Eftilagimod Alpha (a Soluble LAG-3 Protein) Combined With Pembrolizumab in Second-Line Metastatic NSCLC Refractory to Anti-Programmed Cell Death Protein 1/Programmed Death-Ligand 1-Based Therapy: Final Results from a Phase 2 Study.

Eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, triggers antigen-presenting cell and T-cell (CD4 After confirmed progression on anti-PD-(L)1-based first-line therapy, patients received efti (30 mg subcutaneously every 2 weeks for eight 3-week cycles and then every 3 weeks for up to 54 weeks) plus pembrolizumab (200 mg intravenously every 3 weeks for up to 105 weeks). The primary endpoint was the objective response rate by modified Response Evaluation Criteria in Solid Tumors version 1.1 for immune-based therapies. Secondary endpoints included disease control rate, progression-free survival, overall survival (OS), and tolerability. Exploratory endpoints included tumor growth kinetics and predefined subgroup analyses. Programmed cell death-ligand 1 tumor proportion score was assessed centrally. Thirty-six patients were enrolled from April 2019 to August 2021 using Simon's two-stage design. Most patients (81.8%) had low or negative (<50%) PD-(L)1 tumor proportion score. First-line therapy was anti-PD-(L)1-based for all patients, combined with chemotherapy for 66.7%. The confirmed objective response and disease control rates were 8.3% and 33.3%. The median progression-free survival was 2.1 months and the median OS was 9.9 months. Patients exhibiting high PD-(L)1 expression or acquired resistance to PD-(L)1 inhibitors revealed superior response and survival outcomes, and OS was closely correlated with disease control. No treatment-emergent adverse event led to permanent discontinuation of study treatment. Efti plus pembrolizumab was well-tolerated and revealed signs of antitumor activity in patients with NSCLC resistant to PD-(L)1 inhibitors, warranting further investigation. Trial registration number: NCT03625323.

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Dr. Krebs reports grants or contracts from Novartis and Roche; consulting fees from Bayer, Guardant Health, Immutep, Janssen, Roche, and Seattle Genetics; and honoraria and travel support from Janssen and Roche. Dr. Forster reports grants from 10.13039/100008349Boehringer Ingelheim, 10.13039/100004334Merck, and Merck Sharp & Dohme; conference support and honoraria for advisory and consultancy work from Achilles, Amgen, AstraZeneca, Bayer, Boxer, Bristol-Myers Squibb, Celgene, EQRx, Immutep, Ixogen, Janssen, Merck, Merck Sharp & Dohme, Oxford VacMedix, Pharmamar, Roche, Takeda, Transgene, and UltraHuman. Dr. Iams reports consulting fees from Amgen, AstraZeneca, Bristol-Myers Squibb, Catalyst, Daiichi Sankyo, Elevation Oncology, EMD Serono, G1 Therapeutics, Genentech, Guardant Health, Jazz Pharma, Janssen, Merus, Mirati, Novocure, Sanofi, Takeda, and Tempus; honoraria from EMD Serono; and travel support from Biodesix and Tempus. Dr. Clay reports consulting fees from Therapeutic Goods Administration (Australia); honoraria from AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Roche, Specialised Therapeutics and Wiley; travel support from 10.13039/100004325AstraZeneca and 10.13039/501100022274Daiichi Sankyo; advisory board participation for AstraZeneca, Cipla, Foundation Medicine, Ipsen, Janssen, Merck KGaA, Pfizer, and Takeda; fiduciary duty for Medical Oncology Group of Australia; and stock ownership in Reliis. Dr. Barba reports payment or honoraria from Bristol-Myers Squibb, Takeda, Novartis, Sanofi, Pfizer, Merck Sharp & Dohme, and Pierre Fabre; travel support from 10.13039/100009947Merck Sharp & Dohme, 10.13039/100004319Pfizer, 10.13039/100004339Sanofi, 10.13039/100002491Bristol-Myers Squibb, and Roche. Ms. Perera reports employment with Immutep GmbH. Mr. Mueller reports employment with Immutep GmbH and stock ownership in Immutep Ltd. Dr. Triebel reports employment with Immutep SAS; stock ownership in and board membership of Immutep Ltd.; and has several patents pending or issued and others planned. The remaining authors declare no conflict of interest.