An international, phase III FRESCO-2 study met its primary and key secondary endpoints, showing significant improvements in overall survival (OS) and progression-free survival (PFS) with fruquintinib given orally in a heavily pretreated patient population with refractory metastatic colorectal cancer (mCRC). The benefit of fruquintinib over placebo was evident by the 34% reduction in risk of death and 68% reduction in risk of disease progression or death.
The rate of PFS at 6 months was 24% for patients in the fruquintinib group versus 1% in the placebo group. A disease control rate (DCR) with fruquintinib of 56% is notable.
Fruquintinib was well tolerated in this heavily pretreated population. The findings are published on 15 June 2023 in The Lancet by Dr. Arvind Dasari of the Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center in Houston, TX, US, and colleagues.
Fruquintinib is a highly selective and potent oral tyrosine kinase inhibitor of VEGFR1-3, which are key regulators of angiogenesis associated with tumour growth and metastasis. The authors explained in the background that in the phase III FRESCO study conducted in patients with mCRC who had received at least two previous lines of chemotherapy, treatment with fruquintinib resulted in significant improvement compared with placebo in OS and PFS which led to its approval in China in 2018. However, at the time of the FRESCO study, VEGF inhibitors or EGFR inhibitors were not routinely included into the standard of care in China, and regorafenib and trifluridine-tipiracil were not yet approved.
An ongoing phase I/Ib expansion cohort study of fruquintinib in the US, which included patients with mCRC with or without previous trifluridine-tipiracil or regorafenib, showed encouraging preliminary antitumour efficacy and safety, further supporting the investigation of fruquintinib in a population with refractory mCRC.
The international, randomised, double-blind, placebo-controlled, phase III FRESCO-2 study evaluated the efficacy and safety of fruquintinib at 124 hospitals and cancer centres across 14 countries among patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both.
Eligible patients were randomly assigned 2:1 to receive fruquintinib 5 mg capsule or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. The primary endpoint was OS, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected OS events had occurred. Final analysis occurred after 480 OS events.
Between 12 Aug 2020 and 2 December 2021, 934 patients were assessed for eligibility and 691 were enrolled of whom 461 were randomly assigned to receive fruquintinib and 230 to placebo. Patients had received a median of 4 lines of previous systemic treatment for metastatic disease, and 502 of 691 patients (73%) had received more than 3 lines.
Median OS was 7.4 months in the fruquintinib group versus 4.8 months in the placebo group (hazard ratio [HR] 0.66, 95% CI 0.55–0.80; p < 0.0001). The Kaplan-Meier plot for OS showed an early separation of the curves in favour of the fruquintinib group, which was maintained over the duration of the study. Median PFS was 3.7 months in the fruquintinib group versus 1.8 months in the placebo group (HR 0.32, 95% CI 0.27–0.39; p < 0.0001).
Subgroup analyses of OS and PFS showed results that were consistent with the benefit observed in the intention-to-treat population across nearly all prespecified subgroups, including by randomisation stratification factors of previous treatment with trifluridine-tipiracil or regorafenib, RAS mutation status, and duration of metastatic disease. Furthermore, OS and PFS benefits were also consistent regardless of number of previous lines of treatment for metastatic disease.
Investigator-assessed objective response was documented in 7 of 461 patients (2%) in the fruquintinib group compared with none in the placebo group (adjusted difference 2%, 95% CI 0.4–2.7; p = 0.059). No complete responses were observed. The median duration of response (DoR) in the fruquintinib group was 10.7 months and maximum DoR was ongoing at greater than 16.9 months. In the fruquintinib group, DCR was 56% compared with 16% in the placebo group (adjusted difference 39%, 95% CI 32.8–46.0; p < 0.0001).
Grade 3 or worse adverse events occurred in 286 of 456 patients (63%) who received fruquintinib and 116 of 230 patients (50%) who received placebo. The most common grade 3 or worse adverse events in the fruquintinib group included hypertension (14%), asthenia (8%), and hand-foot syndrome (6%). There was one treatment-related death in each group, intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group.
The authors commented that since the inception of this study, there were advances in the treatment landscape for mCRC that have targeted specific, small subpopulations of patients with alterations such as KRAS G12C and HER2. Furthermore, COVID-19 pandemic hindered the completion of blood-based circulating tumour DNA correlative analyses as unanticipated supply chain issues prevented the timely distribution and collection of test kits necessary to collect samples. Although the inability to complete these exploratory analyses prevented a deeper understanding of whom might benefit from fruquintinib, the absence of these data did not affect the primary and secondary endpoint analyses or overall conclusions.
FRESCO-2 is the first study to show efficacy of an oral VEGFR inhibitor in patients who have received previous trifluridine-tipiracil or regorafenib, or both. The observed reduction in the overall risk of death and risk of progression or death with fruquintinib compared with placebo suggests that inhibition of the VEGF pathway remains an effective management strategy for mCRC, even in the later line setting and in patients with previous exposure to antiangiogenic agents. The findings from FRESCO-2 show that fruquintinib is effective and well tolerated in a broad population of patients with heavily pretreated mCRC. True extent of fruquintinib benefit will be more clear following analyses of the quality-of-life (QoL) assessments.
In an accompanied comment, professors Erika Martinelli and Fortunato Ciardiello of the Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli in Naples, Italy wrote that the results of the FRESCO-2 study support the clinical relevance of angiogenesis inhibition even in the more advanced lines of treatment. The results support the introduction of the angiogenesis inhibitor fruquintinib as a novel treatment option in the continuum of care for patients with mCRC after failure of most available chemotherapies and targeted drugs, including other antiangiogenic agents.
Further clinical research will be needed to define the optimal sequence of treatments for patients with mCRC, in whom the first two lines of treatment have failed and who could potentially benefit from at least three further lines of therapy (e.g., trifluridine-tipiracil with or without bevacizumab, regorafenib, and fruquintinib), to extend the concept of continuum of care and improve survival and QoL.
The study was sponsored by HUTCHMED.
