Who might better benefit from KRAS and PD-1 combos? New Mirati drug study offers a clue

Immune checkpoint inhibitors such as anti-PD-1 therapies, which work by unleashing T cells’ anti-tumor power, have become a standard of care for non-small cell lung cancer. Targeted therapies have also served as powerful tools against cancers bearing specific genetic alterations. But resistance may develop against both types of therapies, so scientists and drugmakers have been considering pairing them up.

With the recent FDA approval of Amgen’s Lumakras, that combinational approach is being explored in KRAS inhibition.

In a new study published in Science Advances, scientists at the U.K.’s Francis Crick Institute shed some lights on the effect of targeted KRAS G12C inhibition on anti-tumor immunity. The team also showed in mice how combining a KRAS inhibitor with an anti-PD-1 drug might work better in some tumors, offering insight into potential patient selection criteria for drug development efforts exploring such combos.

“As the [KRAS] mutation is present in about one third of lung cancer cases, it is a promising therapeutic target,” the study’s senior author, Julian Downward, Ph.D., said in a statement.

Digging into the effect of KRAS mutations on the immune system, Downward and colleagues found in both cell lines and mouse models that in lung cancer, cancer-related KRAS could tamp down the interferon signaling, which is known to be critical for an anti-tumor immune response and sensitivity to immunotherapy.

Treating lung tumors with a Mirati Therapeutics KRAS inhibitor called MRTX1257 could reverse that immune evasion mechanism by enhancing an interferon response and remodeling certain immune factors, the team showed. MRTX1257 is a compound closely related to Mirati’s adagrasib, which is currently under FDA review for KRAS-mutant non-small cell lung cancer.

What’s more, in a mouse model of immune-evasive KRAS-mutant lung cancer, treatment with the Mirati drug blocked immunosuppressive myeloid cells from entering the lung tumor microenvironment while boosting the recruitment and activation of cancer-killing T cells.

The way MRTX1257 remodeled the tumors’ surrounding environment gave the scientists hope that the treatment might sensitize these tumors to immune checkpoint inhibitors.

But to their disappointment, in two groups of mice carrying different immune-resistant tumors, or “cold” tumors, adding a PD-1 inhibitor or a combination of PD-L1 and LAG-3 antibodies didn’t improve the response to KRAS inhibition alone, the team found.

“We therefore concluded that despite the profound [tumor microenvironment] remodeling triggered by KRAS G12C inhibition, it may not be sufficient to render highly immune resistant tumors sensitive to [immune checkpoint blockade],” the researchers wrote in the study.

Downward and his teammates then turned to a new immune-responsive model of KRAS-mutant lung cancer. There, treatment with MRTX1257 alone completely eradicated tumors in 28% of the mice, and the number of complete responders rose to 66% when anti-PD-1 therapy was added to the KRAS drug. Further analysis showed that immune infiltration and activation of immune-related genes were further enhanced in tumors treated with the combo than KRAS inhibition alone.

The Francis Crick study comes as Amgen is about to report first clinical data for its first-in-class KRAS inhibitor Lumakras (sotorasib) in combination with either Merck’s PD-1 inhibitor Keytruda or Roche’s PD-L1 inhibitor Tecentriq from two early-stage CodeBreaK trials at the upcoming World Conference on Lung Cancer annual meeting.

Before that, Mirati has shared some promising early tumor response data for adagrasib in combination with Keytruda both in newly diagnosed KRAS G12C-mutant NSCLC in the phase 2 KRYSTAL-7 trial and in various patients in the phase 1/2 KRYSTAL-1 study.

Some patients in adagrasib’s KRYSTAL-1 and Lumakras’ CodeBreaK studies had failed on prior treatment with immunotherapy and were therefore likely to have tumors resistant to checkpoint inhibitors. Findings from the current study suggest that these patients may be less likely to benefit from combinations of KRAS inhibitors with immunotherapies, the Francis Crick scientists wrote in the study.

The researchers are calling for clinical trials to include patients bearing “hot” tumors with high immune cell infiltration to ensure best chance of success.

Besides, for the many clinical trials that are testing combinations of KRAS inhibitors with other targeted therapies, the researchers said it’s important to confirm that KRAS inhibition’s beneficial effects on the tumor microenvironment are not lost before pairing therapies up in clinical trials. Therefore, the team suggests that some “vertical” combinations of KRAS inhibitors with SHP2 inhibitors upstream or CDK4/6 inhibitors downstream of the RAS signaling pathway may be more promising.