Researchers show genetic mutations in advanced lung cancer may predict improved outcomes

Newswise — New Haven, Conn. — 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,” said lead study author 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. “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.”

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.

Support for this study was provided by Merck.

About Yale Cancer Center Yale Cancer Center (YCC) is one of only 51 National Cancer Institute (NCI-designated comprehensive cancer) centers in the nation and the only such center in southern New England. Comprehensive cancer centers play a vital role in the advancement of the NCI’s goal of reducing morbidity and mortality from cancer through scientific research, cancer prevention, and innovative cancer treatment.

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