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Merck follows Bristol’s suit, pulling Keytruda’s SCLC nod. Is the FDA’s accelerated approval reckoning finally here?

Merck is voluntarily withdrawing Keytruda’s U.S. indication in small cell lung cancer amid an FDA review of accelerated approvals that didn’t pan out in confirmatory trials. (Merck)

Several cancer drugs cleared under the FDA accelerated approval program have remained on the market for years despite failing trials designed to confirm earlier-stage success. The FDA simply hasn’t acted in the face of those flops.

Critics have called out the agency for compromising its regulatory standards to no result. Until now.

In recent weeks, drugmakers suddenly began pulling indications for their immuno-oncology therapies after their failures in confirmatory trials. The latest? Merck & Co. for its megablockbuster PD-1 inhibitor Keytruda in small cell lung cancer (SCLC).

The New Jersey pharma is voluntarily withdrawing Keytruda’s U.S. indication in third-line SCLC, the company said Monday. Merck said it made the decision after talking to the FDA, and the retraction process is expected to be complete over the coming weeks.

As Merck put it, its call to account at the FDA is “part of an industrywide evaluation of indications based on accelerated approvals that have not yet met their post-marketing requirements.”

Indeed, the Keytruda withdrawal followed a similar move by Bristol Myers Squibb for its rival PD-1 inhibitor Opdivo. BMS pulled Opdivo at the end of 2020, also in SCLC. Just a few days ago, AstraZeneca did the same for its PD-L1 drug Imfinzi, but in previously treated bladder cancer.

Keytruda won accelerated approval in SCLC in June 2019 based on tumor response rate and duration of response data from the phase 1 Keynote-028 trial and phase 2 Keynote-158.

But, last January, the drug flunked its phase 3 in that form of lung cancer. The Keynote-604 trial found that adding Keytruda to chemotherapy couldn’t outdo solo chemo at prolonging the lives of newly diagnosed patients with extensive-stage SCLC. The study was supposed to serve as the confirmatory trial for the original SCLC nod.

RELATED: Merck’s Keytruda misses key mark in small cell lung cancer trial, dashing big expansion hopes

Keytruda rounds out the rule of three, pointing to a possible clean out at the FDA to finally remove accelerated nods doled out based on surrogate markers but later contradicted in confirmatory studies—or those that simply didn’t honor their post-marketing data commitments.

The accelerated approval pathway was first introduced in 1992 in response to the HIV pandemic and was updated in 2012 to allow conditional nods based on surrogate clinical endpoints that are “reasonably likely” to predict clinical benefit. The program is heavily used in oncology to bring breakthrough therapies to patients faster.

RELATED: Opdivo’s in small cell lung cancer no more as Bristol Myers pulls out after trial failure

While green lights granted under this pathway are contingent on outcomes from confirmatory trials, very few have actually revoked a failed indication—until recently.

Bristol Myers pulled Opdivo in third-line SCLC after the med failed two confirmatory studies that tested either Opdivo or a combo of Opdivo and fellow CTLA4 inhibitor Yervoy in earlier lines of treatment. And AstraZeneca removed Imfinzi in second-line bladder cancer after the phase 3 Danube trial couldn’t back the use of solo Imfinzi or a cocktail with CTLA4 inhibitor tremelimumab in previously untreated patients.

With these three I-O withdrawals, other Keytruda approvals might be in danger. For example, the drug’s use in liver cancer patients previously treated with Bayer’s Nexavar; that’s an accelerated approval based on tumor shrinkage data from the phase 2 Keynote-224 trial. In the phase 3 Keynote-240 trial, Keytruda failed to extend either the lives of patients or the time patients lived without their disease worsening.

RELATED: After Imfinzi’s double flop, AstraZeneca walks away from FDA bladder cancer nod

Opdivo suffered a similar setback in front-line liver cancer with the CheckMate-459 trial, which was meant to confirm its 2017 nod for post-Nexavar patients. A year ago, the Opdivo-Yervoy combo also snagged an accelerated approval in the second-line liver cancer setting.

There’s also Keytruda’s indication in third-line gastric or gastroesophageal junction adenocarcinoma. The drug stumbled in Keynote-061 and Keynote-062 trials for previously treated and front-line patients, respectively. Those two failures were registered in 2017 and 2019, before the SCLC flop at hand, but the third-line conditional nod remains in place.

So far, it’s not clear what specific standards the FDA’s using in persuading the companies to withdraw their failed indications. Back in 2017, Roche was allowed to keep Tecentriq’s conditional approval in previously untreated cisplatin-ineligible bladder cancer and in patients who’ve had platinum chemo despite a confirmatory trial miss.


Originally posted on fiercepharma.com