FDA Approval Sought for Fruquintinib in Refractory Metastatic Colorectal Cancer

A new drug application seeking the approval of fruquintinib (HMPL-013) for use in the treatment of patients with refractory metastatic colorectal cancer (mCRC) has been submitted to the FDA, according to an announcement from HUTCHMED Limited.¹

The application is based on data from the phase 3 FRESCO-2 trial (NCT04322539). Fruquintinib plus best supportive care (BSC; n = 461) resulted in a median overall survival (OS) of 7.4 months (95% CI, 6.7-8.2) vs 4.8 months (95% CI, 4.0-5.8) with placebo plus BSC (n = 230) in this patient population (HR, 0.662; 95% CI, 0.549-0.800; P < .001), meeting the trial’s primary end point.

Moreover, the median progression-free survival (PFS) reported in the fruquintinib arm was 3.7 months (95% CI, 3.5-3.8) vs 1.8 months (95% CI, 1.8-1.9) in the placebo arm (HR, 0.321; 95% CI, 0.267-0.386; P < .001), meeting a key secondary end point of the trial.

“This FDA submission is a significant milestone for patients in the United States with mCRC, one of the most common and deadly cancers in the United States and worldwide. Fruquintinib is an important treatment option for patients with mCRC in China, where it has been available to patients since 2018,” Dr Michael Shi, head of R&D and chief medical officer of HUTCHMED, stated in a press release.¹ “We look forward to working with our partner Takeda to commercialize fruquintinib outside of China, and we remain on track to submit regulatory filings in Europe and Japan later this year.”

Fruquintinib is a highly selective and potent oral TKI of VEGFR-1, VEGFR-2, and VEGFR-3.² The agent was previously explored as a third- or later-line treatment option in Chinese patients with mCRC as part of the phase 3 FRESCO trial (NCT02314819).³ Data indicated that fruquintinib (n = 278) improved median OS over placebo (n = 138), at 9.3 months and 6.6 months, respectively (HR, 0.65; 95% CI, 0.51-0.83; P < .001). Fruquintinib also improved median PFS by 1.9 months vs placebo (HR, 0.26; 95% CI, 0.21-0.34; P < .001).

These data supported the September 2018 approval of fruquintinib capsules in China for use in patients with mCRC who progressed on at least 2 previous systemic antineoplastic therapies including fluoropyrimidine, oxaliplatin, and irinotecan, with or without previous VEGF or EGFR therapies.⁴

The FRESCO-2 trial enrolled patients with mCRC who previously received chemotherapy with fluoropyrimidine, oxaliplatin, or irinotecan; a VEGF inhibitor; and if they had RAS wild-type disease, an EGFR inhibitor.² To be eligible for enrollment, patients must have progressed on or been intolerant to TAS-102 (Lonsurf) and/or regorafenib (Stivarga). They also needed to have previously received an immune checkpoint inhibitor or a BRAF inhibitor, if indicated.

Notably, to ensure that the population was reflective of clinical practice, the number of regorafenib-pretreated patients was limited to 344.

Participants were randomly assigned 2:1 to receive fruquintinib at a daily dose of 5 mg as part of a 3-weeks-on/1-week-off schedule in combination with BSC or placebo plus BSC. They continued to receive treatment until disease progression or intolerable toxicity.

Key stratification factors comprised previous therapy received (TAS-102 vs regorafenib vs TAS-102 and regorafenib), RAS mutational status (wild-type vs mutant), and duration of metastatic disease (≤18 months vs >18 months).

Other secondary objectives of the trial included objective response rate (ORR), disease control rate (DCR), and safety.

Data from the trial were presented during the 2022 ESMO Congress and the data cutoff date was June 24, 2022. The median age across the arms was 64 years (range, 25-86), and slightly more than half of patients were male. Most patients in the fruquintinib and placebo arms, respectively, were from Europe (71.4% vs 72.2%), followed by North America (17.8% vs 18.3%) and the Asia Pacific region (10.8% vs 9.6%).

The median number of prior therapies received in the investigative arm was 5 (range, 2-16), with 27.1% of patients having received up to 3 prior lines and 72.9% having received more than 3 prior lines. In the control arm, the median number of prior lines of therapy was 5, with a range of 2 to 12 lines. In this group, 27.8% of patients received up to 3 prior lines of treatment, and 72.2% received more than 3 lines.

Previous treatment in the fruquintinib and placebo arms included VEGF inhibition (96.5% vs 96.1%, respectively) and EGFR inhibition (39.0% vs 38.3%). Patients also received prior TAS-102 (52.1% vs 52.6%), regorafenib (8.7% vs 7.8%), or both agents (39.3% vs 39.6%).

Additional data indicated that the confirmed ORR with fruquintinib was 1.5% vs 0% with placebo (adjusted difference, 1.5; 95% CI, 0.4%-2.7%; two-sided P = .059). The DCRs in the investigative and control arms were 55.5% and 16.1%, respectively (adjusted difference, 39.4; 95% CI, 32.8-46.0; P < .001).

Regarding safety, those in the investigative arm received a median of 3.00 cycles of fruquintinib; those in the control arm received a median of 2.00 cycles of placebo. Moreover, 68.4% and 47.8% of patients, respectively required dose interruptions; 26.5% and 4.3% of patients, respectively, required dose reductions.

Additionally, 98.9% of patients who received fruquintinib experience any-grade treatment-emergent adverse effects (TEAEs) vs 92.6% of those given placebo; effects were grade 3 or higher in 62.7% and 50.4% of patients, respectively. Treatment-related AEs that were grade 3 or higher occurred in 36.0% of those in the investigative arm and 11.3% of those on the control arm. Serious TEAEs occurred in 37.5% and 38.3% of patients, respectively, with grade 3 or higher effects observed in 35.5% and 37.0% of patients, respectively. Toxicities led to death for 10.5% and 19.6% of patients, respectively.

The most common grade 3 or higher TEAEs to occur in at least 15% of patients in either the fruquintinib or placebo arms included hypertension (13.6% vs 0.9% asthenia (7.7% vs 3.9%), decreased appetite (2.4% vs 1.3%), diarrhea (3.5% vs 0%), hypothyroidism (0.4% vs 0%), fatigue (3.9% vs 0.9%), hand-foot syndrome (6.4% vs 0%), abdominal pain (3.1% vs 3.0%), nausea (0.7% vs 0.9%), proteinuria (1.8% vs 0.9%), and constipation (0.4% vs 0%).

HUTCHMED shared plans to file a marketing authorization application to the European Medicines Agency and an NDA to the Japan Pharmaceuticals and Medical Devices Agency later this year.

References

1. HUTCHMED completes rolling submission of NDA to US FDA for fruquintinib for the treatment of refractory metastatic colorectal cancer. News release. March 31, 2023. Accessed March 31, 2023. https://www.hutch-med.com/rolling-submission-of-us-nda-for-fruquintinib-mcrc-completed/
2. Dasari NA, Lonardi S, Garcia-Carbonero R, et al. LBA25 FRESCO-2: a global phase III multiregional clinical trial (MRCT) evaluating the efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer. Ann Oncol. 2022;33(suppl 7):S1391-S1392. doi:10.1016/j.annonc.2022.08.021
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. Chi-Med announces the approval of fruquintinib capsules for previously treated colorectal cancer in China. News release. Hutchinson China MediTech Limited. September 5, 2018. Accessed March 31, 2023. https://www.globenewswire.com/news-release/