Combining KRAS Inhibitors With PI3K and Checkpoint Blockade to Improve Response Durability

As KRAS inhibitors move further into the clinic across pancreatic, lung, and colorectal cancers, attention in the field has increasingly turned toward combination strategies. Single-agent KRAS inhibition can trigger compensatory activation of parallel signaling pathways that allow tumor cells to survive the initial hit, and separately, KRAS itself has been shown to help tumor cells evade immune surveillance. Both observations have shaped current thinking about which combination partners are most likely to succeed. Early phase trials pairing KRAS inhibitors with agents such as PI3K pathway inhibitors and immune checkpoint inhibitors have already begun to generate clinical data across multiple tumor types and lines of therapy.

In an interview with CancerNetwork®, Frank McCormick, PhD, FRS, DSc (Hon), laid out the rationale behind the emerging combination landscape. McCormick explained that inhibiting KRAS prompts tumor cells to activate alternative survival pathways, making PI3K pathway inhibitors a logical partner to blunt that adaptive rebound. He also detailed the rationale for combining KRAS inhibitors with checkpoint inhibitors, noting that because KRAS itself helps tumor cells evade immune detection, suppressing KRAS should, in principle, make tumors more visible to the immune system and more responsive to checkpoint blockade. He identified this immune-engaging combination approach as one of the most promising paths toward long-term, durable responses in patients going forward.

McCormick is a professor in the Helen Diller Family Comprehensive Cancer Center and holder of the David A. Wood Distinguished Professorship of Tumor Biology and Cancer Research at UCSF.

Transcript:

There are a number of different options. For one thing, when you inhibit KRAS, the cells have a response by activating other pathways to compensate for the sudden loss of KRAS, and those help them survive. Targeting those short-term adaptive responses makes the KRAS drugs more effective. Right now, a class of drugs called PI3K pathway inhibitors will be tested to prevent that rebound effect. Then there are other classes of combinations which can hopefully wake up the immune system, and that’s the paradigm in lung cancer, where the combinations most likely to be in the front line will be KRAS drugs plus a checkpoint inhibitor.

Because KRAS itself makes cells less visible to the immune system, in theory suppressing KRAS should make the tumor cells more visible to the immune system, so that drugs that target the immune checkpoint should be more effective. That’s a class of combination which is probably the best hope for the future, when the immune system can really kick in, and that gives patients the best hope of having a very long-term, durable response. There are other subsets of combinations which will be tested, but combinations that make the initial hit more effective, and combinations that wake up the immune system are the 2 types of combinations which will be most effective in the near future.