Japan seeks approval of fruquintinib for previously treated metastatic colorectal cancer

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

The NDA is supported by data from the Phase 3 FRESCO-2 study (NCT04322539) and results from the Phase 3 FRESCO study (NCT02314819) conducted in China.

FRESCO-2 data, lancetIn this population, fruquintinib (n = 461) significantly improved overall survival (OS) compared with placebo (n = 230), with medians of 7.4 months (95% CI, 6.7-8.2) and 4.8 months. 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 mCRC patients enrolled in FRESCO with disease progression after at least two chemotherapy regimens. 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; 95% CI, 0.51-0.83 , 95% CI, 0.51-0.83). P < .001).³

“We are pleased to take this important step together with our partner Takeda to bring fruquintinib to patients in Japan,” said Michael, Head of Research and Development and Chief Medical Officer, HatchMed (China) Limited.・Dr. Shi said in a press release.¹ “Backed by strong clinical data sets and success in China, we believe fruquintinib is an important option for these patients and are optimistic about its impact if approved in Japan. Currently , there is real regulatory momentum for fruquintinib and we are excited to see this drug move onto the global stage.”

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

Patients had to be 18 years of age or older, unless based in Japan. The latter were required to be at least 20 years old. In addition, participants had to have measurable disease according to RECIST v1.1 criteria and an ECOG performance status of 0 or 1.

Participants will be randomly assigned 2:1 to receive oral fruquintinib at a dose of 5 mg once daily from days 1 to 21 of a 28-day treatment cycle or matching placebo. It was done. Patients were treated until disease progression, intolerable toxicity, patient withdrawal of consent, physician’s decision to discontinue, death, or study completion or discontinuation. All patients also received best supportive care (BSC) based on local clinical practice.

Stratification factors included previous treatment (TAS-102 vs regorafenib vs both). R.A.S. mutational status (wild type vs mutant), duration of metastatic disease (≤18 months vs >18 months).

OS was the primary endpoint of the trial, and progression-free survival (PFS) was an important secondary endpoint. Other secondary endpoints include objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety. Researchers also investigated health-related quality of life, pharmacokinetics, and pharmacodynamics.

Baseline demographic and disease characteristics were well balanced between treatment groups.Overall, the median age was 64 years (interquartile range [IQR], 56-70). More than half of the patients (63%) had tumors that were: R.A.S. Mutations and liver metastases (72%). Patients had received a median of 4 prior lines of therapy (IQR, 3-6), and most (73%) had received 3 or more prior therapies for metastatic disease. Regarding previous treatments, 52% of patients had previously received her TAS-102, 8% had previously received regorafenib, and 39% had received both treatments.

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

Regarding safety, 99% of those in the fruquintinib group and 93% of those in the placebo group experienced at least one adverse effect (AE). Grade 3 or higher AEs were reported in 63% and 50% of patients, respectively. The most common high-grade AEs reported in the study and control groups, 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 were found to be fatal in 20% of patients in the placebo group compared with 11% in the fruquintinib group. In each group, he found one death was related to treatment. Patients receiving fruquintinib experienced intestinal perforation, and patients receiving placebo had cardiac arrest.

FRESCO enrolled patients with histologically and/or cytologically confirmed mCRC that progressed after two or more standard chemotherapy regimens. 3 patients ranged in age from 18 to 75 years, had ECOG performance status of 0 or 1, and left ventricular ejection fraction <10. At least 50%, measurable disease by RECIST v1.1 criteria, life expectancy of at least 12 weeks, and acceptable bone marrow, liver, and kidney function.

Patients were randomly assigned 2:1 to oral fruquintinib 5 mg daily or matching placebo in combination with BSC as part of a 28-day treatment cycle. Treatment continued for 3 weeks and then stopped for 1 week until disease progression, intolerable toxicity, patient withdrawal of consent, physician decision to discontinue, or death.Stratification factors included her previous VEGF treatment (yes vs. no); class Mutation status (wild type vs. mutant).

OS again served as the primary endpoint of the trial. Key secondary endpoints consisted of PFS, ORR, DCR, and DOR. Investigators also looked into safety.

The mean age of the 416 patients randomized was 54.6 years, and 38.7% were female. Demographics, disease characteristics, and previous treatments received at baseline were found to be comparable in both groups. However, it was noted that there were more men in the placebo group than in the fruquintinib group. Most patients had liver metastases (66.5% vs. 73.9%), a history of VEGF inhibitors (30.2% vs. 29.7%), and a history of EGFR inhibitors (14.4% vs. 13.8%). class mutation (43.5% vs 46.4%).

Additional findings show that as of the data cutoff date of January 17, 2017, the median PFS for the fruquintinib arm was 3.71 months (95% CI, 3.65-4.63) compared to 1.84 months (95% CI, 3.65-4.63) for the placebo arm. %CI, 1.81-1.84) (HR, 0.26). ; 95% CI, 0.21-0.34; P < .001). The ORRs observed in the study and control groups were 4.7% and 0% (95% CI, 2.1% to 7.2%), respectively. DCR was 62.2% vs. 12.3%, respectively (95% CI, 42.0%-57.8%; P < .001).

Among safety-evaluable patients (n = 278), 98.6% in the fruquintinib arm vs. 88.3% in the placebo arm experienced at least one treatment-emergent AE (TEAE). These effects were grade 3 or higher in 61.2% and 19.7% of patients, respectively. Additionally, serious AEs were reported in 15.5% of patients receiving fruquintinib versus 5.8% of patients receiving placebo.

The most common grade 3 or 4 AEs experienced in the research arm included hypertension (21.2%), hand-foot reaction (10.8%), and proteinuria (3.2%). Toxicity requiring hospitalization or extension of existing hospital stay was required in her 14.4% and her 5.1% of patients, respectively. Fatal TEAEs occurred in 3.2% of the study group and 1.5% of the control group. TEAEs led to discontinuation of fruquintinib in 15.1% of patients and discontinuation of placebo in 5.8% of patients.

In May 2023, FDA grants priority review to NDA seeking approval of fruquintinib Adult patients with previously treated mCRC.^Four This application was also supported by the FRESCO-2 and FRESO findings. Regulators are expected to determine the DNA by November 30, 2023. European Medicines Agency verifies and accepts marketing authorization application For priority review of drugs in the same indication.^Five The drug is already approved for use in this population in China.¹

References

1. HatchMed announced the submission of a new drug application for fruquintinib for previously treated metastatic colorectal cancer in Japan. news release. HATCH MED (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, Ronaldi S, Garcia-Carbonero R et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicenter, randomized, 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 RH Effect of fruquintinib versus placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. Japan Automobile Manufacturers Association. 2018;319(24):2486-2496. doi:10.1001/jama.2018.7855
4. Takeda and HatchMed announced that their new drug application (NDA) for fruquintinib for the treatment of previously treated metastatic colorectal cancer has been granted priority review. news release. Takeda Pharmaceutical and HatchMed Co., Ltd. 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- Priority Review Granted/
5. Takeda and HatchMed announce marketing authorization application for 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/