Merck's Keytruda flops bladder cancer trial, giving Roche's Tecentriq an open shot

Merck & Co.’s Keytruda has several clinical wins under its belt that have led to a long list of FDA approvals. But it can’t count newly diagnosed bladder cancer as another triumph—at least, not for now.

Keytruda, whether used alone or in combination with chemotherapy, failed to significantly stall the progression of tumors or prolong patients’ lives compared with standard-of-care chemo, Merck said Tuesday.

There was an improvement on both markers in favor of the Keytruda-chemo combo, but the benefit didn’t cross the statistical significance threshold. Full results are expected to be shared at an upcoming medical meeting.

Failure of the phase 3 Keynote-361 trial could endanger Keytruda’s conditional FDA approval for first-line bladder cancer in cisplatin-ineligible patients whose tumors express PD-L1 at a combined score of at least 10 or in patients who aren’t able to receive any platinum-containing chemo regardless of PD-L1 status. Merck said it will discuss the new data with regulatory authorities.

In a Wednesday note, SVB Leerink analyst Daina Graybosch said she doesn’t expect the nod will be in jeopardy, pointing to other Keytruda confirmatory trial failures in previously treated liver cancer and small cell lung cancer, neither of which has led to the FDA pulling an approval. 

The FDA doled out the first-line bladder cancer green light in 2017 but later narrowed it in 2018 after the agency noticed some patients performed even worse than those who got chemo.

Roche’s rival PD-L1 inhibitor Tecentriq suffered a similar fate when the FDA also limited its bladder cancer use in 2018. The difference is, Keytruda proved it could extend patients’ lives over chemo in the second line while Tecentriq surprisingly failed in the setting but still managed to keep that nod.

RELATED: ESMO: Roche's Tecentriq-chemo combo barely tops chemo in bladder cancer

Now, Keytruda’s flop could give Tecentriq a chance at a bigger share of the front-line market, especially as AstraZeneca’s Imfinzi, both as a monotherapy and in tandem with the company’s own experimental CTLA-4 inhibitor tremelimumab, also failed to show an overall survival benefit.

Last fall, Roche reported that the IMvigor130 trial testing the Tecentriq-chemo pairing against chemo had come up positive. The combo cut the risk of disease progression or death by 18% in previously untreated bladder cancer, regardless of PD-L1 expression level. Overall survival data were not mature at that time.

Not all Tecentriq bladder cancer trials have gone according to Roche’s plan, though. Recently, the drug failed to fend off tumor progression in the phase 3 Imvigor010 trial in muscle-invasive bladder cancer patients after surgery.

Keytruda had its own victory in that department, having recently become the first PD-1/L1 drug to win an FDA nod to treat non-muscle invasive bladder cancer that’s unresponsive to standard Bacillus Calmette-Guerin treatment.

Despite the current failure, Keytruda still has other opportunities in first-line bladder cancer. Seattle Genetics recently unveiled that in the phase 1b/2 EV-103 trial—also known as Keynote-869—pairing its Astellas-partnered antibody-drug conjugate Padcev with Keytruda in newly diagnosed cisplatin-ineligible patients shrank tumors in 79% of patients with PD-L1-high tumors and in 69% in PD-L1-low cases, with altogether 54% of responses lasting at least 12 months. The phase 3 EV-302 trial is evaluating Padcev-Keytruda with or without chemotherapy in new patients regardless of their eligibility for cisplatin chemo.

Graybosch argues that the Padcev pairing is now even more important for Keytruda in first-line bladder cancer after the Keynote-361 defeat.