Oncologists long stymied by the dearth of options for treating refractory metastatic colorectal cancer (mCRC) are heralding a new therapy expected to be approved by the FDA before the end of the year.
"There have been very few oral VEGF [vascular endothelial growth factor] inhibitors [for mCRC]," said Howard Hochster, MD, Director of Gastrointestinal Oncology at Rutgers Cancer Institute of New Jersey, "and none as successful as this drug."
The drug is fruquintinib, an oral, small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFRs). Hochster saw its benefits firsthand as a member of an international team of researchers who tested it in a randomized, Phase III, double-blind trial. The study, dubbed FRESCO-2, was published in The Lancet (2023; http://htts://doi.org/10.1016/S0140-6736(23)00772-9). The FDA in May granted priority review for the new drug application and set a decision date of November 30, 2023. Fruquintinib was developed in China, where it was approved in 2018.
Fruquintinib impressed clinicians by significantly extending survival in patients who had progressed through or been unable to tolerate all standard cytotoxic and targeted therapies. The 461 patients in the investigational arm had a median overall survival of 7.4 months from the time of enrollment, compared to 4.8 months for the 230 patients in the placebo arm. Progression-free survival was 3.7 months in the fruquintinib group-twice as long as the placebo group's median of 1.8 months.
Treatments "Desperately Needed"
Of the 153,020 people the American Cancer Society predicts will be diagnosed with CRC in 2023, about 20 percent will have metastatic disease at the time of diagnosis. Another 35 percent will develop it after treatment. Although treatment advances in recent years have extended mCRC survival to approximately 30 months, only 15 percent survive 5 or more years.
"Most patients with metastatic colorectal cancer progress through all available therapies and their cancer stops responding," said Arvind Dasari, MD, Associate Professor at the University of Texas MD Anderson Cancer Center and principal investigator for the FRESCO-2 study. "Novel therapies are desperately needed."
Ardaman Shergill, MD, Medical Oncologist at the University of Chicago Medical Center, agrees. She was driven to coauthor the FRESCO-2 study by her distress seeing young patients exhaust existing mCRC therapies.
"Younger and younger patients are getting diagnosed with CRC," she said. "It's very difficult to not have options for them." While the overall incidence of CRC has dropped in the past 2 decades, it has increased in people under 55, who now account for one in five CRC patients.
Fruquintinib stands out from existing late-line therapies for mCRC because of its comparatively mild side effects and its efficacy against mutations that resist other targeted treatments. "It seems to be very well-tolerated with easily manageable side effects," Dasari said. "Given the excellent side effect profile, it also does not affect the quality of life of patients."
A quality-of-life analysis of FRESCO-2 participants published in the Journal of Clinical Oncology supports his observation (2023; doi: 10.1200/JCO.2023.41.4_suppl.67). Sixty-three percent of patients taking fruquintinib experienced Grade 3 or worse adverse events. The most common were hypertension (14%), asthenia (8%), and hand-foot syndrome (6%). Fifty percent of placebo patients also experienced Grade 3 or worse adverse events, suggesting many of the events were unrelated to treatment. Moreover, patients receiving fruquintinib continued treatment almost twice as long as those receiving a placebo.
In comparison, the combination of trifluridine and tipiracil, which are standard therapies in advanced mCRC patients, is associated with anemia, fatigue, nausea, and neutropenia sometimes serious enough to prompt treatment delays. Regorafenib, another standard treatment, is linked to liver toxicity that can be life-threatening. All FRESCO-2 patients had been treated before the trial with trifluridine-tipiracil, regorafenib, or both, receiving a median of four lines of systemic therapy.
Another key advantage of fruquintinib over standard late-line therapies is its action against tumors with the RAS mutation. Such patients do not respond to standard anti-VEGF and anti-EGFR therapies, yet FRESCO-2 patients with the mutation responded to fruquintinib. "This drug benefits everyone with metastatic colorectal cancer and is not limited to a small subset," Dasari said.
Targeting More Selective Therapies
Fruquintinib's strong action with minimal adverse effects comes from its highly selective targeting of VEGFRs 1, 2, and 3. The drug was designed to target receptors that promote tumor angiogenesis while minimizing off-target toxicities. If approved by the FDA, the manufacturer claims it will be the first CRC therapy in the U.S. targeting all three VEGFRs. Less selective therapies, including regorafenib and bevacizumab, are more likely to cause untoward effects.
Some researchers see fruquintinib's benefits reaching beyond patients who've run out of options. "There are a lot of discussions on how to combine fruquintinib with other drugs not just in the refractory setting, but also in earlier lines of therapy," Dasari said.
"What we do with it," Shergill said, "combining it with other agents, has the potential for a breakthrough." She referred to the recently published SUNLIGHT study, which showed that bevacizumab combined with trifluridine-tipiracil significantly improved overall survival in patients with mCRC patients compared with trifluridine-tipiracil alone.
Participants had been treated with one or two previous chemotherapy regimens, fewer than the FRESCO-2 participants. Those in the investigative arm had a median survival of 10.8 months, 3.3 more than those in the placebo arm, fueling hopes that fruquintinib combinations might also yield better outcomes when given earlier in the course of disease (J Clin Oncol 2023; doi: 10.1200/JCO.2023.41.4_suppl.4).
Cynthia Washam is a contributing writer.