Failed trial dashes Merck’s hopes for Keytruda in first-line bladder cancer

Checkpoint inhibitors have already transformed the treatment of bladder cancer that has relapsed after chemotherapy, but Merck & Co/MSD’s bid to move its Keytruda drug into front-line use has stalled.

The results of the KEYNOTE-361 trial showed that adding PD-1 inhibitor Keytruda (pembrolizumab) to platinum-based chemo for previously untreated advanced urothelial carcinoma (UC) – the most common form of bladder cancer – didn’t improve outcomes for patients whose disease had metastasised to other parts of the body.

Keytruda is already approved as a first-line treatment for UC in patients who can’t tolerate cisplatin-based chemo – as is Roche’s PD-L1 inhibitor Tecentriq (atezolizumab) – but the failed study prevents broader use of Merck’s drug in these patients and offers an advantage to rival drugs.

Previously-untreated bladder cancer is split roughly 50:50 between patients who can and cannot be treated with chemotherapy.

In KEYNOTE-361, Keytruda plus chemo was numerically better than chemo alone on the two primary endpoints of overall survival and progression-free survival, but the difference wasn’t large enough to be statistically significant, according to Merck.

The PD-1 inhibitor was also tested as a monotherapy against chemo in the trial, but this data wasn’t analysed “since superiority was not reached for OS or PFS in the Keytruda combination arm”.

It’s not the first checkpoint inhibitor to fail in this setting. In March, AstraZeneca revealed that its PD-L1 inhibitor Imfinzi (durvalumab) – given on its own and in combination with experimental CTLA4 inhibitor tremelimumab – was also unable to improve on chemo in first-line metastatic UC.

Last year, however, Roche showed that Tecentriq given alongside chemotherapy was more effective than chemo alone in previously-untreated patients in the IMvigor130 trial, setting up regulatory filings that would consolidate its lead in this type of tumour.

Merck KGaA/Pfizer’s PD-L1 inhibitor Bavencio (avelumab) meanwhile claimed the distinction of becoming the first checkpoint inhibitor to improve OS in previously-untreated UC patients in the JAVELIN Bladder 100 trial, although that involved use of the drug as first-line maintenance rather than initial treatment.

For now, this is a set-back for Merck’s hopes of extending the reach of Keytruda in bladder cancer. That said, aside from its approval in treatment-naïve cisplatin-ineligible and second-line UC, Keytruda is the first checkpoint inhibitor to get approval in the US for high risk non-muscle-invasive bladder cancer (NMIBC).

NMIBC is the most commonly encountered form of bladder cancer, accounting for around 75% of the 80,000 new cases each year in the US. Keytruda has been cleared for use in high-risk patients who don’t respond to Merck’s TICE Bacille Calmette-Guérin (BCG) vaccine and are unwilling or unable to have surgery to remove the bladder.