Abstract 40P
Background
Inactive LKB1 (LKB1neg) represents a key unmet need in NSCLC treatment, requiring novel strategies. Preclinical evidence highlights that targeting glucose deprivation can exploit metabolic vulnerabilities. Metformin (met) inhibits mitochondrial metabolism and reduces ATP availability in LKB1neg NSCLC, while fasting-mimicking diet (FMD) induces metabolic crisis. This trial evaluated the safety and efficacy of met ± FMD (300 kcal/day for 5 days) with first-line therapy in advanced LKB1neg NSCLC.
Methods
Patients (pts), with LKB1neg (defined as absence in IHC expression or presence of Stk11 mutations (mut)), were enrolled in three different cohorts: FAME (chemotherapy (CT) ± Immunotherapy (IO) + met + FMD), MERCY (CT ± IO + met) or BORN (observational, any treatment). The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, objective response rate (ORR), and overall survival (OS). Sample sizes (30 pts per cohort) aimed to detect a 4.8-month (mo) PFS increase vs. historical control (KEYNOTE 189).
Results
From 05/2019 to 04/2023, 157 pts were enrolled (FAME: 9, MERCY: 15, BORN: 133). Median (m) follow-up was 50.4 mo in the BORN arm. All FAME and MERCY pts were followed until death, except 3 (observed for 16.1–24.2 mo). Median age was 69 years; 67% male, 73% ECOG PS 0-1, 82.2% had Stk11 mut (29% also LKB1-negative), and 53.5% had KRAS co-mutations, 44% G12C. In pts treated with first-line CT-IO (FAME: 8, MERCY: 13, BORN: 38) the mPFS were 4.7 mo [95% CI: 0.4–10.8], 4.7 mo [95% CI:2.0–14.0] and 4.4 mo [95% CI:2.8–6.4], the ORR were 57.1%, 16.7% and 20.6%, the mOS were 14.4 mo [95% CI:0.4–26.5] and 11.5 mo [95% CI:2.6–27.5] and 8.5 mo [95% CI:3.8–14.4], respectively. Among Stk11 mut pts, mPFS were 4.7 mo [95% CI: 0.4–10.8], 5.5 mo [95% CI:0.2–22.7] and 3.9 mo [95% CI:2.2–5.8] and the mOS were 19 mo [95% CI:0.4–26.5], 11.5 mo [95% CI:1.3–34.6] and 8.4 mo [95% CI:3.7–14.4], respectively. 23.8% pts experienced a G3 or more treatment related AE.
Conclusions
The trial was closed due to low recruitment, preventing demonstration of the targeted PFS improvement. However, a doubling mOS was observed in pts with Stk11 mut treated in the FAME arm vs. BORN arm.
Clinical trial identification
NCT03709147.
Legal entity responsible for the study
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
Funding
AIRC IG20085.
Disclosure
M. Occhipinti: Financial Interests, Personal, Other, fees for travel, accommodation and expenses: Lilly; Financial Interests, Personal, Other, honoraria, consulting or advisory role: BMS; Financial Interests, Personal, Other, honoraria, consulting or advisory role: AstraZeneca, MSD. M. Brambilla: Financial Interests, Personal, Other, Travel grant: Lilly. C. Proto: Financial Interests, Personal, Other, fees for travel, accommodation and expenses; research funding and consulting or advisory fees: AstraZeneca, MSD, Roche; Financial Interests, Personal, Other, research funding and consultant: BMS; Financial Interests, Personal, Other, consulting or advisory fees: Janssen; Financial Interests, Personal, Other, research funding: Pfizer, Celgene, Daiichi Sankyo. A. Prelaj: Financial Interests, Personal, Other, Training of personnel: AstraZeneca, Italfarma; Financial Interests, Personal, Invited Speaker, the hive project: Discussant: Roche; Financial Interests, Personal, Advisory Board, Advisory board in Lung Cancer project: BMS; Financial Interests, Personal, Other, travel grant: Janssen; Financial Interests, Personal, Advisory Board: Janssen, AstraZeneca; Financial Interests, Personal, Invited Speaker: MEDSIR, Novartis, Lilly; Financial Interests, Institutional, Invited Speaker: Bayer, BMS, AstraZeneca, Lilly, MSD, SPECTRUM, Roche. T. Beninato: Financial Interests, Personal, Other, Honoraria, Travel accommodation and conference grants: MSD; Financial Interests, Personal, Other, Travel accommodation and conference grants: Sanofi, Pfizer, Lilly. 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, AstraZenca/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, Janssen 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 accommodations: Merk. L. Mazzeo: Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Conference Grants: Daiichi Sanyo; Financial Interests, Personal, Invited Speaker, Conference Grants: LEOPharma, Sanofi. C. Vernieri: Financial Interests, Personal, Other, consulting fees/advisory board, honoraria as speaker: Novartis; Financial Interests, Personal, Other, consulting fees/advisory board: Pfizer, Daiichi Sankyo, Menarini Steamline; Financial Interests, Personal, Other, honoraria as speaker, consulting fees/advisory board: Eli Lilly; Financial Interests, Personal, Other, honoraria as speaker: Istituto Gentili, Accademia Nazionale di Medicina. D. Signorelli: Financial Interests, Personal, Other, fees: AstraZeneca, Roche, BMS, Sanofi, Novartis, Boehringer Ingelheim; Financial Interests, Institutional, Other, fees: Lilly, Pfizer. F.G.M. De Braud: Financial Interests, Personal, Other, consulting fees/advisory board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, Menarini, AstraZeneca, Pierre Fabre, Mattioli 1885, MCCann Health, Taiho; Financial Interests, Personal, Other, research grant/funding, IQVIA Speaker Bureau, consulting fees/advisory board: MSD; Financial Interests, Personal, Other, research grant/funding, consulting fees/advisory board: Novartis; Financial Interests, Personal, Other,., IQVIA Speaker Bureau, consulting fees/advisory board: Incyte; Financial Interests, Personal, Other, research grant/funding, IQVIA Speaker Bureau, consulting fees/advisory board: BMS; Financial Interests, Personal, Other, research grant/funding: F. Hoffmann-LaRoche Ltd, Ignyta Inc, Merck Sharp & Dohme Spa, Kymab, Tesaro, MedImmune LCC, LOXO Oncology Inc, DAICHI SANKIO, Basilea Pharmaceutica, Janssen-Cilag International NV, Merck KGAA; Financial Interests, Personal, Other, IQVIA Speaker Bureau: Healthcare Research & Pharmacoepidemiology, Merck group, Servier, Dephaforum, Seagen, Nadirex, Ambrosetti, Itanet; Financial Interests, Personal, Other, IQVIA Speaker Bureau: Amgen. G. Lo Russo: Financial Interests, Personal, Advisory Board: MSD, Novartis, AstraZeneca, BMS, Sanofi, Pfizer, Roche, Lilly, GSK, Daiichi, Johnson & Johnson, Regeneron, Merck, Pierre Fabre; Financial Interests, Personal, Invited Speaker: ITALFARMACO, Merck, BMS, Lilly, Sanofi; Financial Interests, Institutional, Other, contribute for meeting organization: Janssen; Financial Interests, Institutional, Other, contribute for meeting organization: Bayer; Financial Interests, Personal, Other, travel accommodation: Amgen, MSD; Financial Interests, Institutional, Other, Contribute to meeting organization: Beigene; Financial Interests, Institutional, Invited Speaker: MSD, BMS, Roche, GSK, Celgene, Novartis, AstraZeneca, Amgen, Lilly. All other authors have declared no conflicts of interest.