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PARIS -- The multitargeted VEGF receptor inhibitor fruquintinib achieved statistically significant improvement in overall survival (OS) in treatment-refractory metastatic colon cancer, according to a randomized trial reported here.

Median OS improved from 4.8 months with best supportive care (BSC) and placebo to 7.4 months with BSC plus fruquintinib. The magnitude of improvement exceeded assumptions for the trial. Progression-free survival also improved with the VEGF inhibitor.

The heavily treated patient population had received a median of five prior therapies, including regorafenib (Stivarga) in about half of cases, N. Arvind Dasari, MD, of the University of Texas MD Anderson Cancer Center in Houston, reported at the European Society for Medical Oncology (ESMO) annual congress.

"These results are both clinically and statistically significant and consistent across all prespecified subgroups," said Dasari. "Fruquintinib was also well tolerated and consistent with a prior established safety profile. Overall, these results are consistent with [a prior trial conducted in China] and support a new practice-changing global oral treatment option for patients with metastatic colorectal cancer, enriching the treatment continuum for these patients."

Patients with refractory metastatic colorectal cancer (mCRC) have limited treatment options and a poor prognosis. Approved almost 10 years ago, regorafenib remains the only tyrosine kinase inhibitor (TKI) with an indication for mCRC.

The VEGF pathway is a key mediator of angiogenesis. Fruquintinib is a selective and potent inhibitor of VEGF receptors 1, 2, and 3, Dasari noted. In the , conducted in China, fruquintinib resulted in statistically significant improvement in overall survival (OS) and progression-free survival (PFS), and received an approved indication for mCRC in fourth line and beyond.

Dasari reported findings from the , which was designed to evaluate fruquintinib in a more diverse, multiregional patient population. Investigators at sites in the U.S., Europe, Australia, and Japan enrolled patients with mCRC and a treatment history that included chemotherapy, anti-VEGF therapy, and anti-EGFR therapy. Patients with progression or intolerance to TAS-102, and regorafenib were eligible, as well as patients previously treated with an immune checkpoint inhibitor or a BRAF inhibitor.

All patients received BSC and were randomized 2:1 to fruquintinib or placebo. Treatment continued until disease progression or development of unacceptable toxicity.

OS was the primary endpoint, and the principal statistical assumption was that the control arm would have a median OS of 5.0 months, which would be improved to 6.8 months with fruquintinib.

Data analysis included 691 randomized patients, who had a median follow-up of 11.2 months. Almost all of the patients had prior exposure to a VEGF inhibitor, about 40% had received an EGFR inhibitor, and about 60% had received TAS-102 or regorafenib. About 40% had received both. Dasari said the patient population resembled the patients that clinicians see in clinical practice.

The primary analysis showed a 2.6-month improvement in median OS with fruquintinib, which translated into a survival hazard of 0.662 (95% CI 0.549-0.800, P<0.001).

Treatment with fruquintinib more than doubled the median PFS, from 1.8 months with placebo to 3.7 months. The difference represented a 68% reduction in the hazard ratio (95% CI 0.267-0.386, P<0.001).

The OS and PFS benefits were consistent across all prespecified subgroups, said Dasari.

Seven patients in the fruquintinib arm had objective responses versus none in the placebo arm. The clinical benefit rate (response plus stable disease) was 55.5% with fruquintinib and 16.1% with placebo.

Grade ≥3 treatment-related adverse events occurred in 36.0% of the fruquintinib group and 11.3% of the placebo arm. Rates of fatal treatment-emergent adverse events (TEAEs) were 10.5% with fruquintinib and 19.6% with placebo.

The most common grade ≥3 TEAEs in the arm were hypertension (13.6%), asthenia (7.7%), and hand-foot syndrome (6.4%).

If FRESCO-2 had sought to define fruquintinib as a "me too" drug, the appropriate design would have been a head-to-head comparison with regorafenib and would have enrolled patients with no prior exposure to a TKI, said ESMO invited discussant Filippo Pietrantonio, MD, of the National Cancer Institute in Milan, Italy. The primary endpoint would have been noninferiority or equivalence.

Instead, FRESCO-2 was designed to validate fruquintinib as another evidence-based option for mCRC. Even so, the trial set a high bar, as almost half the patients were 65 or older, had received multiple prior lines of therapy, and there were limitations on the proportion of patients with prior regorafenib treatment.

"Despite the challenges, FRESCO-2 is a positive trial, so fruquintinib may be a new standard-of-care option in patients with refractory metastatic colorectal cancer," said Pietrantonio. "This agent significantly prolonged overall survival and progression-free survival independently from prior treatment."

"Sustained inhibition of angiogenesis is still important in later treatment lines, and fruquintinib provided an additional incremental gain of survival," he added. "Real world and phase IV data are necessary to further assess the safety of fruquintinib, especially in underrepresented populations, and quality-of-life data are necessary as well."

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