Abstract 1133P
Background
Adagrasib is a KRASG12C inhibitor selected for favorable properties, including long half-life (∼24 h), dose-dependent PK, and CNS penetration; it has demonstrated clinical activity in patients (pts) with KRASG12C NSCLC (ORR 43%; median OS 12.6 months), including in pts with CNS metastases (intracranial ORR per mRANO-BM criteria 33%).
Methods
KRYSTAL-1 is a multicohort Phase 1/2 study of adagrasib in pts with advanced solid tumors harboring a KRASG12C mutation. Here we report additional practice-informing safety analyses from Cohort A, a Phase 2 study with registrational intent, evaluating adagrasib capsules 600 mg orally BID in pts with previously treated NSCLC; these analyses include time to onset, time to resolution, and the management of treatment-related adverse events (TRAEs).
Results
As of the October 15, 2021 data cut, 116 pts (female 65%; median age 64 years; ECOG PS 1 83.6%) received adagrasib; median follow-up was 12.9 months (95% CI 11.8–13.5). Median duration of treatment was 5.7 months (range 0–19.6). TRAEs of any grade occurred in 97.4% of pts: 52.6% grade 1–2, 44.8% grade ≥3. Overall, >92% of new onset TRAEs occurred within the first 3 cycles; very few new grade ≥3 TRAEs occurred after cycle 3. TRAEs led to a dose reduction in 51.7% of pts, dose interruption in 61.2% of pts, and discontinuation in 8 pts (6.9%). GI-related TRAEs (diarrhea, nausea, vomiting) occurred in 84.5% of pts, leading to dose reductions in 23 pts (19.8%). Median time to onset was 0.43 weeks (range 0.1–33.0) for GI TRAEs and 3.14 weeks (range 1.1–9.0) for increased ALT and AST. Median time to resolution after initial occurrence of GI TRAEs was 2.07 weeks (range 0.1–50.1) and of increased ALT and AST was 1.71 weeks (range 0.3–15.1). GI TRAEs were manageable with concomitant antidiarrheals (48.3%) and antiemetics/antinauseants (87.1%). Additional data for the most common (>10%) TRAEs and other TRAEs of interest will be presented.
Conclusions
Adagrasib demonstrated a manageable AE profile in pre-treated pts with KRASG12C-mutated NSCLC. Most TRAEs were low grade, occurred early in treatment, and resolved quickly, resulting in a low (6.9%) discontinuation rate.
Clinical trial identification
NCT03785249.
Editorial acknowledgement
Third-party medical writing support, under the direction of the authors, was provided by Rebecca Benatan, BSc, of Ashfield MedComms, an Ashfield Health company, and was funded by Mirati Therapeutics, Inc.
Legal entity responsible for the study
Mirati Therapeutics, Inc.
Funding
Mirati Therapeutics, Inc.
Disclosure
J. Zhang: Financial Interests, Invited Speaker: AstraZeneca, Regeneron, MJH Life Sciences, Sanofi, Novartis; Financial Interests, Advisory Board: AstraZeneca, Hengrui; Financial Interests, Research Grant: AstraZeneca, Biodesix, Nilogen, Genentech, Mirati Therapeutics; Financial Interests, Project Lead: AstraZeneca, Biodesix, Nilogen, Genentech, Mirati Therapeutics; Financial Interests, Principal Investigator: AstraZeneca, Biodesix, Nilogen, Genentech, Mirati Therapeutics; Financial Interests, Training: Novartis; Financial Interests, Sponsor/Funding: AbbVie, AstraZeneca, BeiGene, Genentech, Hengrui, Merck, Mirati Therapeutics, Nilogen, Novartis; Financial Interests, Advisory Role: AstraZeneca, Eli Lilly, Nexus Health, Bayer, Biodesix, Hengrui, Novartis, Novocure, Bristol Myers Squibb, Sanofi, Takeda Oncology, Cardinal Health, Daiichi Sankyo, Mirati Therapeutics; Financial Interests, Other: Mirati Therapeutics. K. Leventakos: Financial Interests, Advisory Board: AstraZeneca, Jazz Pharmaceuticals, Mirati Therapeutics, Regeneron, Targeted Oncology, Janssen, Takeda; Financial Interests, Research Grant: AstraZeneca, Mirati Therapeutics; Financial Interests, Other, Consulting: Boehringer Ingelheim Pharmaceuticals. T.A. Leal: Financial Interests, Advisory Board: Beyond Spring Pharmaceuticals, Bristol Myers Squibb, Merck, Takeda, Genentech, Invision First Lung, AstraZeneca, Novocure, Jazz Pharmaceuticals, EMD Serono, Boehringer Ingelheim, Blueprint Medicines, Daiichi Sankyo. N. Pennell: Financial Interests, Advisory Board: Merck, Eli Lilly / Loxo, Janssen, Genentech, Pfizer, Mirati Therapeutics, Sanofi Genzyme; Financial Interests, Research Grant: Mirati Therapeutics. M. Barve: Financial Interests, Stocks/Shares: Texas Oncology Physician Associates; Financial Interests, Funding: Mary Crowley Cancer Research. A.S. Paulson: Financial Interests, Invited Speaker: Cardinal Health, Ideo Oncology; Financial Interests, Writing Engagements: Incyte, Novartis, Hutchinson; Financial Interests, Advisory Board: Amgen, BMS, Eisai, Ipsen, AAA, Incyte, Exelixis, Pfizer, QED Therapeutics, Lilly, Mirati Therapeutics, Hutchinson; Financial Interests, Stocks/Shares: Aptose, Actinium, Alexion; Financial Interests, Principal Investigator: Ipsen, Novartis, BMS, Exelixis, Hutchinson, Taiho, Lilly, AstraZeneca, Incyte, Deciphera, G1 Therapeutics, Zentalis. L. Bazhenova: Financial Interests, Stocks/Shares: Epic Sciences; Financial Interests, Other, Data monitoring committee: ORIC; Financial Interests, Advisory Board: Turning Point Therapeutics, Daiichi, BMS, Janssen, Merck, Regeneron, Bayer, Takeda, Boehringer Ingelheim, Novartis, Genentech, Sanofi, AstraZeneca, Blueprint, Mirati; Financial Interests, Other, Scientific committee: Neuvogen; Financial Interests, Research Grant: Beyondspring. M.L. Johnson: Financial Interests, Other, Consulting: AbbVie, Amgen, Astellas, AstraZeneca, Axelia Oncology, Black Diamond, Boehringer Ingelheim, Bristol Myers Squibb, Calithera, CytomX, Daiichi Sankyo, EcoR1, Editas Medicines, Eisai, EMD Serono, G1 Therapeutics, Genentech/Roche, Genmab, GlaxoSmithKline, Gritstone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck, Mirati Therapeutics, Oncorus, Regeneron, Ribon Therapeutics, Sanofi-Aventis, Turning Point Therapeutics. R.C. Chao: Financial Interests, Full or part-time Employment: Mirati Therapeutics; Financial Interests, Stocks/Shares: Mirati Therapeutics, Merck, Pfizer. K. Velastegui: Financial Interests, Full or part-time Employment: Mirati Therapeutics. C. Qian: Financial Interests, Full or part-time Employment: Mirati Therapeutics; Financial Interests, Stocks/Shares: Mirati Therapeutics. W. Bleker: Financial Interests, Full or part-time Employment: Mirati Therapeutics. A. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol-Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Invited Speaker: LAM Therapeutics, Roche, AstraZeneca, Novartis, Boehringer Ingelheim, Astellas Pharma, MedImmune, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mersana, Mirati Therapeutics, Rubius, Synthekine, Blueprint Medicines.