5MO - First-line adagrasib (ADA) with pembrolizumab (PEMBRO) in patients (pts) with advanced/metastatic KRASG12C-mutated non-small cell lung cancer (NSCLC) and PD-L1 =50% from the phase II portion of KRYSTAL-7

Background

First-line ADA, a KRAS^G12C inhibitor, plus PEMBRO demonstrated encouraging preliminary activity in pts with advanced/metastatic KRAS^G12C-mutated NSCLC and PD-L1 ≥50%, with a manageable safety profile, in the KRYSTAL-7 phase II study (median follow-up [FU] 10.1 mo; Garassino et al. Ann Oncol 2023; NCT04613596). Here we report updated data with longer FU.

Methods

Pts with advanced/metastatic KRAS^G12C-mutated NSCLC and known PD-L1 tumor proportion score received first-line ADA (400 mg orally BID) plus PEMBRO (200 mg IV Q3W). The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included duration of response (DOR) and progression-free survival (PFS) assessed by investigator, overall survival (OS), and safety.

Results

As of August 23, 2024, 149 pts received ADA plus PEMBRO. In 54 pts with PD-L1 ≥50%, ORR was 59.3% (95% CI, 45.0–72.4), median DOR was 26.3 mo (95% CI, 26.3–NE), median PFS was 27.7 mo (95% CI, 8.1–NE; 18-mo PFS rate 50.7% [95% CI, 35.5–64.0]; median FU 22.6 mo), and 18-mo OS rate was 62.4% (95% CI, 47.5–74.1; median FU 24.9 mo; Table). Among all 149 pts, treatment-related adverse events (TRAEs) of any grade (G) were reported in 94.6% of pts (G3/4 in 68.4%); three G5 TRAEs were reported (pneumonia [n = 2]; pneumonitis [n = 1]). The most common TRAEs (any G) were nausea (55.7%), diarrhea (47.0%), and ALT increase (39.6%), which were mainly G1/2. TRAEs led to discontinuation of ADA in 13.4% of pts, PEMBRO in 23.5% of pts, and both ADA and PEMBRO in 6.7% of pts.Table 5MO

Efficacy summary in patients with KRASG12C-mutated NSCLC and PD-L1 ≥50%

TTR, time to response. aDOR and TTR reported in responders only (n = 32); bMedian PFS follow-up: 22.6 months; cMedian OS follow-up: 24.9 months.

Conclusions

With extended FU, first-line ADA plus PEMBRO continued to demonstrate promising efficacy in pts with KRAS^G12C-mutated NSCLC and PD-L1 ≥50%, with a manageable safety profile. The phase III portion of KRYSTAL-7, comparing first-line ADA plus PEMBRO vs PEMBRO alone in pts with advanced/metastatic KRAS^G12C-mutated NSCLC and PD-L1 ≥50%, is ongoing and recruiting.

Clinical trial identification

NCT04613596.

Editorial acknowledgement

Third-party medical writing support, under the direction of the authors, was provided by Jessica Traynor, PhD, 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

M.C. Garassino: Financial Interests, Personal, Advisory Board: Eli Lilly, SeaGen International GmbH, Eli Lilly, Incyte, GSK, Bayer Healthcare Pharmaceuticals, Blueprint Medicines, AstraZeneca and Daiichi Sankyo Oncology Teams, Roche, Daiichi Sankyo, Mirati Therapeutics, Inc, Daiichi Sankyo/AstraZeneca, AstraZeneca Poland, Daiichi Sankyo, Inc., MSD, Eli Lilly, Pfizer, AstraZeneca/MedImmune, Sanofi Genzyme corporation, Sanofi/Prex, Regeneron Pharmaceuticals, Eli Lilly, Mirati Therapeutics, Inc., Janssen pharmaceutical, io biotech, Merck, Novocure, Nuvation, Pfizer, Revolution medicine, Roche, Merck, AstraZeneca, Bayer, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Gilead, Mirati; Financial Interests, Personal, Invited Speaker: WebMD, WebMD Oncology/Takeda, MSD Italia, Srl, GrupoPacifico-Secretaria Técnica ICAPEM/AstraZeneca, S. O.S S.r.l, Medscape, ecancer, Ideology, Gilead, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker, Global Experts Meeting: AstraZeneca; Financial Interests, Personal, Other, AstraZeneca SPAIN: Invitation to a lung cancer investigator meeting: AstraZeneca; Financial Interests, Personal, Advisory Board, Advisory Boards: Takeda, Daiichi Sankyo, BeiGene; Financial Interests, Personal, Other, PACIFIC-R Global Scientific Committee: AstraZeneca; Financial Interests, Personal, Other, Steering Committee member and Co-chair at the AstraZeneca Lung Cancer Summit 2019: AstraZeneca; Financial Interests, Personal, Other, MK-3475 KN671 Steering Committee.: MSD; Financial Interests, Personal, Other, Pacific 6 International Coordinating Investigator: AstraZeneca; Financial Interests, Personal, Other, Jannesen Scientific Advisory Board and Therapeutic Area Steering Committee Meeting on Lung Cancer: Janssen; Financial Interests, Personal, Expert Testimony: AstraZeneca UK; Financial Interests, Personal, Other, Pfizer Global Lung Cancer Educational Programme - Steering Committee: Pfizer; Financial Interests, Personal, Other, Seattle Genetics Lung Cancer Platform Study: Seattle Genetics; Financial Interests, Personal, Other, GSK Lung Cancer Global Council: GSK; Financial Interests, Personal, Other, PACIFIC-R Scientific Committee: AstraZeneca UK; Financial Interests, Personal, Other, GSK-Garassino-ZEAL Steering Committee 2020–23: GSK; Financial Interests, Personal, Advisory Board, Advisory Board: AbbVie, Abion, Bayer; Financial Interests, Personal, Advisory Board, Advisory boards: Merck, Sanofi, Gilead; Financial Interests, Personal, Invited Speaker, Satellite Symposium: Merck; Financial Interests, Personal, Invited Speaker, Invited speaker: Medscape; Financial Interests, Personal, Advisory Board, Invited speaker: OncoHost; Financial Interests, Personal, Advisory Board, Advisor: Boehringer; Financial Interests, Personal, Invited Speaker, Member of the MK-3475 KN671 Steering Committee (KEYNOTE-671): MSD; Financial Interests, Personal, Invited Speaker, Coordinating investigator for the MK-3475 KEYNOTE 189: MSD; Financial Interests, Personal and Institutional, Invited Speaker, Pacific 6 Steering Committee and International Coordinating Investigator: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Steering Committee ML41118 Roche: Roche; Financial Interests, Institutional, Invited Speaker, TURNING POINT: Bayer; Financial Interests, Institutional, Invited Speaker, A Phase 1: Janssen; Financial Interests, Institutional, Invited Speaker, Array 818–202: Pfizer; Financial Interests, Institutional, Invited Speaker, PAPILLON Study: Janssen; Financial Interests, Institutional, Invited Speaker, Phase II: Celgene Corporation, Spectrum Pharmaceuticals, Merk Serono; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker, Phase 3: Bluprint; Financial Interests, Institutional, Invited Speaker, Phase III: Amgen, GSK Research & Develpoment Ltd., Novartis; Financial Interests, Institutional, Invited Speaker, Phase III - CEACAM5: Sanofi; Financial Interests, Institutional, Invited Speaker, Phase I-JNJ-61186372, a Human Bispecific EGFR and cMet Antibody: Janssen; Financial Interests, Institutional, Invited Speaker, Phase 3 Study RESILIENT: Ipsen Bioscience Inc.; Financial Interests, Institutional, Invited Speaker, Phase II - SAVANNAH: AstraZeneca S.p.A.; Financial Interests, Institutional, Invited Speaker, phase III NEOCOAST: MedImmune LCC; Financial Interests, Institutional, Invited Speaker, Phase II - coast: MedImmune LCC; Financial Interests, Institutional, Invited Speaker, Phase III - ADRIATIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Phase III (CANOPY-1): Novartis; Financial Interests, Institutional, Invited Speaker, Phase 1b: Exelixis Inc.; Financial Interests, Institutional, Invited Speaker, Phase 3-GO40241: Roche; Financial Interests, Institutional, Invited Speaker, Phase III- CASPIAN: AstraZeneca; Financial Interests, Institutional, Invited Speaker, MK3475-091 - PEARLS: Merk; Financial Interests, Institutional, Invited Speaker, Phase III - Roche GO29431: Roche; Financial Interests, Institutional, Invited Speaker, Phase III CA209-017: BMS; Financial Interests, Institutional, Invited Speaker, Phase III - ARCTIC: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Phase III - AURA 3: AstraZeneca AB; Financial Interests, Institutional, Invited Speaker, Phase III CA209-057: BMS; Financial Interests, Institutional, Invited Speaker, OPEL/2014/14/067: Otsuka Pharmaceutical Italy S.r.l.; Financial Interests, Institutional, Invited Speaker, Phase II - VISION: Merck KGaA; Financial Interests, Institutional, Invited Speaker, Phase III MK-3475-715: Incyte Corporation; Financial Interests, Institutional, Invited Speaker, Phase 1/2 (TRIDENT-1): Turning Point Therapeutics, Inc.; Financial Interests, Institutional, Invited Speaker, HERTHENA-Lung01: A Phase 2: Daiichi Sankyo Development Ltd.; Financial Interests, Institutional, Invited Speaker, Phase II ATLANTIC: AstraZeneca S.p.A.; Financial Interests, Institutional, Invited Speaker, Clinical trial: Affimed; Financial Interests, Institutional, Invited Speaker, Clinical trial poziotinib: spectrum; Non-Financial Interests, Personal, Principal Investigator, STYLE Trial: Pfizer; Non-Financial Interests, Personal, Principal Investigator, Studio TYME: Eli Lilly; Non-Financial Interests, Personal, Principal Investigator, People: MSD; Non-Financial Interests, Personal, Principal Investigator, FAME trial: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, POST-ALK: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, Bando finalizzata Mesotelioma: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, TERAVOLT: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, Progetto Timoma: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, APOLLO: Istituto Nazionale dei Tumori; Non-Financial Interests, Personal, Principal Investigator, Beverly: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Personal, Principal Investigator, IND227: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Personal, Principal Investigator, RAMES: GOIRC; Non-Financial Interests, Personal, Principal Investigator, Studio CHANCE: GOIRC; Non-Financial Interests, Personal, Principal Investigator, Creta trial: Sant’Orsola Malpighi - Bologna (Alma Mater Studiorum Università Bologna); Non-Financial Interests, Personal, Principal Investigator, MILES 5: Istituto dei Tumori Pascale - Napoli; Non-Financial Interests, Personal, Principal Investigator, LIPI: GUSTAVE-ROUSSY PARIGI LIPI TRIAL- no profit; Non-Financial Interests, Personal, Principal Investigator: AO Spedali Civili Brescia; Non-Financial Interests, Personal, Principal Investigator, phase III trial: European Thoracic Oncology Platform (ETOP); Non-Financial Interests, Personal, Leadership Role, Honorary President and Founder: Women for Oncology Italy; Non-Financial Interests, Personal, Other, Member of ASCO Scientific Committee (2018–2021): ASCO; Non-Financial Interests, Personal, Leadership Role, Board member: AIOT (Associazione Italiana Oncologia Toracica); Non-Financial Interests, Personal, Member: AIOM, AIOT; Non-Financial Interests, Personal, Member, WCLC annual congress Lung Cancer Track: WCLC; Non-Financial Interests, Personal, Member, Scientific Committee: IPOP (Italian lung cancer charity), TUTOR (Italian thymic malignancies charity); Non-Financial Interests, Personal, Member, Member since 2013–2018: EMA Scientific Advisory Group (SAG); Non-Financial Interests, Personal, Other, Scientific Programme Committee: AACR; Non-Financial Interests, Personal, Leadership Role, previous ESMO National Societies Committee Chair and ESMO Council Member: ESMO; Other, Personal, Other, Travel, Accommodations, Expenses: Pfizer; Other, Personal, Other, Relationships to Disclose Travel, accommodations, Expenses: Roche, AstraZeneca; Other, Personal, Other, travel and accommodation: Merk. W. Theelen: Financial Interests, Institutional, Research Grant: MSD, AstraZeneca, Regeneron. P.A. Jänne: Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals; Financial Interests, Personal, Royalties: Labcorp; Financial Interests, Personal, Sponsor/Funding: AstraZeneca, Boehringer Ingelheim, Lilly, Revolution Medicines, Takeda Oncology, Daiichi Sankyo; Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Lilly, SFJ Pharmaceuticals, Vorronoi, Daiichi Sankyo, Novartis, Biocartis, Takeda Oncology, Transcenta, Silicon Therapeutics, Syndax, Nuvalent, Allorion Therapeutics, Accutar Biotech, AbbVie, Blueprint Medicines, Dizal Pharmaceuticals; Financial Interests, Personal, Other, Expert testimony: AstraZeneca. M. Domine Gomez: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, PharmaMar, Pfizer, F. Hoffmann-La Roche, Takeda; Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, PharmaMar, Pfizer, F. Hoffmann-La Roche, Takeda; Financial Interests, Personal, Principal Investigator: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Gilead/MSD, PharmaMar, Pfizer, F. Hoffmann-La Roche, Takeda. E. Nadal: Financial Interests, Personal, Invited Speaker: F. Hoffmann-La Roche, Bristol Myers Squibb, MSD, Boehringer Ingelheim, Lilly, Pfizer, Sanofi, AstraZeneca, Takeda, Amgen, Qiagen, Janssen; Financial Interests, Personal, Advisory Board: F. Hoffmann-La Roche, Bristol Myers Squibb, MSD, Boehringer Ingelheim, Lilly, Janssen, Pfizer, Merck Serono, Daiichi Sankyo, AstraZeneca, Takeda, Amgen, Sanofi, Qiagen, Janssen; Financial Interests, Personal, Funding: F. Hoffmann-La Roche, Bristol Myers Squibb, Merck Serono; Non-Financial Interests, Personal, Advisory Role: Pfizer, F. Hoffmann-La Roche, Apollomics, Transgene. L. Paz-Ares: Financial Interests, Personal, Invited Speaker: Lilly, MSD, F. Hoffmann-La Roche, Merck KGaA, AstraZeneca, Novartis, Amgen, Pfizer, Bayer, Bristol Myers Squibb, Mirati Therapeutics, a Bristol Myers Squibb company, GSK, Janssen, Takeda, Regeneron, Sanofi, BeiGene, Gilead; Financial Interests, Personal, Advisory Board: Lilly, MSD, F. Hoffmann-La Roche, PharmaMar, Merck KGaA, AstraZeneca, Novartis, Amgen, Pfizer, Sanofi, Bayer, Bristol Myers Squibb, Mirati Therapeutics, a Bristol Myers Squibb company, GSK, Janssen, Takeda, Regeneron, BeiGene, Gilead; Financial Interests, Personal, Member of Board of Directors: Altum Sequencing, Stab Therapeutics; Financial Interests, Personal, Stocks/Shares: Altum Sequencing, Stab Therapeutics; Financial Interests, Institutional, Funding: MSD, AstraZeneca, Bristol Myers Squibb, Pfizer, PharmaMar; Financial Interests, Institutional, Principal Investigator: Lilly, MSD, F. Hoffmann-La Roche, PharmaMar, Merck KGaA, AstraZeneca, Novartis, Amgen, Pfizer, Sanofi, Bayer, Bristol Myers Squibb, Mirati Therapeutics, a Bristol Myers Squibb company, GSK, Janssen, Takeda, Regeneron, BeiGene, Gilead. E. Felip: Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, F. Hoffmann-La Roche, Genentech, Gilead, Janssen, Johnson & Johnson, Medical Trends, Medscape, Merck Serono, MSD, Novartis, Peervoice, Pfizer, Regeneron; Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, F. Hoffmann-La Roche, Gilead, GSK, iTeos Therapeutics, Janssen, Johnson & Johnson, MSD, Novartis, Pierre Fabre, Pfizer, Regeneron, Turning Point Therapeutics; Financial Interests, Personal, Other, Support for attending meetings and/or travel: AstraZeneca, Janssen, F. Hoffmann-La Roche; Financial Interests, Personal, Other, Independent member of the board: Grifols. E. Schaefer: Financial Interests, Personal, Advisory Board: Daiichi Sankyo. J. Porter: Financial Interests, Personal, Other, Speaker’s bureau: Amgen, Bristol Myers Squibb, EMD Serono, G1 Therapeutics, Inc., Guardant, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, a Bristol Myers Squibb company, Regeneron, Takeda, Merck; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, G1 Therapeutics, Jazz Pharmaceuticals, Merck, Lilly, Regeneron, Takeda, Boehringer Ingelheim, AbbVie, AstraZeneca; Financial Interests, Personal, Principal Investigator: LUNG:NSCLC:METASTATIC: 1ST LINE: R3767-ONC-2236, LUNG:NSCLC: 1ST LINE: KRAS G12C MT: KRYSTAL-7; Financial Interests, Personal, Other, Expert testimony: Guardant. L. Jimenez-Kurlander: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. C. Lane: Financial Interests, Personal, Full or part-time Employment: Mirati Therapeutics, a Bristol Myers Squibb company, Bristol Myers Squibb. A. Sachdeva: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. L. Eccles: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb. 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, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi, ArriVent Biopharma, Synthekine, GSK, Crispr Therapeutics, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, Blueprint Medicines; Financial Interests, Personal, Leadership Role: NEXT Oncology Virginia. All other authors have declared no conflicts of interest.