Biomarker TMB Not A Reliable Predictor of Treatment Response in Lung Cancer

Two studies conclude that biomarker TMB is not a predictor of immunotherapy response in lung cancer patients treated with Keytruda and/or Chemotherapy

Immunotherapy is a promising new approach in oncology, but it does not work equally well for all types of cancer or for all patients with a specific cancer type. Researchers are therefore exploring various biomarkers that might help identify individuals who are likely to respond well.

Keytruda is a PD-1 checkpoint inhibitor, a type of immunotherapy that helps the immune system fight cancer. PD-1 is a receptor on T cells that plays a role in regulating immune function. Some tumors can hijack PD-1 to turn off immune responses against them. Drugs that block PD-1 or its binding partner, known as PD-L1, can release the brakes and restore T-cell activity. People with higher levels of PD-L1 in their tumors tend to do better on checkpoint inhibitors, but this is not a reliable predictor of individual response.

Another biomarker candidate is tumor mutational burden, a measure of the number of genetic changes in a tumor. Studies have shown that so-called “hot” or inflamed tumors filled with immune cells are more susceptible to checkpoint inhibitors. Such tumors typically have a large number of mutations, sometimes called neoantigens, which attract T cells. Thus, researchers have hypothesized, measuring TMB might predict response.

This turned out not to be the case, however, in two clinical trials that compared Keytruda plus Alimta (pemetrexed) and carboplatin platinum-based chemotherapy versus standard-of-care chemotherapy alone in people with previously untreated metastatic nonsquamous lung cancer (NSCLC).

TMB was not significantly associated with overall response rate, progression-free survival or overall survival in either the Keytruda plus chemotherapy or chemotherapy-only groups, Corey Langer, MD, of the University of Pennsylvania’s Abramson Cancer Center reported this week at the World Conference on Lung Cancer (WCLC) in Barcelona. There was also no correlation between TMB and PD-L1 levels.

Summarizing the study results, Langer, suggested that TMB is “not ready for prime time” as a predictor of treatment response. 

Marina Garassino, MD, of Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, presented findings from a similar analysis of participants in Keynote-089.