Japanese Approval Sought for Fruquintinib in Previously Treated Metastatic Colorectal Cancer

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A new drug application (NDA) seeking the approval of fruquintinib (Elunate) for the treatment of adult patients with previously treated metastatic colorectal cancer (mCRC) has been submitted to Japan’s Ministry of Health, Labour, and Welfare.¹

The NDA is supported by data from the phase 3 FRESCO-2 trial (NCT04322539), as well as findings from the phase 3 FRESCO trial (NCT02314819) conducted in China.

Data from FRESCO-2, published in The Lancet, showed that fruquintinib (n = 461) significantly improved overall survival (OS) vs placebo (n = 230) in this population, at median of 7.4 months (95% CI, 6.7-8.2) and 4.8 months (95% CI, 4.0-5.8), respectively (HR, 0.66; 95% CI, 0.55-0.80; P < .0001).² Fruquintinib (n = 278) also improved OS over placebo (n = 138) in Chinese patients with mCRC who experienced disease progression after at least 2 previous chemotherapy regimens and were enrolled in FRESCO; the median OS was 9.3 months (95% CI, 8.2-10.5) vs 6.6 months (95% CI, 5.9-8.1), respectively (HR, 0.65; 95% CI, 0.51-0.83; P < .001).³

“Alongside our partner Takeda, we are pleased to take this key step toward bringing fruquintinib to patients in Japan,” Michael Shi, MD, head of R&D and chief medical officer of HUTCHMED (China) Limited, stated in a press release.¹ “Supported by a strong clinical data set, and its success in China, we believe that fruquintinib is an important option for these patients and are optimistic about the impact it will have if approved in Japan. There is now real regulatory momentum behind fruquintinib, and we are excited to see this drug take to the global stage.”

The international, randomized, double-blind, placebo-controlled FRESCO-2 trial enrolled patients with histologically or cytologically confirmed metastatic colorectal adenocarcinoma who had received all standard therapies, including fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF therapy, and anti-EGFR therapy, and experienced progression on or had intolerance to trifluridine and tipiracil (TAS-102; Lonsurf) or regorafenib (Stivarga).²

Patients needed to be at least 18 years of age unless based in Japan; the latter were required to be 20 years or older. Moreover, they needed to have measurable disease by RECIST v1.1 criteria and an ECOG performance status of 0 or 1.

Participants were randomly assigned 2:1 to receive oral fruquintinib at a dose of 5 mg or matched placebo administered once daily on days 1 to 21 of 28-day treatment cycles. Patients received treatment until progressive disease, intolerable toxicity, withdrawn patient consent, physician decision to discontinue, death, or study completion or termination. All patients also received best supportive care (BSC), which was based on local clinical practice.

Stratification factors included prior therapy (TAS-102 vs regorafenib vs both), RAS mutational status (wild type vs mutant), and duration of metastatic disease (≤18 months vs >18 months).

OS served as the trial’s primary end point, and progression-free survival (PFS) represented an important secondary end point. Other secondary end points included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety. Investigators also examined health-related quality of life, pharmacokinetics, and pharmacodynamics.

Demographic and disease characteristics at baseline were well balanced between the treatment arms. Overall, the median age was 64 years (interquartile range [IQR], 56-70). More than half of patients (63%) had tumors harboring a RAS mutation and liver metastases (72%). Patients had received a median of 4 prior lines of therapy (IQR, 3-6), with most (73%) having received more than 3 prior lines for metastatic disease. Regarding prior treatment, 52% of patients received prior TAS-102, 8% had prior regorafenib, and 39% had both.

Additional data showed that the median PFS with fruquintinib was 3.7 months (95% CI, 3.5-3.8) vs 1.8 months (95% CI, 1.8-1.9) with placebo (HR, 0.32; 95%. CI, 0.27-0.39; P < .0001). The ORR in the investigative arm was 2% (95% CI, 0.6%-3.1%) vs 0% (95% CI, 0.0%-1.6%) with placebo (95% CI, 0.4%-2.7%; P = .059). The median DOR with fruquintinib was 10.7 months (95% CI, 3.9-not estimable). The DCRs with fruquintinib and placebo were 56% (95% CI, 50.9%-60.1%) and 16% (95% CI, 11.6%-21.5%), respectively (95% CI, 32.8%-46.0%; P < .0001).

Regarding safety, 99% of those in the fruquintinib arm and 93% of those in the placebo arm experienced at least 1 adverse effect (AE); grade 3 or higher AEs were reported in 63% and 50% of patients, respectively. The most common any-grade AEs reported in the investigative and control arms, respectively, included hypertension (37% vs 9%) and asthenia (34% vs 23%). The most common grade 3 or higher AEs included hypertension (14% vs 1%), asthenia (8% vs 4%), and hand-foot syndrome (6% vs 0%).

AEs proved to be fatal for 11% of those given fruquintinib vs 20% of those who received placebo. One death was determined to be related to treatment in each arm; the patient who received fruquintinib experienced intestinal perforation and the patient given placebo had cardiac arrest.

FRESCO enrolled patients with histologically and/or cytologically confirmed mCRC that had progressed after 2 or more standard chemotherapy regimens.3 Patients were between the ages of 18 and 75 years, had an ECOG performance status of 0 or 1, left ventricular ejection fraction of at least 50%, measurable disease by RECIST v1.1 criteria, a life expectancy of at least 12 weeks, and acceptable bone marrow, liver, and renal function.

Patients were randomly assigned 2:1 to oral fruquintinib at 5 mg daily or matching placebo, both paired with BSC, as part of 28-day treatment cycles. Treatment continued for 3-weeks-on followed by 1-week-off until progressive disease, intolerable toxicity, withdrawn patient consent, physician decision to discontinue, or death. Stratification factors included prior VEGF treatment (yes vs no) and KRAS mutational status (wild type vs mutated).

OS again served as the primary end point of the trial. Key secondary end points comprised PFS, ORR, DCR, and DOR. Investigators also examined safety.

In the 416 patients who underwent randomization, the mean age was 54.6 years and 38.7% were women. Demographics, disease characteristics, and previous treatments received at baseline proved to be comparable between the arms; however, more men were noted to be in the placebo arm vs the fruquintinib arm. Most patients had liver metastases (66.5% vs 73.9%), had prior VEGF inhibitors (30.2% vs 29.7%), prior EGFR inhibitors (14.4% vs 13.8%), and harbored KRAS mutations (43.5% vs 46.4%).

Additional findings showed that at the data cutoff date of January 17, 2017, the median PFS with fruquintinib was 3.71 months (95% CI, 3.65-4.63) vs 1.84 months (95% CI, 1.81-1.84) with placebo (HR, 0.26; 95% CI, 0.21-0.34; P < .001). The ORRs observed in the investigative and control arms were 4.7% and 0%, respectively (95% CI, 2.1%-7.2%); the DCRs were 62.2% vs 12.3%, respectively (95% CI, 42.0%-57.8%; P < .001).

In safety-evaluable patients (n = 278), 98.6% of those given fruquintinib vs 88.3% of those who received placebo experienced at least 1 treatment-emergent AE (TEAE); these effects were grade 3 or higher in 61.2% vs 19.7% of patients, respectively. Moreover, serious AEs were reported in 15.5% of those who received fruquintinib vs 5.8% of those given placebo.

The most common grade 3 or 4 AEs experienced in the investigative arm included hypertension (21.2%), hand-foot reaction (10.8%), and proteinuria (3.2%). Toxicities requiring hospitalization or extension of an existing hospital stay were needed for 14.4% and 5.1% of patients, respectively. Fatal TEAEs occurred in 3.2% of those in the investigative arm and 1.5% of those in the control arm. TEAEs resulted in fruquintinib discontinuation in 15.1% of patients and placebo discontinuation in 5.8% of patients.

In May 2023, the FDA granted priority review to an NDA seeking the approval of fruquintinib in adult patients with previously treated mCRC.⁴ The application was also supported by findings from FRESCO-2 and FRESO. The regulatory agency is expected to decide on the DNA by November 30, 2023. In June 2023, the European Medicines Agency validated and accepted a marketing authorization application for priority review for the agent in the same indication.⁵ The agent is already approved in China for use in this population.¹

References

1. HUTCHMED announces submission of new drug application for fruquintinib for previously treated metastatic colorectal cancer in Japan. News release. HUTCHMED (China) Limited. September 29, 2023. Accessed October 2, 2023. https://www.hutch-med.com/hutchmed-announces-submission-of-new-drug-application-for-fruquintinib-for-previously-treated-metastatic-colorectal-cancer-in-japan/
2. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53. doi:10.1016/S0140-6736(23)99772-9
3. Li J, Qin S, Xu R-H, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: The FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855
4. Takeda and HUTCHMED announce new drug application (NDA) for fruquintinib for treatment of previously treated metastatic colorectal cancer granted priority review. News release. Takeda and HUTCHMED Limited. May 25, 2023. Accessed October 2, 2023. https://www.takeda.com/newsroom/press-releases/takeda-and-hutchmed-announce-new-drug-application-for-fruquintinib-for-treatment-of-previously-treated-metastatic-colorectal-cancer-granted-priority-review/
5. Takeda and HUTCHMED Announce Marketing Authorization Application of Fruquintinib for Previously Treated Metastatic Colorectal Cancer Validated by the European Medicines Agency. News release. June 15, 2023. Accessed October 2, 2023. https://www.takedaoncology.com/news/news-releases/takeda-and-hutchmed-announce-marketing-authorization-application-of-fruquintinib/