Fruquintinib/BSC Demonstrates OS/PFS Benefit in Refractory mCRC, Irrespective of Prior Treatment

Treatment with fruquintinib (HMPL-013) plus best supportive care (BSC) led to improved overall survival (OS) and progression-free survival (PFS) vs placebo plus BSC in patients with refractory metastatic colorectal cancer (mCRC), irrespective of number of prior lines of therapy or type of prior treatment, according to data from subgroup analyses of the phase 3 FRESCO-2 trial (NCT04322539) presented at the 2023 ASCO Annual Meeting.¹

Among all patients treated with fruquintinib (n = 461), the median OS was 7.4 months (95% CI, 6.7-8.2 vs 4.8 months (95% CI, 4.0-5.8) in those treated with placebo (n = 230; HR, 0.662; 95% CI, 0.549-0.800; P < .001). In patients who received 4 or less prior lines of therapy, the median OS was 7.6 months (95% CI, 6.6-8.5) with fruquintinib (n = 247) and 5.1 months (95% CI, 3.9-6.3) for placebo (n = 123; HR, 0.702; 95% CI, 0.541-0.912; P = .003). In patients who received more than 4 prior lines of therapy, the median OS was 7.1 months (95% CI, 6.3-8.5) with fruquintinib (n = 214) and 4.6 months (95% CI, 3.4-5.9) with placebo (n = 107; HR, 0.595; 95% CI, 0.453-0.781; P < .001).

“Fruquintinib demonstrated longer OS and PFS vs placebo in patients with mCRC irrespective of prior number of lines of therapy and type of prior treatment,” lead author Arvind N. Dasari, MD, of The University of Texas MD Anderson Cancer Center in Houston, and colleagues, wrote in a poster presentation.

In May 2023, the FDA granted priority review to the new drug application (NDA) seeking the approval of fruquintinib for use in the treatment of adult patients with previously treated mCRC.² The NDA was supported by prior data from FRESCO-2 presented at the 2022 ESMO Congress.³

The trial enrolled patients with mCRC who had received all standard treatments for their disease, including fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, anti-VEGF therapy, anti-EGFR therapy for RAS wild-type disease, and trifluridine/tipiracil (TAS-102; Lonsurf) or regorafenib (Stivarga). Patients with mismatch repair–deficient/microsatellite instability–high disease were also required to have received additional therapy with an immune checkpoint inhibitor, and those with BRAF V600E–mutated tumors must have had additional therapy with a BRAF inhibitor.¹

The global, multicenter, randomized, placebo-controlled trial was conducted in the United States, Europe, Japan, and Australia. A total of 691 patients were randomly assigned to receive fruquintinib at 5 mg daily in a 3-weeks-on/1-week-off schedule plus BSC or placebo plus BSC. Notably, 686 patients received a minimum of 1 dose of study drug.

Patients were stratified by prior treatment (TAS-102 vs regorafenib vs both), RAS status (mutant vs wild-type), and duration of metastatic disease (≤18 months vs >18 months). The primary end point of the trial was OS, and PFS was a key secondary end point. Other secondary end points included overall response rate, safety, and disease control rate.

For the subgroup analysis, patients were grouped by number of prior of lines of therapy (≤4 vs >4). Efficacy and safety data were analyzed for these groups, and for subgroups based on type of prior therapy. The median follow-up was 11.3 months for patients treated with fruquintinib and 11.2 months for patients who received placebo.

The baseline characteristics were well balanced between the group of patients who received 4 or fewer lines of therapy and the group that received more than 4. The median age of patients was 64 years (range, 25-82) and 63 years (range, 30-82) in those who had 4 or less prior lines of therapy and received fruquintinib and placebo, respectively. The median age was 63 years (31-81) and 65 years (range, 35-86) for those who had more than 4 prior lines of therapy in the fruquintinib and placebo arms, respectively.

Among patients who received 4 or less prior lines of therapy, 51.4% of patients in the fruquintinib arm and 36.6% of patients in the placebo arm were female. In patients who had more than 4 prior lines of therapy, 41.6% of patients who received fruquintinib and 42.1% of patients who received placebo were female.

In the 4 or less prior lines of therapy group, 44.9% of patients who received fruquintinib and 52.2% who received placebo had an ECOG performance status of 0; 39.7% and 36.4% of patients who received more than 4 prior lines of therapy treated in the fruquintinib arm and placebo arm, respectively, had an ECOG performance status of 0.

The primary site at first diagnosis for patients on the trial included left colon (41.3% for the fruquintinib/4 or less lines of therapy group; 39.8% for the placebo/4 or less lines of therapy group; 42.1% for the fruquintinib/more than 4 lines of therapy group; 40.2% for the placebo/more than 4 lines of therapy group) right colon (23.1%; 26.8%; 18.7%; 18.7%), left and right colon (1.2%; 0.8%; 0.5%; 0.9%), unknown site of colon (5.7%; 4.9%; 5.1%; 6.5%), and rectum only (28.7%; 27.6%; 33.6%; 33.6%). Notably, 73.3%, 67.5%, 73.8%, and 68.2% of patients showed signs of liver metastasis, respectively.

The duration of metastatic disease was more than 18 months in the majority of patients in each arm (85.0% for the fruquintinib/4 or less lines of therapy group; 90.2% for the placebo/4 or less lines of therapy group; 100% for the fruquintinib/more than 4 lines of therapy group; 99.1% for the placebo/more than 4 lines of therapy group), and the majority of patients had RAS-mutant disease (68.8%; 70.7%; 56.5%; 54.2%).

Prior anticancer treatment included VEGF biologics (94.3% for the fruquintinib/4 or less lines of therapy group; 93.5% for the placebo/4 or less lines of therapy group; 99.1% for the fruquintinib/more than 4 lines of therapy group; 99.1% for the placebo/more than 4 lines of therapy group), EGFR biologics (31.2%; 29.3%; 48.1%; 48.6%), regorafenib (12.6%; 11.4%; 4.2%; 3.7%), TAS-102 (65.6%; 71.5%; 36.4%; 30.8%), and regorafenib and TAS-102 (21.9%; 17.1%; 59.3%; 65.4%).

Additionally, the median number of prior lines of anticancer treatment for metastatic disease in all patients in the fruquintinib arm was 4 (range, 2-16) compared with 4 (range, 2-12) for all patients in the placebo arm.

The median duration of exposure of fruquintinib was 2.76 months (range, 0.4-19.1) vs 1.84 months (range, 0.4-5.8) for placebo in patients who underwent 4 or less prior lines of therapy. In patients who received more than 4 prior lines of therapy, the median duration of exposure of fruquintinib was 3.45 months (range, 0.3-17.6) vs 1.84 months (range, 0.3-12.0) for placebo.

Additional data showed the median PFS was 3.7 months (95% CI, 3.5-3.8) for all patients who received fruquintinib vs 1.8 months (95% CI, 1.8-1.9) in those treated with placebo (HR, 0.321; 95% CI, 0.267-0.386; P < .001). In patients who received 4 or less prior lines of therapy, the median PFS was 3.5 months (95% CI, 2.9-3.7) with fruquintinib and 1.9 months (95% CI, 1.8-1.9) for those treated with placebo (HR, 0.323; 95% CI, 0.251-0.417; P < .001). In patients who received more than 4 lines of therapy, the median PFS was 3.7 months (95% CI, 3.6-4.0) with fruquintinib and 1.8 months (95% CI, 1.7-1.9) with placebo (HR, 0.300; 95% CI, 0.229-0.393; P < .001).

Among all patients, fruquintinib elicited an OS benefit irrespective of prior anticancer treatment, including anti-VEGF (7.4 months vs 4.9 months), anti-EGFR (7.4 months vs. 4.4 months), regorafenib (10.2 months vs 8.2 months), TAS-102 (7.7 months vs 5.1 months), and regorafenib plus TAS-102 (6.8 months vs 4.4 months).

Fruquintinib also produced a PFS benefit across all prior anticancer treatment subgroups, including anti-VEGF (3.7 months vs 1.9 months), anti-EGFR (3.7 months vs. 1.9 months), regorafenib (3.6 months vs 1.9 months), TAS-102 (3.6 months vs 1.9 months), and regorafenib plus TAS-102 (3.7 months vs 1.8 months).

“Fruquintinib demonstrated consistent OS and PFS benefit compared with placebo in patients who had been previously treated with an anti-VEGF, regorafenib, or TAS-102,” study authors wrote in the poster presentation.

Any grade treatment-emergent adverse effects (TEAEs) occurred in 98.4% of patients treated with fruquintinib and 91.0% of patients given placebo in the 4 or less prior lines of treatment group. Rates of any-grade TEAEs were 99.5% and 94.4% for fruquintinib and placebo in the more than 4 prior lines treatment group, respectively. Of these TEAEs, 60.4% and 45.1% were grade 3 or higher in the patients treated with fruquintinib or placebo in the 4 or less prior treatment group, respectively, and 65.4% and 56.5% were grade 3 or higher for fruquintinib and placebo arms in the more than 4 prior lines of treatment group, respectively.

“The overall safety profile was consistent in patients who received 4 or less prior lines of therapy or more than 4 prior lines of therapy,” Dasari noted.

In the four groups, rates of any-grade treatment-related AEs (TRAEs) were 87.3%, 56.6%, 85.8%, and 56.5%, respectively, and rates of grade 3 or higher TRAES were 37.1%, 9.8%, 34.6%, and 13%, respectively.

In the safety population, the most frequent grade 3 or higher TEAEs in more than 5% or more of patients in either fruquintinib group included hypertension, palmar plantar erythrodysesthesia, and asthenia.

“These results were consistent with the effect observed in the overall population, supporting fruquintinib as a treatment option for patients with refractory mCRC, irrespective of prior number of lines of therapy or type of prior anticancer treatment,” Dasari concluded.

References

1. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Subgroup analyses of safety and efficacy by number and types of prior lines of treatment in FRESCO-2, a global phase III study of fruquintinib in patients with refractory metastatic colorectal cancer. J Clin Oncol. 2023;41 (suppl 16):3604. doi:10.1200/JCO.2023.41.16_suppl.3604
2. 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 June 5, 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/ 
3. Dasari NA, Lonardi S, Garcia-Carbonero R, et al. 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