- The case for broadly using Merck & Co.'s Keytruda with chemotherapy in treating metastatic lung cancer appears even stronger following fresh data presented by the drugmaker at the World Conference on Lung Cancer in Barcelona.
- Study analyses done by Merck showed the combination to be similarly effective regardless of whether treated patients tested positive for PD-L1 or for high levels of tumor mutational burden, two biomarkers commonly used to guide treatment with immunotherapy.
- "In the setting of chemo combinations, it does not appear that PD-L1 or TMB influences the outcome," said Roy Baynes, head of global clinical development at Merck, in an interview.
Biomarkers are a central part of cancer immunotherapy's commercial story.
Merck's now leading position in the field hinged in large part on its decision to initially take a more conservative approach and test Keytruda (pembrolizumab) only in patients whose tumors expressed high levels of PD-L1. That choice led to the first approval for an immunotherapy in previously untreated lung cancer.
Rival Bristol-Myers Squibb, by comparison, sought early on to prove its drug Opdivo (niovlumab) in a broader population and failed, a setback that allowed Merck to catch up and then surpass Bristol-Myers in market share.
And while both drugs can deliver strong benefits for some patients, others see little improvement — making more critical efforts by drugmakers to understand who should receive treatment.
In lung cancer, Keytruda plus chemotherapy has become standard treatment thanks to strong data in several Phase 3 studies.
A pooled analysis presented Tuesday of three of those trials — KEYNOTE-021, -189 and -407 — strengthen the case that the pairing should be used regardless of whether patients' tumors express PD-L1.
Across 428 study participants who didn't express PD-L1, measured by a tumor proportion score of less than 1%, Keytruda plus chemo reduced the risk of death by 44% versus chemo alone.
While data from KEYNOTE-189 already supported broad use of Keytruda together with chemo, Merck's pooled analysis helps reinforce that conclusion further.
"PD-L1 remains an excellent biomarker in the setting of monotherapy," said Baynes. "It does not impact the outcome with chemo combinations."
Perhaps more interestingly, Merck reached a similar conclusion regarding tumor mutation burden, a biomarker more favored by immunotherapy rivals Bristol-Myers and AstraZeneca.
Retrospective study of KEYNOTE-189 and KEYNOTE-021 found no difference in survival between treated patients who were TMB-high or TMB-low, defined using a cut-off threshold of 175 mutations per exome.
In both groups in KEYNOTE-189, Keytruda plus chemo cut the risk of death by 36% compared to chemo alone.
"There does not appear to be a role for tTMB in identifying patients with metastatic NSCLC who will experience a survival benefit from Keytruda in combination with chemotherapy," said Merck in a statement to BioPharma Dive, referring to tissue TMB.
Both Bristol-Myers and AstraZeneca have used TMB in recent Phase 3 studies, hoping to find a group of patients in which their respective immunotherapies show a significant benefit.
That effort came up empty for AstraZeneca in its NEPTUNE study, while data from Bristol-Myers has shown TMB-high and TMB-low patients benefited similarly from treatment with Opdivo plus its other immunotherapy Yervoy (ipilimumab).
An attempt to win approval for that combo based on those progression-free survival results led to a regulatory delay before Bristol-Myers eventually pulled its application, seemingly on questions of TMB's utility.
Recent results from that same study showed Opdivo and Yervoy helped patients live longer than just chemo, but didn't show a similar effect for Opdivo plus chemo — an outcome that could limit the impact of any approval the pharma might gain in the future. More data is expected from that study later this month at the annual meeting of the European Society of Medical Oncology.