Bazhenova Details Potential Pathways Forward for Targeting KRAS Mutations in NSCLC

Despite the FDA approvals of adagrasib (Krazati) and sotorasib (Lumakras), developing new combination regimens remains an important area of interest for the treatment of patients with KRAS G12C–mutant advanced non–small cell lung cancer (NSCLC), according to Lyudmila A. Bazhenova, MD.

“The issue with KRAS inhibition is that the efficacy is not as good as what we expect to see from EGFR- and ALK-[targeted agents] and KRAS is not an ATP, it’s a GTP so it’s a different mechanism of activation and deactivation,” Bazhenova said in an interview with OncLive^® during the 24th Annual International Lung Cancer Congress^®. “It is not realistic to expect single-agent KRAS G12C inhibitors to be as efficacious as TKI [monotherapies]. Therefore, we are looking at combinatorial therapy and there are several options.”

Findings from the phase 1/2 KRYSTAL-1 trial (NCT03785249), which supported the December 2022 accelerated approval of adagrasib for adult patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, showed an objective response rate (ORR) of 43% (95% CI, 34%-53%) with a median duration of response (DOR) of 8.5 months (95% CI, 6.2-13.8) in 112 patients whose disease had progressed on or after platinum-based chemotherapy and an immune checkpoint inhibitor.¹ Data from the phase 1/2 CodeBreaK 100 trial (NCT03600883) supported sotorasib’s May 2021 accelerated approval in the same patient population, displaying an ORR of 36% (95% CI, 28%-45%) with a median DOR of 10 months (range 1.3+-11.1) among 124 patients who disease had progressed on or after at least 1 prior systemic therapy.²

In the interview, Bazhenova, a medical oncologist and professor of medicine at UC San Diego Health in California, discussed upcoming inhibitors of interest in the combination therapy space for patients with KRAS G12C–mutant NSCLC.

OncLive: What agents are currently available for patients with NSCLC harboring KRAS mutations?

Bazhenova: KRAS mutations are seen in approximately 30% of patients with NSCLC and half of those mutations are KRAS G12C mutations. It’s important to test your patient for the KRAS G12C mutation because we now have 2 FDA-approved drugs, adagrasib and sotorasib, and approval is currently in the second line for patients who have previously received and progressed after platinum doublet therapy with or without immunotherapy.

Both drugs were initially tested in single-arm monotherapy studies. It is hard to determine which drug is better because at this point we are limited to cross-trial comparisons. The ORR for both adagrasib and sotorasib is approximately 40% and the median progression-free survival is unfortunately shorter than what we see with EGFR- and ALK-[targeted agents]. The median overall survival is approximately 12 months. The drugs do come with toxicities and both compounds mainly have gastrointestinal [GI] toxicities, such as diarrhea, nausea, and vomiting.

How does the safety profile of immunotherapy differ from that of adagrasib and sotorasib?

The adverse effects [AEs] from immunotherapy and targeted therapies are completely different. Most of the time we are using immunotherapy in combination with chemotherapy, so there still is nausea, vomiting, and fatigue from chemotherapy. Then the immunotherapy adds the additional immune-related AEs, [including] diarrhea, dermatitis, pneumonitis, and colitis. [Those toxicities are] managed completely differently than the main AEs from adagrasib and sotorasib. For adagrasib and sotorasib, we mainly see GI toxicity], which responds to anti-diarrheal medications, dose holds, and dose reductions.

Given that most oncology drugs start as single agents before finding their place in combination regimens, what is on the horizon for these KRAS G12C-targeted agents?

One combination [strategy] is with immunotherapy and attempts at that have been made with both sotorasib and adagrasib. Unfortunately, when you combine sotorasib with immunotherapy toxicity is prohibitive. Adagrasib in combination with immunotherapy looked a little bit better [but] dose reduction [was required] with both of those drugs.

It’s also important to look at those drugs in combination with chemotherapy. We had a presentation of the SCARLET study [jRCT2051210086] at the 2023 ASCO Annual Meeting which showed that sotorasib and platinum doublet [chemotherapy] resulted in an ORR of [88.9]%, which is fairly respectable. It was a small number of patients, [which] we have to be cautious about. The other combinations which make sense based on the preclinical data are combinations with [inhibitors of either] EGFR, SHIP, and SOS1.

What are some emerging agents targeting other KRAS mutations in NSCLC?

Other mutations in KRAS are seen in lung cancer, such as KRAS G12D, G12A, and G13 mutations. Our currently available drugs will not work for the non–KRAS G12C mutations, because they don’t have a place to bind unless there is a cysteine at the end of the mutation.

There are several compounds that look very encouraging in that space. I’d like to highlight the KRAS(ON) inhibitors [which are different from] adagrasib, a KRAS(OFF) inhibitor, because they work on a KRAS [mutation] in an off state.

Another interesting compound in preclinical development is MRTX1133. We don’t have any clinical data yet, but preclinically it looks interesting.

How have therapies evolved for patients who are experiencing resistance to treatment?

We are learning how to manage patients with KRAS mutations and at the same time we are also learning how resistance happens when the patient progresses on KRAS inhibitors. As expected from what we know from other oncogenic resistance, we see on-target resistance, mutations in a KRAS binding area—the H95 mutation and Y96 mutation—and then also off-target resistance, developing amplifications in BRAF or amplifications in other oncogenes.

We also have seen transformations, lineage plasticity, [which] have been recorded. There are a couple of compounds, such as KRAS(ON) inhibitors, that could potentially work if the patient develops resistance to the KRAS G12C inhibitors. It’s certainly something to look out for.

Currently, the way we determine if the drug continues to work in lung cancer is not by simply doing imaging, it’s [more than] a CT scan. Doing monitoring with circulating tumor DNA is not considered standard of care right now. When we do a CT scan, if we see that the tumor is progressing, then in some institutions we will do a post progression biopsy to try to understand what the mechanism of resistance to that drug is, and then see if we can try to choose the next treatment specifically targeting that mechanism of resistance.

References

1. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. FDA. December 12, 2022. Accessed August 17, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc
2. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. May 28, 2021. Accessed August 17, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc