Merck's Keytruda survives FDA scrutiny in bladder cancer, but ends up with a smaller label

The updated bladder cancer indication for Merck's Keytruda marks a further step down from the original accelerated approval doled out in 2017. (Merck & Co.)

After a positive opinion from a panel of independent FDA advisers, Merck has won a full FDA go-ahead for Keytruda in newly diagnosed advanced bladder cancer. But there’s a catch.

The FDA has converted Keytruda’s conditional nod in newly diagnosed advanced bladder cancer into a full approval, Merck said Tuesday. But the new label only covers patients who are ineligible for any platinum-containing chemotherapy.

The updated indication marks another step down from the drug’s original accelerated approval, which the FDA awarded in 2017 for front-line patients who aren’t suitable for a specific type of platinum-based chemotherapy, cisplatin.

For Keytruda’s use in front-line bladder cancer, problems emerged in mid-2018. Partway through the confirmatory phase 3 Keynote-361 trial, an independent data monitoring committee noted that patients who had low PD-L1 expression levels performed even worse on Keytruda than those who were on platinum chemotherapy.

The FDA immediately restricted the drug’s use to cisplatin-ineligible patients with PD-L1 levels at a combined positive score of at least 10, plus all patients who can’t take any form of platinum therapy.

Later, the full Keynote-361 data showed that even a Keytruda-chemotherapy regimen failed to significantly outperform solo chemo.

Thanks to that trial flop, the FDA targeted the drug’s front-line bladder cancer indication in its recent campaign to analyze accelerated approvals for checkpoint inhibitors that haven’t panned out in confirmatory trials.

RELATED: FDA panel backs Merck's Keytruda nod in 1L bladder cancer—but new limits could be coming

In April, an advisory committee convened by the FDA voted 5-3 in favor of keeping Keytruda’s already-limited front-line bladder cancer nod in place. But the experts suggested that the label could be further trimmed to only include those who aren’t eligible for any platinum chemo. The FDA has now followed that recommendation.

Meanwhile, the availability of Pfizer and Merck KGaA’s PD-L1 inhibitor Bavencio in the front-line setting for platinum-eligible patients gave the advisory committee and the FDA more reason to cut back on Keytruda. Since late last June, that drug has carried a full FDA approval for first-line patients who haven’t progressed on platinum-containing chemotherapy.

Even if it's in the form of a smaller label, keeping Keytruda's front-line indication is a win for Merck. Under pressure from FDA’s industry-wide review, the New Jersey pharma has withdrawn Keytruda’s indications in third-line stomach cancer and third-line small cell lung cancer.

RELATED: Roche joins the FDA accelerated approval revamp team, nixing a Tecentriq bladder cancer nod

For its part, Roche’s PD-L1 inhibitor Tecentriq also struggled in a confirmatory trial in front-line bladder cancer. That led the FDA to limit its conditional nod to cisplatin-eligible patients with PD-L1 expression covering at least 5% of tumor-infiltrating immune cells and patients who aren’t suitable for any platinum chemo.

During the same advisory committee meeting in April, an FDA panel voted 10-1 in favor of keeping Tecentriq’s conditional nod pending final analysis of the confirmatory IMvigor130 trial, which is expected in 2022.

In addition, Roche has removed Tecentriq’s conditional nod in second-line bladder cancer amid the FDA’s campaign. Keytruda’s second-line advanced bladder cancer use remains intact, and so does its nod for high-risk, non-muscle-invasive bladder cancer.