FDA Grants Fruquintinib Fast Track Status for mCRC

The FDA has granted a fast track designation to fruquintinib for the treatment of patients with metastatic colorectal cancer (mCRC) who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, VEGF-directed therapy, and if RAS wild-type, EGFR-directed therapy, according to a recent announcement by Chi-Med.¹

Chi-Med retains all rights to fruquintinib outside of China and is partnered with Eli Lilly and Company in China.

The highly selective and potent VEGFR inhibitor was designed to strengthen kinase selectivity as a way to reduce off-target effects, boost tolerability, and provide more consistent target coverage. Preclinical data with fruquintinib have demonstrated favorable tolerability with the agent in patients, with a low potential for drug–drug interactions, according to the company, adding that these factors suggest that fruquintinib may be appropriate for use in combination with other therapies in oncology.

The agent was first approved for marketing in September 2018 by the China National Medical Products Administration for use in patients with mCRC who had received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan, including those who had previous anti-VEGF therapy and/or anti-EGFR therapy if they had RAS wild-type disease. Two months later, in November 2018, the product was commercially launched by Lilly under the trade name Elunate.

In the randomized, double-blind, multicenter phase 3 FRESCO trial, 416 patients between the ages of 18 and 75 with mCRC who had progressed after at least 2 lines of chemotherapy but had not received a VEGFR inhibitor were randomized 2:1 to receive either oral fruquintinib at 5 mg (n = 278) or oral placebo (n = 138) once daily for 21 days, followed by 7 days off in 28-day cycles until progressive disease, unacceptable toxicity, or study withdrawal.

The primary end point of the study was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate, and disease control rate. Investigators also evaluated duration of response with the agent. Safety outcomes looked at treatment-emergent adverse effects (TEAEs).

Of the 416 patients, 97.1% (n = 404) completed the trial. Results showed that fruquintinib significantly prolonged the median OS compared with placebo, at 9.3 months versus 6.6 months, respectively (HR, 0.65; 95% CI, 0.51-0.83; P <.001).² A significant improvement was also observed with regard to median PFS with fruquintinib versus placebo, at 3.7 months versus 1.8 months, respectively (HR, 0.26; 95% CI, 0.21-0.34; P <.001).

With regard to safety, TEAEs that were grade 3/4 in severity were reported in 61.2% (n = 170) of patients who received the VEGFR inhibitor versus 19.7% (n = 27) of those who were given placebo. Furthermore, 15.5% (n = 43) of patients on the fruquintinib arm experienced serious AEs compared with 5.8% (n = 8) of those on the placebo arm; 14.4% (n = 40) and 5.1% (n = 7) of those treated with fruquintinib versus placebo, respectively.

Patients with mCRC are generally given chemotherapy with the potential to receive targeted agents, as well. In an effort to examine the potential impact of previous treatment with targeted therapies on the efficacy of fruquintinib, investigators conducted a subgroup analysis.³

Of 278 patients who were treated with fruquintinib, 111 had received prior treatment with targeted therapy (PTT; 84, anti-VEGF; 40, anti-EGFR; 13, both). In the PTT subgroup, fruquintinib significantly prolonged OS with a median 7.69 months versus 5.98 months with placebo (HR, 0.63; P = .023), as well as PFS, with a median 3.65 months versus 1.84 months with placebo (HR, 0.24; P <.001). Fruquintinib also demonstrated benefit in patients who had been given prior anti-VEGF therapy with regard to OS (n = 84; HR, 0.68; 95% CI, 0.45-1.03) and PFS (HR, 0.24; 95% CI, 0.15-0.38).

In the non-PTT subgroup, the median OS reported with fruquintinib was 10.35 months versus 6.93 months with placebo (HR, 0.63; P = .01). The median PFS in this subgroup with fruquintinib and placebo was 3.81 months and 1.84 months, respectively (HR, 0.28; P <.001).

No accumulative grade ≥3 TEAEs were reported in the PTT subgroup. Rates of grade ≥3 TEAEs with fruquintinib proved to be comparable between the PTT and non-PTT subgroups, at 61.3% versus 61.1%. The most common drug-related grade ≥3 TEAEs observed with the agent was hypertension (20.7%, PTT subgroup vs 21.6%, non-PTT subgroup), hand-foot-skin reaction (7.2% vs 13.2%, respectively), and proteinuria (5.4% vs 1.8%).

Chi-Med is in the process of initiating FRESCO-2, a phase 3 registration study (NCT04322539), in patients with refractory mCRC in the United States, Europe, and Japan. Trial enrollment is expected to begin in mid-2020.

“The US FDA acknowledged that the totality of the fruquintinib clinical data, including the FRESCO-2 study, if positive; the prior positive phase 3 FRESCO study demonstrating improvement in OS that led to fruquintinib approval for mCRC in China in 2018; and additional completed and ongoing supporting studies in mCRC; could support a new drug application for the treatment of patients with mCRC in the third-line setting,” the company wrote in a press release.

References

1. Chi-Med announces fruquintinib granted US FDA fast track designation for metastatic colorectal cancer. News release. Chi-Med. June 18, 2020. Accessed June 18, 2020. bit.ly/3d8kIaw.
2. 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
3. Xu R, Li J, Bai Y-X, et al. Subgroup analysis by prior anti-VEGF or anti-EGFR target therapy in FRESCO, a randomized, double-blind, phase 3 trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 36(suppl 15):3537. doi:10.1200/JCO.2018.36.15_suppl.3537