Merck took a dominant position in frontline lung cancer with the approval of a combination of Keytruda and chemo. And it isn’t just waiting around to see if any combination of a PD-(L)1 with a CTLA4 can come along and knock it off its market-leading perch.

The pharma giant has launched a Phase III study combining its checkpoint star with the Bristol-Myers drug. Researchers are recruiting 548 patients at sites around the world, according to the listing at clinicaltrials.gov.

The jury is still definitely out on how a PD-(L)1/CTLA-4 combo will work. Yervoy and its class has been effective in improving survival rates, but they’re also associated with significant toxicity, which makes their use problematic.

Merck also has its own CTLA-4 (MK-1308), which it is combining with Keytruda. So why add Yervoy to the mix?

The simplest explanation may be that Merck, which has hundreds of combo studies underway, is trying everything. It’s also been spurred on by Bernstein’s Tim Anderson.

Since 2016, we have argued it would be wise for MRK to run combination trials of Keytruda+Yervoy trial in 1L lung cancer.  Even though MRK does not own Yervoy, it could still easily design a study like this, and it would be a hedge against the possibility that AZN’s MYSTIC and BMY’s Checkmate-227 show that CTLA4+PDx combination therapy is viable (its viability remains unclear at the moment).

MYSTIC, of course, has proven to be something of an embarrassment to AstraZeneca so far, with durvalumab and tremelimumab missing the first goal on progression-free survival. They’re still shooting for overall survival, though, and aren’t completely counted out in a field that routinely provides extraordinary surprises.

Anderson has urged Merck to “go big or go home” on this front. I have no idea what Merck, which went big on Keytruda several years ago, thought of that. But Anderson has some influence here and is not to be ignored.

The trial will only enroll high PDL1 expressers (>50%), and boldly, it will compare this combination to Keytruda monotherapy (which has become standard of care anyway; recall that MYSTIC and ‘227 don’t have a PDx as a comparator, but only conventional chemotherapy). The primary endpoints are PFS and OS, but results won’t be in hand until 2022 per clinicaltrials.gov (link); this timeline is arguably conservative.

Bristol-Myers and CytomX, meanwhile, are working on a new CTLA-4 that they hope will prove just as efficacious or more while significantly less toxic.