KRAS Inhibition May Improve Efficacy of Immune Checkpoint Blockade in Lung Cancer

New research suggests that some patients with lung cancer might benefit from combining a KRAS inhibitor with immune checkpoint inhibition, according to a new report.

The study, published in Science Advances, is based on experiments in mice, but the authors say the findings could help direct future clinical trials in humans. They noted that a significant unmet need remains in lung cancer treatment.

Despite recent advances in immunotherapy, lung cancer remains the deadliest cancer type, killing 1.8 million people each year. The most common type of lung cancer, non–small cell lung cancer (NSCLC), has a 5-year survival rate of just 25%, the authors noted.

The introduction of immune checkpoint blockades, such as anti–programmed cell death protein-1 (PD-1) therapy, has led to prolonged responses in some patients.

“However, only a minority of patients respond and, of those that do, many develop resistance over time,” the authors wrote.

Thus, a significant amount of current research focuses on trying to find ways to combine immune checkpoint blockades with other therapies in order to boost efficacy.

One potential strategy for a combination therapy is KRAS inhibition. KRAS is a gene that helps control cell growth and death. KRAS mutations are present in about one-third of lung adenocarcinoma cases, making it a promising therapeutic target, the study authors said. Historically, they noted, inhibiting KRAS was “notoriously difficult.” However, last year, the FDA granted an accelerated approval to sotorasib (Lumakras) for patients with KRAS G12C–mutated NSCLC. The G12C mutation is present in about 40% of patients with KRAS-mutated NSCLC.

The investigators therefore decided to see whether combining KRAS inhibition with immune checkpoint blockade would lead to positive effects in mice. They found that it did—but only for certain patients.

In patients with “immune hot” tumors, with high numbers of active T cells, the treatment helped control the cancer. In cases where there was not already a strong immune response—so-called “immune cold” cancers—the therapy did not produce a meaningful result.

The mouse-model findings could help investigators better identify the patients most likely to respond to immune checkpoint blockade/KRAS inhibitor combination therapy. This is particularly important because most of the earlier clinical trials assessing the combination have involved patients who have already been nonresponders to immune checkpoint therapy. The new report suggests those patients are likely not “immune hot” and so they would not be ideal candidates for immune checkpoint blockade/KRAS inhibitor therapy.

“KRAS inhibitors are very new, so there’s still a lot to learn about when they are most effective and which other treatments they can safely be combined with to give patients the best chance of living longer,” said Miriam Molina Arcas, PhD, principal research scientist at the Crick Institute’s Oncogene Biology Laboratory, in a statement. “Our study is an important part of this, suggesting that combining immune checkpoint blockade with a KRAS inhibitor is likely to work in specific cancers. It is crucial this is factored into the design of future clinical trials.”

In addition to their findings related to KRAS inhibition, the study also helped explain the role of KRAS mutations. The investigators found that mutated KRAS weakens immune signals and boosts tumor-friendly molecules. Inhibiting the mutated gene also inhibited those pro-tumor effects.

Reference

Mugarza E, van Maldegem F, Boumelha J, et al. Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. Sci Adv. Published online July 20, 2022. doi:10.1126/sciadv.abm8780