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FDA's decision to request the voluntary recall of the oral weight-loss drug lorcaserin (Belviq, Belviq XR) earlier this year came after a careful analysis of postmarketing safety data that revealed excess cancer risk and death.

Among the 12,000 patients in the CAMELLIA-TIMI 61 trial, there were 520 cancers among patients on lorcaserin (7.7%) compared with 470 (7.1%) in those on placebo, and the investigational arm saw more patients with multiple primary tumors (20 vs 8) and cases of metastatic disease (34 vs 19), reported John Sharretts, MD, of the FDA's Office Division of Metabolism and Endocrinology Products in Silver Spring, Maryland, and colleagues at the agency.

At a median of 3.3 years follow-up, 52 deaths (0.9%) from cancer occurred among patients on lorcaserin versus 33 with placebo (0.6%), as described in the .

"The agency recognizes the importance of weight-loss therapies, but the magnitude of clinical benefit associated with modest weight reduction is uncertain, and this benefit may manifest only after years of sustained weight loss," the group wrote. "Cancer risk may also be higher among patients using lorcaserin over the long term."

Overall, patients on lorcaserin had a slightly higher, though non-significant, rate of any cancer versus placebo patients (rate ratio [RR] 1.09, 95% CI 0.96-1.24), which increased when excluding common skin cancers (RR 1.16, 95% CI 0.98-1.36).

While acknowledging that the observed cancer risk was low, the FDA reviewers concluded that the drug's potential benefits do not outweigh these risks.

During the first 180 days of the trial, new cancer cases were similar between the two groups (76 and 77 in the investigational and placebo arms, respectively). But point estimates from 180 to 900 days from randomization (taken every 60 days) were consistently above 1.0, the authors noted.

"In keeping with a long-latency safety signal, cancer risk was elevated among patients in the lorcaserin group for all latency periods beyond 180 days," the group wrote. "The higher incidence of cancer-related death in the lorcaserin group is also troubling. Although we cannot exclude the possibility that the observed imbalances are due to chance, conducting another trial to confirm or refute the signal isn't feasible."

The oral weight-loss drug lorcaserin was first approved in 2012 as an adjunct to diet and exercise. A previous application was turned away "in part because nonclinical carcinogenicity studies revealed an increased incidence of several tumor types in rats exposed to the drug," the group noted. But further preclinical and clinical data submitted by the applicant at the time, along with an 18-4 vote in favor of approval from an FDA advisory committee, eventually allayed the agency's concerns.

"The cancer-related safety signal from nonclinical studies supports the plausibility of an excess cancer risk from lorcaserin, and the consistency of cancer findings in CAMELLIA-TIMI 61 and the robustness of sensitivity analyses further support a causative effect," wrote Sharretts and colleagues. "The increased risk of various cancer types associated with lorcaserin in the clinical study reflects the pattern seen in nonclinical studies."

Colorectal cancer occurred more frequently in the lorcaserin group, with 26 versus 14 with placebo, as did pancreatic cancer (16 vs 2, respectively), lung cancer (40 vs 25), leukemia (12 vs 6), hepatobiliary cancers (10 vs 4), and others. Some neoplasms were less common in the lorcaserin group, including prostate (61 vs 70), endometrial (6 vs 13), and bladder (7 vs 13) cancers.

The agency's decision was based on findings from CAMELLIA-TIMI 61, a randomized placebo-controlled trial, which from 2014 to 2018 randomized 12,000 patients 1:1 to either lorcaserin or placebo. The postmarketing study was designed to assess cardiovascular safety, of which it met its goal, and was not powered to assess cancer endpoints. Participant smoking status and cancer history had been well balanced between the two arms.

In the published data for the safety trial, which focused on lorcaserin's effect on major adverse cardiovascular events, no increased cancer risk was seen. But FDA examined all adverse events post-randomization in the study, rather than just "on treatment" events, wherein the signal for an increased cancer risk emerged.

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