Merck's Pembrolizumab Playbook
- The development of pembrolizumab redefined cancer immunotherapy and rewrote how Merck thinks about building drugs.
- The lessons embedded in pembrolizumab’s development — biomarker selection, innovative trial structure, totality of evidence — are now being used with calderasib, Merck’s next-generation KRAS G12C inhibitor.
- Calderasib is being developed in combination with pembrolizumab itself for patients who are both G12C positive and PD-L1 expressing. The same biomarker logic that defined pembrolizumab’s first approval is now driving its next.
- The FDA recently granted calderasib Breakthrough Therapy Designation for non-small cell lung cancer patients who are both G12C positive and PD-L1 expressing.
Pembrolizumab redefined cancer immunotherapy and rewrote how Merck thinks about building drugs.
The lessons embedded in pembrolizumab’s development — biomarker selection, innovative trial structure, totality of evidence — are now the blueprint. And calderasib, Merck’s next-generation KRAS G12C inhibitor, is the clearest proof that the blueprint is being followed.
When pembrolizumab was in development, the field was divided on trial design. Most companies enrolled broad populations, with no biomarker filter, betting that a wide enough effect would be sufficient for approval. Merck made a different call.
“Others were looking at an all comers population, not looking at biomarkers that might enrich for the response, thinking that all patients may benefit,” Dr. Jane Healy, who leads early clinical development and clinical pharmacology at Merck, tells SurvivorNet Connect. “We felt differently. We wanted to make sure that we were designing the trial to look for the patients that might benefit most.”
Selecting for PD-L1 expression narrowed the population and raised the stakes on the biomarker hypothesis. But it produced a cleaner signal, a stronger approval, and ultimately broader patient access.
The First Tumor Agnostic Approval
That decision set in motion something no drug had done before. Pembrolizumab achieved the first tumor-agnostic FDA approval based on a biomarker — MSI-high, a mutation associated with deficient mismatch repair genes. The regulatory strategy was novel: a basket trial across tumor types as primary evidence, layered with retrospective analysis from existing pembrolizumab trials in lung, melanoma, and bladder cancer.
“We used the totality of those pieces of evidence to make a case for the biomarker,” Dr. Healy says. “It was a really crucial drug strategy for getting access to pembrolizumab across tumor types as quickly as possible in patients that would benefit most.”
That is where the pembrolizumab playbook comes full circle. Calderasib is being developed in combination with pembrolizumab itself for patients who are both G12C positive and PD-L1 expressing. The same biomarker logic that defined pembrolizumab’s first approval is now driving its next.
The trial structure mirrors the MSI-high model: a Phase 3 registration trial in non-small cell lung cancer running alongside a basket study across any tumor type harboring the G12C mutation. Two tracks, building a totality of evidence, exactly as before.
The FDA recently granted calderasib Breakthrough Therapy Designation for non-small cell lung cancer (NSCLC) patients who are both G12C positive and PD-L1 expressing — validating the target, the patient selection, and the combination strategy in a single designation.
A Strategy That Defines the Pipeline
“We believe very strongly and invest very deeply in the importance of biomarkers to reach the right patients,” Dr. Healy says. “And we are using that to inform the subsequent drugs we are developing in the pipeline.”
Pembrolizumab didn’t just succeed as a drug. It became the standard by which every drug that follows it gets built.
