1394TiP - KRYSTAL-7: A phase III study of first-line adagrasib plus pembrolizumab versus pembrolizumab alone in patients with advanced NSCLC with KRASG12C mutation

Background

KRAS mutations are one of the most common oncogenic driver mutations in NSCLC, with the KRAS ^G12C mutation occurring in ∼14% of patients with lung adenocarcinoma. Adagrasib selectively and irreversibly inhibits KRAS^G12C, exhibiting favorable properties including long half-life (23 hrs), dose-dependent pharmacokinetics (PK), and brain penetrance. Studies in mutant KRAS ^G12C tumor models suggest that adagrasib enhances susceptibility to anti-PD-(L)1 immunotherapy by reconditioning the tumor immune microenvironment. In the phase 2 portion of the KRYSTAL-7 trial (NCT04613596), the combination of adagrasib and pembrolizumab (anti-PD-1 therapy) demonstrated encouraging efficacy in patients with previously untreated KRAS ^G12C-mutated NSCLC, particularly in patients with PD-L1 tumor proportion score (TPS) ≥50% (objective response rate 63%, disease control rate 84%, and 12-month progression-free survival [PFS] rate 60.8%), and had a manageable safety profile. Based on these preliminary data, the phase 3 study comparing first-line adagrasib plus pembrolizumab versus pembrolizumab alone in patients with KRAS ^G12C-mutated NSCLC and PD-L1 TPS ≥50% was initiated.

Trial design

The phase 3 portion of the KRYSTAL-7 study is a global, open-label, randomized trial comparing the efficacy and safety of first-line adagrasib (400 mg BID until disease progression) plus pembrolizumab (200 mg Q3W up to 35 cycles) versus pembrolizumab alone (200 mg Q3W up to 35 cycles) in patients with unresectable, locally advanced or metastatic KRAS ^G12C-mutated NSCLC (squamous or nonsquamous) and PD-L1 TPS ≥50%. Patients will be randomized 1:1 to each treatment arm and stratified according to known history of treated or untreated brain metastases (yes versus no), region (Asia Pacific versus non-Asia Pacific), and Eastern Cooperative Oncology Group performance status (0 versus 1). The primary endpoints are PFS by blinded independent central review and overall survival. Secondary endpoints include safety and tolerability, tumor response, adagrasib PK, and health-related quality of life. KRYSTAL-7 is currently open for enrollment.

Clinical trial identification

NCT04613596.

Editorial acknowledgement

Third-party medical writing support, under the direction of the authors, was provided by Tamsyn Mamotte, MSc, of Ashfield MedComms, an Inizio company, and funded by Mirati Therapeutics, a Bristol Myers Squibb company.

Legal entity responsible for the study

Mirati Therapeutics, a Bristol Myers Squibb company.

Funding

Mirati Therapeutics, a Bristol Myers Squibb company.

Disclosure

M.C. Garassino: Financial Interests, Personal, Advisory Board: Eli Lilly, Takeda, Seagen International GmbH, Daiichi Sankyo, Incyte, GSK, Bayer Healthcare Pharmaceuticals, AstraZeneca and Daiichi Sankyo Oncology Teams, Roche, Mirati, a Bristol Myers Squibb Company, Daiichi Sankyo/AstraZeneca, AstraZeneca Poland, MSD, Pfizer, AstraZeneca/MedImmune, Sanofi Genzyme Corporation, Sanofi / Prex, Regeneron Pharmaceuticals; Financial Interests, Personal, Expert Testimony: AstraZeneca; Financial Interests, Personal, Invited Speaker: WebMD, WebMD Oncology/Takeda, AstraZeneca, MSD, MSD Italia, Srl, GrupoPacifico-Secretaria Técnica, ICAPEM/AstraZeneca S.O.S S.r.l, Medscape, eCancer, AstraZeneca, Roche, Bayer, Janssen, Pfizer, Janssen, Celgene Corporation, Amgen, Blueprint, Sanofi, IPSEN Bioscience Inc., AstraZeneca S.p.A, MedImmune LCC, GSK Research & Development Ltd., AstraZeneca, Novartis, Exelixis Inc., Spectrum Pharmaceuticals, Merck Serono, Merck, Bristol Myers Squibb, AstraZeneca AB, Otsuka Pharmaceutical Italy S.r.l, Merck KGaA, Incyte Corporation, Turning Point Therapeutics Inc., Daiichi Sankyo Development Ltd.; Non-Financial Interests, Personal, Leadership Role: Women for Oncology Italy, AIOT (Associazione Italiana Oncologia Toracica), ESMO; Non-Financial Interests, Personal, Member: AIOM, WCLC, IPOP (Italian lung cancer charity), TUTOR (Italian thymic malignancies charity), AIOT, EMA Scientific Advisory Group (SAG); Financial Interests, Personal, Other: AstraZeneca, MSD, Janssen, AstraZeneca UK, GSK, Pfizer, Seattle Genetics; Non-Financial Interests, Personal, Other: ASCO, AACR; Other, Personal, Other: Pfizer, Roche, AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: Pfizer, Eli Lilly, MSD, Istituto Nazionale dei Tumori, GOIRC, Sant'Orsola Malphighi - Bologna (Alma Mater Studiorum Università Bologna), Istituto dei Tumori Pascale - Napoli, GUSTAVE-ROUSSY PARIGI LIPI TRIAL - no profit, O Spedali Civili Brescia, European Thoracic Oncology Platform (ETOP). P.A. Jänne: Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Voronoi, Daiichi Sankyo, Novartis, Sanofi, Takeda Oncology, Mirati Therapeutics, Trasncenta, Silicon Therapeutics, Syndax, Nuvalent, Bayer, Eisai, Allorion Therapeutics, Accutar Biotech, AbbVie, Duality Biologics, Blueprint Medicines, Dizal Pharma; Financial Interests, Personal, Advisory Board, Consulting fees for advice on diagnostic development: Biocartis; Financial Interests, Personal, Advisory Board, Consulting fee for advice on drug development: Merus, Frontier Medicines; Financial Interests, Personal, Advisory Board, Consulting fees for advice on drug development: Hongyun Biotechnology; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, Allorion Therapeutics, Frontier Medicines; Financial Interests, Personal, Royalties, I receive post-marketing royalties from being an inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp: Lab Corp; Financial Interests, Institutional, Research Grant, Sponsored research agreement with my institution: AstraZeneca, Daiichi Sankyo, PUMA, Eli Lilly, Boehringer Ingelheim, Revolution Medicines, Takeda Oncology. F. Barlesi: Financial Interests, Institutional, Advisory Role: Roche/Genentech, Novartis, Bristol Myers Squibb, AstraZeneca/MedImmune, Boehringer Ingelheim, Lilly, Merck Serono, MSD Oncology, Takeda, Bayer, Amgen, Eisai Europe, Sanofi, Mirati, a Bristol Myers Squibb Company; Financial Interests, Personal, Other, Travel, accommodation, expenses: Roche/Genentech; Financial Interests, Institutional, Research Funding: Roche/Genentech, AstraZeneca/MedImmune, Bristol Myers Squibb, Pierre Fabre, AbbVie, Amgen, Bayer, Boehringer Ingelheim, Eisai, Lilly, Ipsen, Innate Pharma, Novartis, Merck Serono, MSD Oncology, Pfizer, Sanofi/Aventis, Takeda. A.I. 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, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi; 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, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, 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, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med, Regeneron, Loxo, Alkermes, Medikine, Black Diamond Therapeutics, Nalo Therapeutics, Scorpion Therapeutics, Arrivent Biopharma. T.S.K. Mok: Financial Interests, Personal, Advisory Role: AbbVie Inc., ACEA Pharma, Adagene, Alpha Biopharma Co., Ltd., Amgen, Amoy Diagnostics Co., Ltd., AstraZeneca (before 1/1/19), AVEO Pharmaceuticals Ltd., BeiGene, BerGenBio ASA, Berry Oncology, BI, Blueprint Medicines Corporation, Bristol Myers Squibb, Bowtie Life Insurance Company Limited, Bridge Biotherapeutics Inc., Covidien LP, C4 Therapeutics Inc., Cirina Ltd., CStone Pharmaceuticals, Curio Science, D3 Bio Ltd., Da Volterra, Daiichi Sankyo, Eisai, Elevation Oncology, F. Hoffmann-La Roche Ltd., Genentech, GLG's Healthcare, Fishawack Facilitate Ltd., G1 Therapeutics Inc., geneDecode Co., Ltd., Gilead Sciences, Inc., Gritstone Oncology, Inc., Guardant Health, Hengrui Therapeutics Inc., HutchMed, Ignyta, Inc., Illumina, Inc., Incyte Corporation, Inivata, IQVIA, Janssen, Lakeshore Biotech Ltd., Lilly, Lunit USA, Inc., Loxo Oncology, Lucence Health Inc., Medscape LLC/ WebMD, Medtronic, Merck Serono, Merck Sharp & Dohme, Mirati, a Bristol Myers Squibb Company, MiRXES, MoreHealth, Novartis, Novocure GmbH, Omega Therapeutics Inc., OrigiMed, OSE Immunotherapeutics, PeerVoice, Pfizer, PrIME Oncology, Prenetics, Puma Biotechnology Inc., Qiming Development (HK) Ltd., Regeneron Pharmaceuticals Inc., Roche Pharmaceuticals/ Diagnostics/ Foundation One, Sanofi-Aventis, SFJ Pharmaceutical Ltd., Simcere of America Inc., Simcere Zaiming, Inc., Summit Therapeutics Sub, Inc., Synergy Research, Takeda Pharmaceuticals HK Ltd., Tigermed, Vertex Pharmaceuticals, Virtus Medical Group, XENCOR, Inc., Yuhan Corporation; Financial Interests, Personal, Leadership Role: AstraZeneca PLC, HutchMed, Aurora; Financial Interests, Institutional, Research Funding: AstraZeneca, Bristol Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SFJ, Takeda, XCovery; Financial Interests, Personal, Stocks or ownership: Alentis Therapeutics AG, AstraZeneca, Aurora Tele-Oncology Ltd., Biolidics Ltd., HutchMed, Prenetics, D3 Bio, Lunit Inc. M. Hochmair: Financial Interests, Personal, Advisory Board: AstraZeneca, Amgen, MSD, Boehringer-Ingelheim, Eli Lilly, Takeda, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Amgen, MSD, Boehringer-Ingelheim, Eli Lilly, Takeda, Roche; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Amgen, MSD, Boehringer-Ingelheim, Eli Lilly, Takeda, Roche. K.J. O'Byrne: Financial Interests, Personal, Other, Advisor/consultant on project development by the company: TriStar; Financial Interests, Personal, Other, Invited speaker; advisory board: BMS; Financial Interests, Personal, Other, Advisory board; invited speaker: AstraZeneca, MSD, Janssen; Financial Interests, Personal, Other, advisory board; invited speaker: Roche; Financial Interests, Personal, Advisory Board: Boehringer-Ingelheim; Financial Interests, Personal, Other, Advisory board: Pfizer; Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Advisory Board, Advice on development of Lasertinib: Yuhan; Financial Interests, Personal, Other, advisory board and invited speaker: Takeda, Seagen; Financial Interests, Personal, Advisory Board, Advice re cabozantinib: Ipsen; Financial Interests, Personal, Advisory Board, Advice of drug development program, advisory board work and invited speaker: BeiGene; Financial Interests, Personal, Invited Speaker, Topic - Tepotinib: Merck; Financial Interests, Personal, Other, Sponsorship for travel, accommodation and registration for ESMO Congress, Paris, 2022: Bayer; Financial Interests, Personal, Other, Sponsorship to ESMO annual congress 2023 - flights, registration and accommodation: Sanofi; Financial Interests, Personal, Stocks/Shares, 5% non-dilutable shares in a start-up Pharma company: RepLuca Pharmaceuticals Pty Ltd.; Financial Interests, Personal, Stocks/Shares, Start-up diagnostics focused on genomics: DGC diagnostics; Financial Interests, Personal, Other, Co-founder, board member and share holder (15%) in the Pharma and biotech company: Carpe Vitae Pharmaceuticals Pty Ltd.; Financial Interests, Personal, Steering Committee Member, Steering committee member 2 trials- CA-209-227- CA-001-050: BMS; Financial Interests, Personal, Steering Committee Member, Steering Committee member LUX-Lung program: Boehringer-Ingelheim; Non-Financial Interests, Other, Chair an education session: foundation medicine. E. Felip: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Lilly, F. Hoffmann-La Roche, Genmab, Gilead Sciences, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point Therapeutics; Financial Interests, Personal, Leadership Role: SEOM; Financial Interests, Personal, Member: Member of the Scientific Advisory Committee for Hospital Universitari Parc Tauli, ETOP IBCSG Partners Member of the Scientific Committee; Financial Interests, Personal, Other, Grant for oncology innovation: Merck; Financial Interests, Personal, Other: Fundación Merck Salud, GRIFOLS; Financial Interests, Personal, Other, Travel, accommodations, expenses: AstraZeneca, Janssen, Roche; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Peervoice, Pfizer, Sanofi, Takeda. F. Cappuzzo: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Mirati, PharmaMar, Novocure, OSE, GALECTO and MSD; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Mirati, Novocure, OSE, and MSD. J. Naidoo: Financial Interests, Personal and Institutional, Advisory Board: Bristol Myers Squibb, AstraZeneca, Daiichi Sankyo, Mirati, Elevation Oncology, Takeda, Pfizer, Roche/Genentech; Financial Interests, Institutional, Coordinating PI: Bristol myers squibb, Astrazeneca, Daiichi Sankyo, Mirati, Elevation Oncology, Takeda, Pfizer, Roche/Genentech; Financial Interests, Institutional, Local PI: Bristol myers squibb, Astrazeneca, Daiichi Sankyo, Mirati, Elevation Oncology, Takeda, Pfizer, Roche/Genentech; Financial Interests, Institutional, Principal Investigator: Bristol Myers Squibb, Astrazeneca, Daiichi Sankyo, Mirati, Elevation Oncology, Takeda, Pfizer, Roche/Genentech; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, AstraZeneca, Amgen, Pfizer, Roche/Genentech; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Daiichi Sankyo, Gilead/Arcus, Summit Therapeutics. B. Wamil: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. J. He: Financial Interests, Personal, Full or part-time Employment: Mirati, a Bristol Myers Squibb Company, Bristol Myers Squibb. M. Reck: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bristol Myers Squibb, BioNTech, Boehringer Ingelheim, Daiichi Sankyo, Gilead, GSK, MSD, Mirati, a Bristol Myers Squibb Company, Pfizer, Regeneron, Sanofi, Roche, Seagen; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Bristol Myers Squibb, BioNTech, Boehringer Ingelheim, Daiichi Sankyo, Gilead, GSK, MSD, Mirati, a Bristol Myers Squibb Company, Pfizer, Regeneron, Sanofi, Roche, Seagen; Financial Interests, Personal, Other, DMSB: Daiichi Sankyo, Sanofi; Financial Interests, Institutional, Research Funding: Boehringer Ingelheim, Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, GSK, Lilly, Mirati, a Bristol Myers Squibb Company, MSD, Merck, Novartis, Regeneron, Sanofi, Roche, Seagen. All other authors have declared no conflicts of interest.