Bristol's shot at eroding Keytruda's lung cancer lead looks dimmer as Opdivo-Yervoy use pulled in EU

Merck & Co.’s Keytruda now looks even safer as the leader in first-line lung cancer, thanks to another setback for chief rival Bristol-Myers Squibb.

Bristol has admitted defeat in its quest for Opdivo-Yervoy combo approval in first-line lung cancer, at least in Europe. The drugmaker withdrew its European application for the duo in previously untreated non-small cell lung cancer (NSCLC) patients—and said it doesn’t plan to try again.

The reason? Reviewers at the European Medicines Agency's Committee for Medicinal Products for Human Use found that multiple changes to the design of a clinical trial made it impossible to evaluate the data, the company said.

The study in question is CheckMate-227, a phase 3 trial divided into three parts. Part 1a is testing Opdivo with or without Yervoy against chemo in patients whose tumors express PD-L1, and Part 1b pits Opdivo-Yervoy or Opdivo-chemo against solo chemo in PD-L1-negative patients, while Part 2 looks at Opdivo in all-comers.

Bristol revamped the trial's design to initially evaluate 1a and 1b together instead, using a biomarker known as tumor mutational burden (TMB). The Opdivo-Yervoy combo did significantly delay tumor progression or death versus chemo in patients with high TMB, but the company voluntarily pulled a TMB-based FDA application in early 2019, citing a request for a survival analysis for the PD-L1-positive Part 1a subgroup.

RELATED: BMS' Opdivo-Yervoy duo nears its shot in first-line lung cancer with FDA 'priority' boost

Along the way though, Part 2 of the trial missed its mark, as Opdivo plus chemo failed to top chemo alone at prolonging first-line NSCLC patients’ lives. The company since put all its hopes on the dual immunotherapy cocktail as a potential chemo-free treatment option.

So, at last year’s European Society for Medical Oncology Congress, Bristol unveiled detailed data for the CheckMate-227 Part 1a group. It showed that the Opdivo-Yervoy combo helped PD-L1-positive patients live a median 17.1 months, compared with 14.9 months posted by chemo. That translates into 21% reduction in the risk of death.

Thanks to that clinical win, the FDA granted priority review for the pairing, with a decision set by May 15. That means though BMS won’t expect an EU nod anymore, it might win one in the U.S.

At least Bristol still has a chance to steal some share from Keytruda, which has already established a dominant position in first-line NSCLC. Last April, the Merck PD-1 king nabbed another FDA nod for Keytruda monotherapy in new NSCLC patients whose tumors express PD-L1—the same patient population included in CheckMate-227 Part 1a.

RELATED: Bristol-Myers warns I-O blockbuster Opdivo will be 'under pressure' in 2020

Based on the Keynote-042 trial, Keytruda demonstrated a survival benefit of 19% against chemo, lower than Opdivo-Yervoy’s 21%. But let’s not forget the Bristol regimen has two drugs. While CheckMate-227 lead investigator Solange Peters argued it could be “practice-changing,” skeptics have questioned its commercial relevance when Keytruda can treat the same patients by itself.

Still, Bristol has another trick up its sleeve. The New Jersey pharma recently said the Opdivo-Yervoy duo, when used on top of two cycles of chemo, also significantly extended patient’s lives in the CheckMate-9LA study.

As Wolfe Research analyst Tim Anderson noted at the time, “The commercial value of CM-9LA will therefore depend on the balance between the clinical benefit and the toxicity.”