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Mechanisms of Acquired Resistance to KRAS G12C Inhibition in Patients With Cancer


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In a study reported in The New England Journal of Medicine, Awad et al identified potential mechanisms of acquired resistance to the KRAS G12C inhibitor adagrasib in patients receiving the agent for treatment of KRAS G12C–mutant cancers.

As noted by the investigators, clinical trials of the KRAS inhibitors adagrasib and sotorasib—both of which bind covalently to KRAS G12C protein—have shown activity in cancers harboring KRAS G12C mutations; however, acquired resistance to single-agent therapy eventually occurs in most patients and the mechanisms of such resistance are currently unknown.

Diverse genomic and histologic mechanisms impart resistance to covalent KRAS G12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer.
— Awad et al

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Study Details

The study included 38 patients with KRAS G12C–mutant cancers treated with adagrasib monotherapy in the KRYSTAL-1 trial who exhibited acquired resistance, defined as stable disease for at least 12 weeks or partial or complete response followed by disease progression. Genomic and histologic analyses compared pretreatment tumor samples with those obtained after the development of resistance.

Key Findings

Among the 38 patients, 27 had non–small cell lung cancer (NSCLC), 10 had colorectal cancer, and 1 had appendiceal cancer.

Putative mechanisms of resistance were identified in 17 patients (45%), with 7 (18%) having one or more coincident mechanisms. Among those with identified mechanisms and available circulating tumor DNA sequencing, the presence of multiple mechanisms appeared to be more common in colorectal cancer (4 of 5 patients) than NSCLC (2 of 7 patients).

Among the 17 patients, 9 (53%) had at least one acquired KRAS mutation or amplification. Mechanisms that did not directly involve KRAS, but were related to the RAS signaling pathway, were identified in 12 (71%).

Overall, acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS G12C allele. Acquired bypass mechanisms of resistance included: MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN.

Histologic transformation from adenocarcinoma to squamous cell carcinoma without identifiable genomic mechanisms of resistance was observed in nine patients with NSCLC and one with colorectal cancer who had a repeat biopsy sample obtained at progression during adagrasib treatment.

An in vitro deep mutational scanning screen was performed to define the landscape of KRAS mutations conferring resistance to KRAS G12C inhibitors using sotorasib and MRTX1257, a compound highly related to adagrasib with an identical binding mode. The MRTX1257 screen identified multiple mutations at codons 12, 68, 95, and 96 that conferred strong resistance, with additional strong MRTX1257 resistance mutations detected at codons 8, 9, 64, 99, and 117. In the sotorasib screen, strong resistance mutations were identified at codons 8, 9, 12, 96, and 117.

The investigators concluded, “Diverse genomic and histologic mechanisms impart resistance to covalent KRAS G12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer.”

Disclosure: The study was funded by Mirati Therapeutics and others. For full disclosures of the study authors, visit nejm.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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