Higher levels of genetic mutations linked to improved outcomes in lung cancer patients

According to new findings by Yale Cancer Center scientists, higher levels of genetic mutations in a tumor biopsy are linked to improved clinical outcomes in patients using pembrolizumab (Keytruda) to treat non-small cell lung cancer (NSCLC). The findings were presented today at the European Society for Medical Oncology (ESMO) conference in Barcelona, Spain.

The study suggest that oncologists will soon be able to match the use of pembrolizumab to lung cancer patients who will benefit most from the agent, the first checkpoint inhibitor to be developed and used in cancer treatment.

As is the case for all such immunotherapeutic drugs, pembrolizumab does not help a subset of patients. Because of that, the oncology community has searched for a test than can tailor therapy for use of these agents to treat lung and other cancers."
Roy S. Herbst, M.D., Ph.D., Chief of Medical Oncology at Smilow Cancer Hospital and Associate Cancer Center Director for Translational Research at Yale Cancer Center, lead study author

Herbst worked with a team of global investigators to analyze two different clinical trials that tested use of pembrolizumab as single therapy in patients with advanced NSCLC. KEYNOTE-010 tested the drug in patients who had been previously treated, such as with chemotherapy, and KEYNOTE-042 enrolled treatment naïve patients.

The scientists determined tissue tumor mutational burden (tTMB) in 253 (24%) of patients in KEYNOTE-010 and in 793 (62%) patients enrolled in KEYNOTE-042. The tTMB calculation was made by comparing whole exome sequencing of tumor tissue to matched normal DNA.

For each study, association of tTMB with outcomes was evaluated. Researchers found that, in both trials, improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR), were associated with patients with high tTMB. As with many patients using checkpoint inhibitors, all of these patients were classified as having PD-L1+ lung cancer. The designation refers to the PD-1 pathway that cancer uses to hide from killer immune cells. Switching on this pathway stops these immune cells from attacking cancer cells, allowing tumors to grow and spread. Pembrolizumab blocks this pathway.

Herbst cautions that these findings are a result of an "exploratory analysis" that was limited to observational subsets of enrolled patients. "The study offers hope that a tried-and-true biomarker that helps patients who benefit from the therapy, and which spare patients who don't from potentially toxic treatment, can be developed," said Herbst.

Yale Cancer Center