Changing the therapeutic landscape for patients with refractory metastatic colorectal cancer: FRESCO-2 supports fruquintinib as a global treatment option

Colorectal cancer is the third most diagnosed cancer and second leading cause of cancer-related death worldwide. Approximately 50% of patients with colorectal cancer will develop metastasis during their disease course and the overall 5-year survival rate for these patients is 15%.

For patients who are intolerant to or progress on standard therapies, later-line treatments including chemotherapy and targeted therapy have both shown incremental benefit on overall survival and progression free-survival but can be associated with treatment-related toxicities that require dose reductions.

“Effective systemic therapies for patients with advanced refractory colorectal cancer are limited. To help respond to this unmet clinical need, the FRESCO-2 phase III study was designed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral VEGFR inhibitor in this patient population,” says Josep Tabernero, Director of the Vall d’Hebron Institute of Oncology (VHIO), Head of the Medical Oncology Department at the Vall d’Hebron University Hospital (HUVH), and co-senior author of this present study*.

In colorectal cancer the vascular endothelial growth factor (VEGF) promotes tumor angiogenesis, which is fundamental to tumor growth, invasion, and metastasis. Over recent years, inhibitors targeting the VEGF tyrosine kinase signaling pathway have been developed to block new blood vessel formation in growing tumors to control disease or halt tumor growth.

Fruquintinib is a new, highly selective oral tyrosine kinase inhibitor that blocks VEGF receptors 1, 2 and 3. “Results of the previous FRESCO study led to the approval of fruquintinib in China for heavily pretreated patients with metastatic colorectal cancer as well as the development of this present FRESCO-2 international study,” observes Tabernero.

FRESCO-2 included 686 patients with refractory metastatic colorectal cancer across 124 different sites in 14 countries, who were randomly assigned 2:1 to receive fruquintinib (456 patients) or placebo (230 patients). Both groups received best supportive care. Patients enrolled in this study had received all currently approved cytotoxic and targeted therapies and progressed on, or been intolerant to, the combination of trifluridine/tipiracil and/or VEGFR inhibitor regorafenib.

Results of this multiregional phase III study show statistically significant improvements in overall survival and progression-free survival in this patient population. The benefit of fruquintinib over placebo was evidenced by the 34% reduction in the clinical variable of risk of death and the 68% reduction in that of risk of disease progression or death. At 6 months, 24% of patients on fruquintinib versus 1% on placebo were progression free.

Overall survival and progression-free survival benefits were observed across nearly all prespecified subgroups, including those with poor prognostic factors. Improvements with fruquintinib were seen regardless of prior therapy, including previous treatment with trifluridine/tipiracil (over 90% of patients) and/or regorafenib.

“These results are particularly significant given that 48% of patients had received prior treatment with regorafenib and suggest that inhibition of angiogenesis remains an important mechanism of disease control even in the later lines of treatment,” says Elena Élez, Principal Investigator of VHIO’s Colorectal Cancer Group, Medical Oncologist at the Vall d’Hebron University Hospital (HUVH), and a co-author of this study.

“The higher selectivity of fruquintinib compared with other approved anti-VEGF/VEGFR therapies could explain the efficacy benefit observed in patients treated with fruquintinib, regardless of previous exposure to regorafenib,” adds Élez.

Fruquintinib was well tolerated in this patient population. Patients treated with fruquintinib stayed on treatment almost twice as long as those on placebo (median 3.1 versus 1.8 months), consistent with favourable efficacy and tolerability of fruquintinib. While grade 3 or higher adverse events occurred in 63% versus 50% on placebo, most adverse events, including hypertension, asthenia, and hand-foot syndrome, could be managed with supportive care and dose modification.

Dose interruption occurred in 47% of patients and dose reductions occurred in 24% of patients, which compares favorably to regorafenib and is promising, particularly considering the later-line setting of these patients. A similar proportion of patients in the fruquintinib and placebo groups discontinued treatment due to adverse events, 20% versus 21%, respectively.

“Results of FRESCO-2 show a statistically and clinically meaningful benefit with a favorable safety profile in patients with chemotherapy-refractory metastatic colorectal cancer from a global population representing current treatment practices. Together with the results of the first FRESCO study conducted in China, our data further support fruquintinib as a new global oral treatment option for these patients upon evaluation by the different regulatory authorities and healthcare reimbursement systems,” concludes Josep Tabernero.

Reference:

Dasari A, Lonardi S, Garcia-Carbonero R, Elez E, Yoshino T, Sobrero A, Yao J, García-Alfonso P, Kocsis J, Cubillo Gracian A, Sartore-Bianchi A, Satoh T, Randrian V, Tomasek J, Chong G, Paulson AS, Masuishi T, Jones J, Csőszi T, Cremolini C, Ghiringhelli F, Shergill A, Hochster HS, Krauss J, Bassam A, Ducreux M, Elme A, Faugeras L, Kasper S, Van Cutsem E, Arnold D, Nanda S, Yang Z, Schelman WR, Kania M, Tabernero J, Eng C; FRESCO-2 Study Investigators. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023 Jun 15:S0140-6736(23)00772-9. doi: 10.1016/S0140-6736(23)00772-9. Epub ahead of print. PMID: 37331369.