Was the Fruquintinib Trial for Metastatic CRC a Win?

Last month, The Lancet published the results of a phase 3 trial that assessed the use of a highly selective, potent oral vascular endothelial growth factor receptor (VEGFR) inhibitor for patients with refractory metastatic colorectal cancer (CRC).

The trial, dubbed FRESCO-2, found that use of fruquintinib “resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer.”

More specifically, the median overall survival benefit was 2.6 months — 7.4 months with fruquintinib vs 4.8 months with placebo — among 691 heavily pretreated adults with metastatic colorectal adenocarcinoma. The difference translated to a 34% reduction in the risk of death with fruquintinib at a median follow-up of about 11 months.

These patients had received “all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib,” a less-selective vascular endothelial growth factor (VEGF) inhibitor, according to investigators led by Arvind Dasari, MD, from MD Anderson Cancer Center, Houston, Texas.

Dasari and colleagues celebrated the results, stressing that “these data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer.”

The VEGF inhibitor has been approved in China for refractory metastatic CRC since 2018, and the recent phase 3 findings support the bid for US Food and Drug Administration (FDA) approval for this indication. The FDA granted fruquintinib priority review in May 2023.

However, in a tweet last month, Vinay Prasad, MD, an oncologist/epidemiologist at the University of California, San Francisco (UCSF), who is an outspoken critic of the pharmaceutical industry, called the trial design “unethical.”

Fruquintinib, he explained, was compared with placebo, not investigators’ choice of treatment for patients dying of CRC.

Trial participants were considered to have refractory cases of CRC after previous lines of systemic treatment had failed. For almost three quarters of patients, more than three lines of therapy had failed, and patients still had options, including fluorouracil (5FU), oxaliplatin, or irinotecan, Prasad argued.

“Everyone who treats CRC would pull [their] mom off the trial and give 5FU and [bevacizumab] or IrOx [irinotecan plus oxaliplatin] or FOLFOX again, perhaps slightly differently,” Prasad tweeted.

The “proof is they give [these drugs] post progression,” he continued. “After the control arm patients progressed, many doctors DID try!” these other options.

Hutchmed, the Hong Kong maker of fruquintinib, which sponsored the trial, did not respond to questions from Medscape Medical News about why the trial was designed with a placebo arm instead of investigators’ choice of treatment.

However, CRC specialist Alan Venook, MD, who was not involved in the trial, weighed in. He explained that he understands Prasad’s concerns but doesn’t necessarily think the trial was unethical.

For patients such as those in FRESCO-2, the impact of current treatment options is “so minimal” that forgoing active drug treatment is “not crazy,” said Venook, a medical oncologist at UCSF.

“If your chances of getting benefit are 1 in 20 and you are much more likely to get toxicity than benefit, you could argue” that having a placebo control arm in the trial is ethical, provided people understand what they are getting into, Venook said.

In the trial, almost two thirds of patients who received fruquintinib had grade 3 or worse toxicities compared with half of placebo patients. The most common were hypertension (14% with fruquintinib vs 1% with placebo), asthenia (8% vs 4%), and hand-foot syndrome (6% vs 0%).

Part of the risk-benefit assessment may also include weighing the estimated costs of fruquintinib against the 2.6-month median overall survival benefit.

“One could debate if 2.6 months of more time is worth the medication getting regulatory approval, or debate pricing when it’s approved, or delve closely into toxicity and quality of life data,” tweeted medical oncologist Temidayo Fadelu, MD, MPH, of Dana-Farber Cancer Center and Harvard Medical School, Boston, Massachusetts, in response to Prasad’s thread. However, like Venook, Fadelu did not consider the trial design or the way the trial was conducted to be unethical.

Venook added that a treatment break is also not out of the question in this context. Some might even say that, given the risk-benefit ratio of current options, a temporary break from treatment “is the right thing to do,” he said.

The study was funded by Hutchmed. Investigators reported ties to Hutchmed and other pharmaceutical companies. Dasari reported grants, contracts, speaker’s fees, and other payments from Hutchmed and other companies. Venook disclosed no relevant financial relationships.

Lancet. Published online June 15, 2023. Full text

M. Alexander Otto is a physician assistant with a master’s degree in medical science. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape and is an MIT Knight Science Journalism fellow. Email: [email protected].

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