Resistance to KRAS G12C Inhibition

Dr Dietrich discusses patients acquiring and providers managing resistance to KRAS inhibition.

Martin Dietrich, MD, PhD: The resistance mechanisms to KRAS G12C are manifold and partly of research interest only because we really don't have a subsequent treatment strategy outside of clinical trials. There are a broad variety of escape mechanisms, overriding mutations, and downstream targets like AKT, the MEK/ERK pathway, MAP kinase. We also see alterations that are directly affecting the KRAS molecule itself, where mutations interfering with active binding are overriding or additional KRAS mutations may be taking over, and that may not be codon 12 dependent for KRAS. The only way of really utilizing this system is by resequencing a tumor upon progression of a KRAS inhibitor and understanding those molecular pieces. This can be done by liquid biopsy, [which] is very easily obtained, or by rebiopsying a new and growing lesion that is then resequenced and potentially hold the answer of why KRAS inhibitors stop responding. That's a field in development that has said most of the responses [and resistances] do happen within the KRAS molecule itself, so [that is] something to look out for upon resequencing. We're nowhere near where we are in ALK and EGFR mutations, where we can really guide step-by-step therapies based on an EGFR resistance or ALK resistance mutations. We may also have to consider switch pathways and alternative options. Genetics is very skilled in finding escape mechanisms, and we have to be broad in our approach to understand them and capture these patterns.

If a patient is treated in second line with a KRAS inhibitor and starts to progress, the options are typically limited; It depends on what the patient has received in the first-line setting. For example, if a patient has received a single agent immunotherapy in the first-line setting, it is very reasonable to challenge a patient with a platinum-based chemotherapy. If a patient had chemotherapy and immunotherapy in the first-line setting, the next step would be a docetaxel-based regimen. The ideal scenario here is to find molecular guidance, and there are [several] trials that are going on that might be of interest. This is a versatile molecule, as it signifies a both targeted and immunotherapy responsive disease. [These trials] are looking at overcoming PD-1 resistance, and those are typically PD-1–based therapies, plus a second immune checkpoint inhibitor; this could be LAG-3, TIM, BTLA or CTLA-4 amongst others. Alternatively, [when] looking at the mechanism of resistance, we see approaches for KRAS resistance with SOS1 inhibitors that are more broadly inhibiting the coupling of KRAS to downstream elements and preventing the accumulation of overactivity. There are targets for switch mechanisms; we would either add additional mechanisms, eg, a combination with a MEK inhibitor, and/or additional targets within the KRAS pathway. It depends on the clinical circumstance and the level of molecular understanding of the setup that would guide us in the subsequent line setting. It's critical to understand that patients that are progressing on a KRAS inhibitor in second line are typically in dire straits, and options are limited and not satisfactory. Clinical trial enrollment should be preferred here as the next step for patients, and a referral to an appropriate clinical trial center should be made.

This transcript has been edited for clarity.

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