Porter Details Future Directions For Treating Patients With KRAS G12C-Mutated NSCLC

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In an interview with OncLive^®, Jason Porter, MD, highlighted how treatments for patients with KRAS G12C-mutated non–small cell lung cancer (NSCLC) are progressing, discussing key points from a presentation he gave during an OncLive Institutional Perspectives in Cancer webinar on lung cancer, which he chaired. Porter, a medical oncologist, hematologist, and director of the Lung Cancer Disease Research Group at West Cancer Center and Research Institute in Memphis, Tennessee, also expanded on what unmet needs still need to be addressed for patients with KRAS-mutated NSCLC.

Additionally, Porter provided further insights from his colleagues’ presentations in another interview.

OncLive: What research is underway to explore the unmet needs of patients with KRAS-mutated NSCLC?

Porter: It is important to understand that many patients who have KRAS G12C mutations are smokers. Often KRAS G12C is there and it’s tumorigenic, but it’s not necessarily alone in the tumorigenesis—other mutations may be present and helping drive the cancer growth and survival. Although we target KRAS, the question is: Are we ever going to be able to target KRAS alone and expect to get good response rates as we do with other oncogenes, like EGFR and ALK?

When we look at patients who have KRAS mutations, unmet needs include those with brain metastases. Luckily, we have some prospective data with brain metastases with adagrasib [Krazati] and we have some retrospective data with sotorasib [Lumakras]. We have an idea of what happens, but 1 place where we need more data [is regarding] whether or not we can rely on KRAS inhibitors or if we need to be seeking other targeted therapies for central nervous system [CNS] disease. Figuring out how often to survey those patients for the development of CNS disease if they didn’t have it at diagnosis [is key].

Another patient population is those with other co-mutations that can confer resistance to first-line therapy with immune checkpoint inhibitors with chemotherapy. That means [we need to] use immune checkpoint combinations where we have data [such as that] from the phase 3 POSEIDON trial [NCT03164616] which looked at patients with STK11 and KEAP1 mutations along with KRAS. [We need to] look at those responses and whether we can improve responses, duration of response, and overall outcomes for those patients.

Additionally, for non-G12C mutations, it is very important that we develop pan-RAS and RAF inhibitors that can target non-G12C [mutations] such as G12D or even G13C. Ways to target these other variants of KRAS mutations is another unmet need. Figuring all of these things out, as well as how to combine these drugs with other therapies so that we can overcome some of the resistance to the primary treatment of KRAS is another place of unmet need.

Are there any trials with KRAS inhibitors that could potentially bring these therapies into other settings?

The combination trials are going to be [helpful] for KRAS-positive NSCLC—the use of at least first-generation KRAS inhibitors as a monotherapy in earlier lines of treatment is going to be less attractive because of primary resistance when other co-mutations are present and when there are more than 1 mechanism of tumorigenesis. With that, the combination trials that add chemotherapy or immune checkpoint inhibitors with chemotherapy to KRAS inhibitors is very intriguing.

Newer generation KRAS inhibitors in development are going to be very attractive. We know with the mechanism of KRAS tumorigenesis where the GTP is bound to that KRAS G12C mutation in the on state we have covalent bonding, but we know there’s upregulation of that KRAS G12C mutation when we target the G12C protein. Therefore, figuring out ways to overcome that upregulation of a protein even with covalent irreversible binding of the inhibitor to the protein is a place that we can investigate, as well as combining with downstream inhibitors or inhibitors of downstream resistance where SHIP2 inhibitors are in development. There are ways to look beyond G12C [at] other proteins that may be active in the resistance and the propagation of disease.

What is the main highlight from your presentation that you would like to impart to your colleagues?

When we look at overall survival, progression-free survival, and the early data with sotorasib as a KRAS G12C inhibitor compared with docetaxel, we saw complete responses [CRs] when we used sotorasib and we don’t see CRs with docetaxel. That means there’s something [there efficacy wise] and some patients will be better selected for use with a KRAS G12C inhibitor. Investigators will continue to look at those patients who had CRs and figure out what else was going on. What did the rest of the background of the tumor look like molecularly? How can we select those patients in the future so that we make a difference between who needs docetaxel and who should receive a KRAS inhibitor at the time of progression of their disease?

The CRs that we saw in these clinical trials merit further investigation because we can’t say that the drug didn’t do as well as docetaxel and it’s not worth further pursuing. We need to continue to figure out who the patients are that need this like we do with every other targeted therapy.