Fruquintinib significantly extends survival in refractory metastatic colorectal cancer
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Key takeaways:
- Patients treated with fruquintinib had median OS of 7.4 months vs. 4.8 months with placebo.
- Grade 3 or greater adverse events occurred in 63% of patients in the fruquintinib cohort and 50% in the placebo cohort.
Treatment with fruquintinib resulted in a significant and clinically meaningful survival benefit when compared with placebo among patients with refractory metastatic colorectal cancer, according to data published in The Lancet.
Results of the randomized phase 3 FRESCO-2 study showed treatment with the VEGFR inhibitor extended median OS by about 2.6 months among this patient population, which has few treatment options and typically poor outcomes.
“It was extremely important to find another option for previously treated patients with metastatic colorectal cancer that would provide meaningful benefit in overall survival and tolerable side effects due to the existing limited treatment options for patients who are microsatellite instability (MSI) stable,” Cathy Eng, MD, FACP, FASCO, professor of medicine in the department of hematology and oncology at Vanderbilt-Ingram Cancer Center, told Healio. “Fruquintinib [Elunate; Chi-Med, Eli Lilly & Co.] was already approved in China following their publication for FRESCO, but given that their practice patterns did not mirror ours at the time with prior bevacizumab in the first and/or second line setting, we created FRESCO-2 to validate the earlier data from China but to also be more inclusive of the patients who follow current practice patterns of prior anti-VEGF therapy in the first- and second-line setting.”
Background and methodology
The double-blind FRESCO-2 study evaluated fruquintinib, a highly selective and potent oral tyrosine kinase inhibitor of VEGF receptors 1, 2 and 3, among 691 adults (median age, 64 years) with heavily pretreated metastatic colorectal adenocarcinoma at 124 hospitals in 14 countries. Eligible patients had previously received all current standard approved cytotoxic and targeted therapies and experienced progression on or intolerance to trifluridine/tipiracil (Lonsurf; Taiho Oncology, Servier) and/or regorafenib (Stivarga, Bayer).
Patients received a median four prior lines of systemic therapy for metastatic disease, with 502 patients (73%) having received more than three lines.
Researchers randomly assigned patients 2:1 to receive a 5 mg capsule of fruquintinib (n = 461) or matched placebo orally (n = 230) on days 1 to 21 of 28-day cycles, in addition to best supportive care.
OS, defined as the time from randomization to death due to any cause, served as the primary endpoint.
Final analysis occurred following 480 OS events.
Results
Researchers reported a median OS of 7.4 months (95% CI, 6.7-8.2) among patients in the fruquintinib cohort and 4.8 months (95% CI, 4-5.8) among patients in the placebo cohort (HR = 0.66; 95% CI, 0.55-0.8).
Grade 3 or greater adverse events occurred in 286 patients (63%) who received fruquintinib and 116 patients (50%) who received placebo. The most frequent of these in the fruquintinib group included hypertension (14%), asthenia (8%) and hand-foot syndrome (6%).
Researchers reported one treatment-related death in each group — due to intestinal perforation in the fruquintinib group and due to cardiac arrest in the placebo group.
Next steps
Eng and colleagues will continue to evaluate quality-of-life data from the trial.
“The most important take-home message is we potentially (pending FDA approval) have a new oral tyrosine inhibitor with selective inhibition for VEGF receptors 1, 2 and 3 that is appropriate for all patients with previously treated metastatic colorectal cancer and is not limited by any particular molecular alteration,” Eng told Healio. “We have had no new FDA drug approvals for patients who are MSI stable (without a targetable molecular alteration) since 2015.
“I understand there are critics that do not see benefit of a superior median OS of 2.6 months, but please keep in mind that is a median; 50% of individuals will exceed 2.6 months,” she added. “Though one should never discuss cross-study comparisons, a median improvement in OS of 2.6 months as a single oral agent in a heavily pretreated patient population is meaningful relative to its other predecessors that were FDA approved with similar phase 3 trial designs in the same setting.”
For more information:
Cathy Eng, MD, FACP, FASCO, can be reached at cathy.eng@vumc.org.
Perspective
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David H. Ilson, MD, PhD
The advent of more therapeutic options for metastatic colorectal cancer and potential for more optimal therapy sequencing have largely been guided by next-generation sequencing of tumors. Despite these incremental advances, treatment of chemotherapy-refractory disease remains an unmet need.
The positive results of the FRESCO-2 trial, comparing the more specific VEGF-targeted agent fruquintinib with placebo in a randomized trial, indicate the utility of ongoing targeting of VEGF even after extensive prior therapy. This trial mandated progressive disease on all active therapies — including prior chemotherapy, bevacizumab, EGFR-targeted therapy in RAS wild-type patients, BRAF-targeted therapy in BRAF V600E-mutant cancers and immune checkpoint inhibitor therapy in MSI-high cancers — and 40% of patients received both prior trifluridine/tipiracil and regorafenib.
The modest but significant benefits in disease control and survival with fruquintinib indicate the further potential for serial VEGF-targeted inhibition by a tolerable oral agent. The results validate the approach of continuation of bevacizumab into first- and second-line therapy and second-line use of ramucirumab (Cyramza, Eli Lilly & Co.) and aflibercept, and the benefit of later-line regorafenib.
The positive results for VEGF targeting with fruquintinib are complemented and supported by the recent positive results of the SUNLIGHT trial. In that trial, adding bevacizumab to late-line trifluridine/tipiracil improved response, PFS and OS compared with trifluridine/tipiracil alone. These results justify extending bevacizumab-based VEGF inhibition into a third line of therapy.
Results of the FRESCO-2 trial will likely establish fruquintinib as yet another later-line VEGF-targeted therapy. Moving this agent to an earlier line of therapy would require comparison with existing anti-VEGF therapy options.
Reference:
Tabernero J, et al. Abstract 4. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 19-21, 2023; San Francisco.
Memorial Sloan Kettering Cancer Center
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