Among patients with KRASG12C-mutant cancers, resistance to the KRAS inhibitor adagrasib was driven by a variety of genomic and histologic mechanisms, researchers reported.
Among 38 patients with KRASG12C-mutant cancers who received adagrasib monotherapy, putative mechanisms of resistance to the experimental KRASG12C–selective covalent inhibitor were seen in 17 patients, or 45% of the cohort, taken from the KRYSTAL-1 trial, according to Mark M. Awad, MD, PhD, of the Dana-Farber Cancer Institute in Boston, and co-authors.
Of those patients, 18% had multiple coincident mechanisms, with acquired KRAS alterations of G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C; high-level amplification of the KRAS G12C allele; acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RETALK, RET, BRAF, RAF1, and FGFR3NF1 and PTEN, they explained in The New England Journal of Medicine.
The majority of patients in the cohort had non-small cell lung cancer (NSCLC), and the authors reported that they were unable “to identify a genomic resistance mechanism” in this disease state; however, they “observed histologic transformation from adenocarcinoma to squamous cell carcinoma,” suggesting that “nongenetic mechanisms of resistance to KRASG12C inhibition may occur, similar to those observed with other targeted therapies in lung cancer.”
“Diverse genomic and histologic mechanisms impart resistance to covalent KRASG12C inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer,” they concluded, adding that, “In aggregate, these data show that a diversity of on-target and off-target mechanisms can confer resistance to KRASG12C inhibitors and support the need for development of additional KRAS inhibitors with alternative modes of binding and different allele specificities.”
In an editorial accompanying the study, Neal Rosen, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, expressed concern at the high number of resistance mutations found in the 17 patients.
“An astonishing variety of lesions were found: KRAS mutations that probably prevent drug binding, lesions that activate RAS by a non-G12C mechanism, and KRAS amplification,” he explained. “Seven patients had additional KRAS mutations; 2 patients had amplification of the KRASG12C allele. A total of 14 patients had lesions that activate components of the pathway upstream or downstream of KRAS—mutant or amplified RTKs, mutant NRAS, MAP2K1 (MEK1), NF1, and various rearrangements (fusions) of RAF and other receptors.”
So, there is the possibility that “RAS inhibitors may be of limited efficacy, given the diversity and frequency of resistance mechanisms,” Rosen wrote, although he acknowledged that there may be “other possible explanations for the plethora of mutations, including inhibition of DNA repair or induction of DNA damage by inhibition of KRASG12C or by the drug itself.”
While the mechanisms of resistance to combination therapy with KRASG12C still need to be pinpointed, “improved drugs will be developed”—such as other G12C inhibitors—”and combinations that are designed to enhance tumor cell death or to prevent adaptive resistance will be tested,” he noted.
The authors performed genomic and histologic analyses—DNA sequencing or circulating tumor DNA sequencing (ctDNA)—that compared pretreatment samples with those obtained after the development of resistance among patients with KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRASG12C)-mutant cancers treated with adagrasib monotherapy in KRYSTAL-1, results from which were presented at the 2020 EORTC-NCI-AACR virtual symposium.
Awad’s group identified three main categories of resistance mechanism, specifically secondary mutations or amplifications in KRAS; alternative oncogenic alterations that activate the RTK-RAS signaling pathway but do not directly alter KRAS itself; and histologic transformation from lung adenocarcinoma to squamous-cell carcinoma.
In terms of the last category, the authors performed an in vitro deep mutational scanning screen to systematically define the KRAS mutation landscape that conferred resistance to KRASG12C inhibitors. For the two NSCLC patients who underwent histologic transformation, one of whom also underwent ctDNA sequencing, Awad and co-authors said it was not likely that “a major known molecular driver of adagrasib resistance,” was missed, but conceded that “it remains possible that more extensive genomic sequencing of these samples could identify other acquired alterations that may have contributed to resistance.”
While this study did not evaluate another experimental KRAS inhibitor, sotorasib, findings from a recent phase II study presented at the 2020 virtual World Conference on Lung Cancer offered positive findings for the agent in KRASG12C-mutant, pretreated NSCLC.
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Diverse genomic and histologic mechanisms impart resistance to single-agent adagrasib in patients with different KRASG12C-mutant cancers, including non-small cell lung cancer (NSCLC).
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Histologic transformation from adenocarcinoma to squamous-cell carcinoma in two cases of NSCLC suggested that nongenetic mechanisms of resistance to KRAS inhibition may be at play.
Shalmali Pal, Contributing Writer, BreakingMED™
Awad reported support from, and/or relationships with, The Mark Foundation for Cancer Research, Lilly, Genentech, Bristol Myers Squibb, AstraZeneca, Merck, Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, ArcherDX, Mirati, NextCure, Novartis, EMD Serono, and Panvaxal/NovaRx.
Rosen reported support from, and/or relationships with, AstraZeneca, BEIGENE, Chugai Pharmaceutical, concarlo holdings, eFFECTOR, Jubilant Therapeutics, MapCure, Ribon Pharmaceuticals, Tarveda, Zai Labs, Fortresa Biotech, Kura Oncology, Ribon Pharmaceuticals, Boehringer Ingelheim, and Pfizer Array.
Cat ID: 120
Topic ID: 78,120,730,120,219,23,24,935,192,925
