threshold of 100 fewer per 1,000 patients with at least a 6.38-point deterioration from baseline in global health status score based on clinical expert input. This outcome was not adjusted for multiplicity and was considered as supportive evidence.

^fRated down 1 level for serious imprecision. Based on clinical expert input, 50 more per 1,000 to 100 more per 1,000 patients with serious adverse events could be considered clinically important. The 95% CI included the possibility of both benefit and harm based on the threshold of 50 more per 1,000 to 100 more per 1,000 patient threshold. Alternatively, if the threshold of 100 more per 1,000 patients was used, the point estimate and 95% CI would indicate little to no clinically important difference, and therefore there would not be concerns for imprecision.

Source: FRESCO-2 Clinical Study Report.¹⁸ Details included in the table are from the sponsor’s Summary of Clinical Evidence.¹⁷

Long-Term Extension Studies

No long-term extension studies were submitted for review.

Indirect Comparisons

One sponsor-conducted an indirect treatment comparison (ITC) comparing the efficacy of fruquintinib with alternative third-line or later-line treatments in patients with mCRC was included in the sponsor’s submission in anticipation of the approval of fruquintinib in the third-line or later-line setting. Fruquintinib was subsequently granted a Notice of Compliance by Health Canada for use in the fourth-line or later-line setting (i.e., following failure of at least 2 lines of standard chemotherapy and either trifluridine-tipiracil or regorafenib). Direct evidence between fruquintinib and a relevant comparator (BSC) in the fourth-line or later-line setting was available from the FRESCO-2 study. The sponsor-conducted ITC, which intended to provide indirect comparative evidence between fruquintinib to trifluridine-tipiracil in combination with bevacizumab in the third-line or later-line setting, was therefore considered to have limited relevance for the purpose of this review and is not further summarized.

Studies Addressing Gaps in the Evidence From the Systematic Review

No additional studies were submitted for review.

Economic Evidence

Cost and Cost-Effectiveness

Table 5: Summary of Economic Evaluation

BSC = best supportive care; CDA-AMC = Canada’s Drug Agency; ICER = incremental cost-effectiveness ratio; mCRC = metastatic colorectal cancer; NMA = network meta-analysis; OS = overall survival; PFS = progression-free survival; QALY = quality-adjusted life-year.

^aThe indication was revised during the review process. The target population described here was aligned with the original proposed indication, although the sponsor’s economic evaluation was modifiable to consider a target population aligned with the revised indication. This also required a change in the primary comparator from tipiracil-trifluridine plus bevacizumab to BSC. The population for the budget impact analysis was also aligned with the original proposed indication.

Budget Impact

CDA-AMC identified 1 key limitation with the sponsor’s analysis. The number of patients eligible for treatment is uncertain. In the absence of more reliable input values to estimate the eligible population size, the sponsor’s base case was maintained. The net budget impact of reimbursing fruquintinib for the treatment of adult patients with mCRC who have been treated with or are not considered candidates for available therapies including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEFG therapy; and an anti-EGFR therapy was estimated to be $27,142,807 (year 1: $9,725,263; year 2: $8,830,251; year 3: $8,587,293).

The sponsor’s budget impact analysis was not designed to assess the reimbursement of fruquintinib as a fourth-line therapy. As a result, the assumptions regarding subsequent treatment use in the sponsor’s analysis were associated with uncertainty. CDA-AMC was unable to assess the budget impact of fruquintinib if it was approved as a fourth-line treatment after trifluridine-tipiracil plus bevacizumab in Canada.

pERC Information

Members of the Committee

Dr. Catherine Moltzan (Chair), Dr. Philip Blanchette, Dr. Kelvin Chan, Dr. Matthew Cheung, Dr. Michael Crump, Annette Cyr, Dr. Jennifer Fishman, Dr. Jason Hart, Terry Hawrysh, Dr. Yoo-Joung Ko, Dr. Aly-Khan Lalani, Amy Peasgood, Dr. Anca Prica, Dr. Adam Raymakers, Dr. Patricia Tang, Dr. Pierre Villeneuve, Danica Wasney.

Meeting date: October 9, 2024

Regrets: Three expert committee member(s) did not attend.

Conflicts of interest: None of the expert committee members who attended the meeting declared a conflict of interest.