Abstract 95P
Background
ADA is a KRASG12C inhibitor approved as monotherapy for pts with previously treated advanced/metastatic KRASG12C-mutated NSCLC and in combination with CETUX, an EGFR inhibitor, in pts with previously treated advanced/metastatic KRASG12C-mutated colorectal cancer (CRC). Preclinical studies have shown efficacy of ADA plus CETUX in KRASG12C-mutated NSCLC models, as dual KRASG12C/EGFR blockade may enhance inhibition of KRAS-dependent signaling. Here we report results from a phase I cohort of the KRYSTAL-1 study (NCT03785249) evaluating ADA plus CETUX in advanced KRASG12C-mutated NSCLC.
Methods
KRYSTAL-1 is a multicohort phase I/II study evaluating the safety and efficacy of ADA in pts with advanced KRASG12C-mutated solid tumors. This phase I cohort evaluated ADA (400 or 600 mg orally BID) plus CETUX (500 mg/m2 intravenously Q2W) in pts with advanced KRASG12C-mutated NSCLC with no available treatment with curative intent or standard of care treatment. Endpoints included safety, objective response rate (ORR) and progression-free survival (PFS) per blinded independent central review, and overall survival (OS).
Results
As of April 30, 2024, 31 pts had received ADA (400 [n=21] or 600 mg BID [n=10]) plus CETUX. Median age was 69 years, 68% were female, and 13%/87% were current/former smokers. In 30 pts evaluable for response (median follow-up 9.8 months), ORR was 40.0% (95% confidence interval [CI], 22.7–59.4) and median PFS was 6.4 months (95% CI, 4.2–14.9). Median OS was 12.4 months (95% CI, 6.8–not estimable). Overall, any grade (G) treatment-related adverse events (TRAEs) occurred in 96.8% of pts, with the most common being nausea (64.5%), diarrhea (58.1%), vomiting (41.9%), and dermatitis acneiform (41.9%). G3/4 TRAEs occurred in 38.7% of pts, with the most common being lipase increase and fatigue (both G3 only; 9.7% each). No G5 TRAEs were observed. TRAEs led to treatment discontinuation in two pts (6.5%) and to any dose modification in 16 pts (51.6%).
Conclusions
ADA plus CETUX was tolerable; however, in contrast to findings in CRC, efficacy with this combination did not appear greater than that observed with ADA monotherapy in previously treated pts with advanced KRASG12C-mutated NSCLC.
Clinical trial identification
NCT03785249.
Editorial acknowledgement
Third-party medical writing support was provided by Flaminia Fenoaltea, MSc, of Ashfield MedComms, an Inizio company, and was funded by Bristol Myers Squibb.
Legal entity responsible for the study
Mirati Therapeutics, a Bristol Myers Squibb company.
Funding
Mirati Therapeutics, a Bristol Myers Squibb company.
Disclosure
J. Zhang: Financial Interests, Personal, Invited Speaker: OSCO, Novartis; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Regeneron, Sanofi, MJN Life Sciences; Financial Interests, Personal, Advisory Board: AstraZeneca, Fosun, Hengrui, Regeneron, Novocure, Sanofi; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca, Genentech, Mirati Therapeutics, a Bristol Myers Squibb company, Nilogen; Financial Interests, Institutional, Principal Investigator: AbbVie, BeiGene, BridgeBio, Bristol Myers Squibb, InnoCare Pharma, Janssen, Kahr Medical, Lilly, Merck, Mirati Therapeutics, a Bristol Myers Squibb company. A. Spira: Financial Interests, Personal, Invited Speaker: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, Bayer, Prelude Therapeutics, AbbVie, Astellas Pharma; Financial Interests, Personal, Stocks/Shares: Lilly; Financial Interests, Institutional, Research Grant: LAM Therapeutics, F. Hoffmann-La Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Incyte, AbbVie, Ignyta, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Rubius, Synthekine, Mersana, Blueprint Medicines, Regeneron, Alkermes, Revolution Medicines, Medikine, Black Diamond Therapeutics, BluPrint Oncology, Nalo Therapeutics, Scorpion Therapeutics, ArriVent Biopharma, Prelude Therapeutics; Financial Interests, Personal, Advisory Role: Incyte, Amgen, Novartis, Mirati Therapeutics, a Bristol Myers Squibb company, Gritstone Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi, ArriVent Biopharma, Synthekine, GSK, Crisp Therapeutics, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, Blueprint Medicines; Financial Interests, Personal, Leadership Role: NEXT Oncology Virginia. K. Leventakos: Financial Interests, Institutional, Invited Speaker: AstraZeneca, OncLive, MJH Life Sciences, MD Outlook, Targeted Oncology; Financial Interests, Institutional, Advisory Board: AstraZeneca, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, a Bristol Myers Squibb company, Regeneron, Takeda, Targeted Oncology; Financial Interests, Institutional, Research Grant: AstraZeneca, Mirati Therapeutics, a Bristol Myers Squibb company; Financial Interests, Institutional, Other, General consulting: Amgen, Boehringer Ingelheim, Daiichi Sankyo, Janssen, Novartis. K. He: Financial Interests, Personal, Advisory Board: Mirati Therapeutics, a Bristol Myers Squibb company, Perthera, Bristol Myers Squibb, Obsidian, Iovance Biotherapeutics, Lyell, Biontech, AstraZeneca, OncoC4; Financial Interests, Institutional, Research Grant: OncoC4; Financial Interests, Institutional, Funding: Mirati Therapeutics, a Bristol Myers Squibb company, Bristol Myers Squibb, Obsidian, Iovance Biotherapeutics, Biontech, OncoC4, Genentech, Sevier; Non-Financial Interests, Personal, Project Lead: Mirati Therapeutics, a Bristol Myers Squibb company, Obsidian, Iovance Biotherapeutics; Non-Financial Interests, Personal, Principal Investigator: OncoC4, Sevier, BeiGene, Mirati Therapeutics, a Bristol Myers Squibb company. S. McCune: Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb. R. Haddad: Financial Interests, Personal, Advisory Board: Curio Science. J. Peguero: Financial Interests, Personal, Research Grant: Mirati Therapeutics, a Bristol Myers Squibb company. H. Ahmad, N. Brand: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. M. Chowdhury, L. Eccles: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. M.V. Negrao: Financial Interests, Personal, Speaker’s Bureau: Ideology, BIO Brasil, OncLive, Medscape, DAVA Oncology, Targeted Oncology; Financial Interests, Personal, Advisory Board: Novartis, Sanofi, Pfizer, Genentech, Lilly, AstraZeneca; Financial Interests, Institutional, Research Grant: Alaunos, AstraZeneca, Pfizer, Genentech, Mirati Therapeutics, a Bristol Myers Squibb company, Bristol Myers Squibb, Lilly, Novartis, Navire; Financial Interests, Institutional, Principal Investigator: Alaunos, AstraZeneca, Pfizer, Genentech, Mirati Therapeutics, a Bristol Myers Squibb company, Bristol Myers Squibb, Lilly, Novartis, Navire; Financial Interests, Personal, Leadership Role, Steering Committee member: Lilly; Non-Financial Interests, Personal, Other, Medical writing support: ApotheCom, Ashfield MedComms; Financial Interests, Personal, Other, Travel expenses: Ideology, DAVA Oncology, Targeted Oncology. All other authors have declared no conflicts of interest.