Merck’s Keytruda is without doubt the king in previously untreated non-small cell lung cancer, but the company wanted to see whether adding another immuno-oncology agent from rival Bristol Myers Squibb would offer additional benefit. Turns out, doing that adds more harm and no good.
Merck decided to stop adding Bristol Myers’ CTLA-4 inhibitor Yervoy to Keytruda in a phase 3 trial among newly diagnosed patients with metastatic NSCLC whose tumors express PD-L1, the New Jersey pharma said Monday.
The termination came after an independent data monitoring committee found the combo was not at all better than solo Keytruda at staving off cancer progression or extending patients’ lives. Instead, more severe side effects cropped up in the dual-therapy arm than in the monotherapy group, to the point where the expert panel is asking patients to stop taking Yervoy or placebo.
“It is very clear that in this study, the addition of ipilimumab did not add clinical benefit but did add toxicity,” Roy Baynes, chief medical officer of Merck Research Laboratories, said in a statement.
This is not the first time the addition of Yervoy to a PD-1 drug didn’t confer additional efficacy. A year ago, BMS revealed that the pairing of Opdivo and Yervoy wasn’t better than solo Opdivo at preventing cancer recurrence when used after surgery in late-stage PD-L1-low melanoma. Fast forward to this October, when the company said even the all-comer population in that CheckMate-915 trial didn’t enjoy better outcomes from the combo.
But the new Keytruda trial failure could cast doubt on a combination of Opdivo and Yervoy in the sense of its competition with Keytruda in the all-important first-line NSCLC indication.
In May, the FDA approved the Opdivo-Yervoy cocktail as a first-line treatment for NSCLC patients whose tumors test positive for PD-L1, and then for the I-O duo alongside two cycles of platinum chemo for first-line patients regardless of PD-L1 status.
The Checkmate-227 trial showed the duo cut the risk of death among PD-L1-positive patients by just 21% over chemo, and the Checkmate-9LA trial showed Opdivo, Yervoy and chemo slash that risk by 31%.
None of those numbers came close to the 51% death risk reduction a Keytruda-chemo combo posted in the Keynote-189 trial. Opdivo by itself has failed to move the needle in first-line NSCLC as well.
As for Keytruda, it nabbed a solo nod in front-line NSCLC in 2016 based on data from the Keynote-024 trial. Updated data presented at September’s European Society for Medical Oncology’s virtual annual meeting showed the drug almost doubled the five-year survival rate over chemo in the same PD-L1-positive patient population included in the currently failed Keynote-598 study.
And now, the Merck trial showed Yervoy isn’t a powerful enough drug to improve upon Keytruda’s showing. Just do the math: Keytruda-Yervoy is not better than Keytruda, and Opdivo failed as solo regimen where Keytruda boasts an approval, so that likely means Opdivo-Yervoy might not outdo solo Keytruda, let alone the Keytruda-chemo pairing.
In a statement, a BMS spokesperson pointed to the Opdivo-Yervoy's survival benefits in Checkmate-9LA and Checkmate-227 as evidence that the pairing does work, stressing the importance of the contribution of Yervoy to the combo.
"Notably, Opdivo plus Yervoy is the first and only dual immunotherapy combination approved anywhere in the world, and to date, it has shown clinical benefit across six different tumor types," the spokesperson said. "Additionally, following years of clinical experience across multiple tumors, the safety profile of Opdivo plus Yervoy is well understood and manageable, with known protocols to address adverse events."
Merck said it will present detailed data from Keynote-598 at an upcoming medical meeting.
Editor's Note: The story has been updated with comments from Bristol Myers Squibb.