Keytruda looks to secure a June double play

Merck & Co faces two US FDA decisions in June, and neither is an obvious guarantee of success.

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As Keytruda established itself definitively as the PD-(L)1 drug of choice in lung cancer Merck & Co moved to broaden its reach. Next up for consideration by a positively predisposed US FDA are front-line head and neck cancer and advanced use in the small-cell type of lung malignancy.

Neither of the newly sought approvals a slam dunk, and even if the approvals are granted there is a risk that they might not translate into a huge prescription uplift. Keytruda already carries the first use on its label, albeit in later lines of the diseases, thanks to accelerated approval based on uncontrolled remission data.

By June 10 the FDA will rule on Keytruda’s approvability in first-line head and neck cancer on the basis of the drug’s positive hit in the Keynote-048 trial.

The irony here is that, while the Merck drug holds second-line head and neck cancer approval, it earlier failed Keynote-040, the trial that was to have confirmed this. Merck has withdrawn a US filing for full second-line registration, and moved instead to file for front-line use based on Keynote-048.

At Esmo last year the Keynote-048 data raised at least as many questions as answers: for instance, in terms of overall survival Keytruda monotherapy beat chemo alone in PD-L1-high subjects, but not in all-comers; Keytruda plus chemo worked in all-comers versus chemo alone, but showed no advantage in high PD-L1 expressers.

Merck appears to be taking two shots at its approval goal, though it has not spelled out precisely which settings it is targeting. When its filing was accepted in February the group said this included use of Keytruda monotherapy or its combination with platinum and 5-FU chemo.

Keytruda in head & neck cancer
Study Trial ID Detail
Keynote-040 NCT02252042 OS, 495 2L subjects
Keynote-048 NCT02358031 OS, PFS, ORR, 882 1L subjects, +/- chemotherapy

Merck faces a separate problem in SCLC, which was once seen as an especially intractable cancer type, but in which important advances have recently been made. These involve the march of immunotherapy, where Bristol-Myers Squibb’s Opdivo, Roche’s Tecentriq and Keytruda itself have yielded registrational data.

The first two already carry SCLC labels, and by June 17 the US FDA will decide on Keytruda’s approvability in patients who have failed two or more prior therapies.

The reason why for Merck a thumbs-up could be a non-event is that Tecentriq already carries a first-line label, courtesy of the Impower-133 trial. This means that the pool of later-line patients who have not already been exposed to immunotherapy will likely be shrinking.

In a similar way Tecentriq threatens to render Opdivo’s own third-line label obsolete. And a separate problem for Bristol is that Opdivo has now flunked two potentially registrational trials, Checkmate-331, in second-line patients, and the front-line Checkmate-451.

For Merck a much more pivotal event is data from the first-line Keynote-604 trial, which will show if Keytruda stands a chance against Tecentriq; however, readout of this has been delayed to December.

Merck’s filing is based on pooled analysis of SCLC cohorts from the Keynote-028 and 158 trials, a dataset in which 88% of the reported responses were seen in PD-L1-positive subjects. The FDA limiting Keytruda’s label to PD-L1 positives is therefore another immediate risk to Merck in SCLC.

Investors will also keep an eye on Astrazeneca’s front-line Caspian study of Imfinzi, due in September, and Pharmamar’s Zepsyre, whose second-line Atlantis trial reads out at the end of the year.

Keytruda in SCLC
Study Trial ID Detail
Keynote-158 NCT02628067 ORR, 1,350 pts w various tumours
Keynote-028 NCT02054806 ORR, 477 pts w various tumours
Keynote-604 NCT03066778 PFS & OS, 453 1L subjects, on top of platinum therapy

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