LBA4 - Randomized phase III study of first-line selpercatinib versus chemotherapy and pembrolizumab in RET fusion-positive NSCLC

Background

Selpercatinib is a highly selective and potent, brain penetrant RET inhibitor, approved for treatment of advanced RET fusion-positive (RET+) NSCLC. Selpercatinib had not previously been evaluated in a randomized trial.

Methods

LIBRETTO-431 (NCT04194944) is a randomized, open-label, phase 3 trial comparing first-line selpercatinib vs chemotherapy (cisplatin/carboplatin + pemetrexed) +/- pembrolizumab. The primary endpoint of blinded independent central review (BICR)-assessed PFS was tested first in patients stratified by investigator’s intent to treat with pembrolizumab, if assigned to the control arm, (ITT-pembro) and then in the ITT population. The pre-planned interim efficacy analysis by BICR occurred after 98 PFS events in the ITT-pembro population. Crossover to selpercatinib was allowed following BICR progression on the control arm.

Results

A total of 261 patients were enrolled from 23 countries. Baseline characteristics were balanced across study arms. At a median follow up of approximately 19 months, selpercatinib demonstrated superior PFS vs control in the ITT-pembro (HR: 0.465, 95% CI: 0.309, 0.699; p-value: 0.0002) and ITT populations (HR: 0.482, 95% CI: 0.331, 0.700; p-value: 0.0001). In the ITT-pembro population, median PFS was 24.8 months (95% CI: 16.9, NE) with selpercatinib vs 11.2 months (95% CI: 8.8, 16.8) with control. Clinically meaningful improvements in ORR, DOR, and intracranial response were also observed with selpercatinib vs control. Time to CNS progression was longer with selpercatinib than control (cause-specific HR 0.26; 95% CI: 0.11, 0.59; p=0.0006). Adverse events observed with selpercatinib and the control arm were generally consistent with those previously reported.

Conclusions

Selpercatinib achieved a statistically significant and clinically meaningful improvement in PFS compared to chemotherapy + pembrolizumab in advanced RET+ NSCLC. LIBRETTO-431 is the first randomized study to demonstrate superior PFS with a targeted therapy vs chemotherapy + a checkpoint inhibitor in a biomarker selected patient population. These data support comprehensive genomic testing at diagnosis and treatment with first-line selpercatinib in patients with advanced RET+ NSCLC.

Clinical trial identification

NCT04194944.

Editorial acknowledgement

Justin Williams, employee of Eli Lilly and Company, provided critical analysis and input with his medical writing assistance.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

H.H.F. Loong: Financial Interests, Institutional, Invited Speaker: Boehringer-Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Eli Lilly, Illumina, Bayer, Guardant Health; Financial Interests, Personal, Advisory Board: Novartis, Takeda. K. Goto: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Amgen K.K., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Amgen Inc., Amoy Diagnosties Co.,Ltd., AstraZeneca K.K., Bayer HealthCare Pharmaceuticals Inc., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., DAIICHI SANKYO Co., Ltd., Eisai Co., Ltd., Guardant Health Inc., Merck Biopharma Co., Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Thermo Fisher Scientific K.K., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K.; Financial Interests, Personal, Expert Testimony: Medpace Japan K.K.; Financial Interests, Personal and Institutional, Funding: Amgen Inc., Amgen K.K., AstraZeneca K.K., Boehringer Ingelheim Japan, Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., DAIICHI SANKYO Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Haihe Biopharma Co., Ltd., Ignyta,Inc., Janssen Pharmaceutical K.K., KISSEI PHARMACEUTICAL CO., LTD., Kyowa Kirin Co., Ltd., Loxo Oncology, Inc., MEDICAL BIOLOGICAL LABORATORIES CO., LTD., Merck Biopharma Co., Ltd., Merus N.V., MSD K.K., Ono Pharmaceutical Co., Ltd., Pfizer Japan Inc., Sumitomo Dainippon Pharma Co., Ltd., Spectrum Pharmaceuticals, Inc., Sysmex Corporation., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Turning Point Therapeutics,Inc., Amgen Astellas BioPharma K.K., Bayer Yakuhin, Ltd., Blueprint Medicines Corporation., Life Technologies Japan Ltd., NEC Corporation., Novartis Pharma K.K.; Non-Financial Interests, Member: American Society of Clinical Oncology, The Japan Lung Cancer Society, Japanese Society of Medical Oncology, The Japanese Cancer Association. B.J. Solomon: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Merck, Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Roche/Genentech; Financial Interests, Personal, Advisory Board: Amgen, Roche-Genentech, Eli Lilly, Takeda, Janssen; Financial Interests, Personal, Full or part-time Employment, Employed as a consultant Medical Oncologist at Peter MacCallum Cancer Centre: Peter MacCallum Cancer Centre; Financial Interests, Personal, Member of Board of Directors: Cancer Council of Victoria, Thoracic Oncology Group of Australasia; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Institutional, Invited Speaker, Principal Investigator and Steering committee Chair: Roche/Genentech, Pfizer; Financial Interests, Institutional, Invited Speaker: Novartis. K. Park: Financial Interests, Personal, Advisory Board: JNJ, AstraZeneca, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Other, DMC member: BeiGene, Incyte; Financial Interests, Personal, Other, Advisor/Consultant: Genius, IMBdx; Financial Interests, Personal, Other, Advisor: ABION; Financial Interests, Personal, Stocks/Shares, Stock option: IMBDx, GENIUS. M. Pérol: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, BMS, Lilly, Novartis, Takeda, Gritstone, Sanofi, Pfizer, Amgen, JANSSEN, GSK, ESAI, IPSEN; Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, MSD, BMS, BOEHRINGER INGELHEIM, Takeda, Illumina, Pfizer, Medscape, Roche; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Takeda, Boehringer Ingelheim; Financial Interests, Personal, Other, DMSB: Roche. E. Arriola: Financial Interests, Personal, Advisory Board: Roche, Boehringer Ingelheim, Lilly; Financial Interests, Personal, Invited Speaker: Takeda, MSD, AstraZeneca, BMS, Thermo Fisher Scientific, Guardant Health, Pfizer; Financial Interests, Personal, Other, Co-founder: Trialing Health; Financial Interests, Institutional, Research Grant: AstraZeneca. S. Novello: Financial Interests, Personal, Invited Speaker: AZ, MSD, Eli Lilly, Novartis, Beigene, Amgen; Financial Interests, Personal, Advisory Board: BI, BMS, Pfizer, Takeda, Roche, Sanofi, Amgen; Financial Interests, Institutional, Invited Speaker, IIT: MSD, BI; Non-Financial Interests, Leadership Role, president of this european advocacy: WALCE. A. Ardizzoni: Financial Interests, Personal, Invited Speaker, Honoraria for lectures: BMS, AstraZeneca, MSD; Non-Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, BMS, Sanofi, Eli Lilly and Company. M. Mak: Financial Interests, Personal, Invited Speaker: Roche, MSD, Sanofi, Takeda, AstraZeneca; Financial Interests, Personal, Expert Testimony: Eli Lilly, Jassen. F.C. Santini: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Lilly. A. Drilon: Financial Interests, Personal, Advisory Board: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem Oncology, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Amgen, Janssen, EcoR1, Monte Rosa; Financial Interests, Personal, Other, CME: Medscape, Onclive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, PeerView Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Options, AiCME; Financial Interests, Personal, Other, CME, Consulting: Axis; Financial Interests, Personal, Other, Consulting: Nuvalent, Merus, EPG Health, mBrace, Harborside Nexus, Ology, TouchIME, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical, Remedica Ltd, RV More; Financial Interests, Personal, Stocks/Shares: Treeline Biosciences; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Personal, Other, stocks: mBrace; Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, PharmaMar, GSK, Teva, Taiho; Financial Interests, Personal, Funding, Research: Foundation Medicine; Non-Financial Interests, Member: ASCO, AACR, IASLC; Other, Food/Beverage: Merck, PUMA, Merus; Other: Boehringer Ingelheim. J. Wolf: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Blueprint, BMS, Boehringer-Ingelheim, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda; Financial Interests, Personal, Invited Speaker: Bayer, Chugai; Financial Interests, Institutional, Research Grant: BMS, Janssen, Novartis, Pfizer. H. Han: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. M. Uh: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. T. Puri: Financial Interests, Personal, Full or part-time Employment, Full time employee of Eli Lilly and Company: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares, Full time employee of Eli Lilly and Company with stock options: Eli Lilly and Company. V. Ilaria: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company - Indianapolis, IN; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company - Indianapolis, IN. C. Zhou: Financial Interests, Personal, Invited Speaker, Honoraria: Eli Lily, Roche, Sanofi, Qilu Pharma, Hengrui, Innovent Biologics, C-Stone, LUYE Pharma, TopAlliance Biosciences Inc; Financial Interests, Personal, Invited Speaker, BI: BI; Financial Interests, Personal, Invited Speaker, MSD: MSD; Financial Interests, Personal, Advisory Board, Advisor: Amoy Diagnositics. All other authors have declared no conflicts of interest.