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Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade., Competing Interests: CCL reports consulting fees from AbbVie, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb (BMS), Daiichi-Sankyo, Merck KGaA, Novartis, PharmaEngine; payment or honoraria from Eli Lilly, Novartis, and Roche; and support for attending meetings or travel from BeiGene, Daiichi-Sankyo, and Eli Lilly. EG reports grants or contracts from Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho, and BeiGene; payment or honoraria from Roche, Genentech, F. Hoffmann-La Roche, Ellipses Pharma, Neomed Therapeutics Inc, Boehringer Ingelheim, Janssen Global Services, SeaGen, Alkermes, Thermo Fisher, BMS, MabDicovery, Anaveon, F-Star Therapeutics, Hengrui; participated on data safety monitoring board or advisory board for Roche, Genentech, Boehringer Ingelheim, Janssen Global Services, Thermo Fisher, Anaveon, MabDiscovery, Novartis and Lilly; and serves as PI or Co-PI for Affimed Gmbh. Amgen SA, Anaveon AG, AstraZeneca AB, Biontech Gmbh, Catalym Gmbh, Cytomx, F. Hoffmann-La Roche Ltd, F-Star Beta Limited, Genentech Inc, Genmab B.V, Hutchison Medipharma Limited, Icon, Imcheck Therapeutics, Immunocore Ltd, Janssen-Cilag SA, Medimmune Llc, Merck KGaA, Novartis Farmacéutica SA, Peptomyc, Ribon Therapeutics, Roche Farma SA, Seattle Genetics Inc, Symphogen A/S, Taiho Pharma Usa Inc PS reports grants or contracts from CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, ONA therapeutics; honoraria from Blueprint Medicines; and consulting fees from Deciphera, Ellipses Pharma, Blueprint Medicines, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie, SQZ biotechnology, CRT Pioneer Fund LP, Adcendo, PharmaMar, Merck Healthcare KGaA, Ysios Capital. DSH reports grants or contracts from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Deciphera, Eisai, Erasca, Fate Therapeutics, Genentech, Genmab, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, Medimmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda, Turning Point Therapeutics, Verstatem, and VM Oncology; travel, accommodation, expenses from Bayer, Genmab, and Telperian; consulting fee from Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Atheneum, Axiom, Barclays, Baxter, Bayer, Boxer Capital, BridgeBio, CDR-life AG, COR2ed, COG, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point, WebMD, and Ziopharm; and other ownership interests for OncoResponse (founder) and Telperian Inc (advisor). LLS reports stock ownership or equity in Agios (spouse); leadership in Treadwell Therapeutics (spouse is co-founder); and consulting fee/advisory board for Merck, Pfizer, AstraZeneca, Roche, Symphogen, GSK, Voronoi, Treadwell Therapeutics, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi-Sankyo, Coherus, Amgen, and Marengo; grant/research support (clinical trials for institution) for Novartis, BMS, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca/Medimmune, Merck, Celgene, Astellas, Bayer, AbbVie, Amgen, Symphogen, Intensity Therapeutics, Mirati, Shattucks, and Avid. MigM reports honoraria from SeaGen, Lilly, AstraZeneca, Pfizer, Daiichi-Sankyo, Roche; consulting fees from Roche, Novartis, AstraZeneca, Daiichi-Sankyo, SeaGen, Lilly, Sanofi; advisory board of Novartis and holds leadership roles in GEICAM (Board of Directors), TRIO. RH reports grants and contacts for clinical trials for institution from AstraZeneca, BMS, Corvus, Eli Lilly, MSD, Novartis, Olema, Oncosec, Roche, SeaGen; honoraria from AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, Roche; participates in advisory board of AstraZeneca, BMS, Eisai, Eli Lilly, Merck, MSD, Novartis, OncoSec, Pfizer, Roche, SeaGen. RAS reports grants from AstraZeneca and Boehringer Ingelheim, and personal fees from AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan, Amgen, Bayer, Puma. TZ reports grants from Genentech Roche, OmniSeq, SeaGen, PGDx, Janssen, AstraZeneca, Pfizer, AbbVie/StemcentrX, Merck, Regeneron, Mirati Therapeutics, Novartis, Merrimack; consulting fees from Genentech Roche, Eli Lilly, Bayer, QED Therapeutics, Eisai, Calithera, Aveo Pharmaceuticals, Amgen, BMS, Dendreaon, Sanofi-Aventis, Janssen, AstraZeneca, Pfizer, Merck, Exelixis; honoraria from MJH Associates, Aptitude Health, PlatformQ, Integrity CE, Vaniam Group, PeerView, and Novartis; travel support from SUO, Kidney Cancer Association, and KCCure; and leadership role in NCI GU Steering Renal Task force, KCA Medical Steering committee, and KCCure Scientific advisory board. BM reports grant from Health and Medical Research Fund, Merck Serono, Boehringer Ingelheim Inc; consulting fees from Viracta therapeutics and Y-Biologics; honoraria from MSD, Novartis, Merck, Y-Biologics, Springer, Elsevier, Daiichi, Taiho, and Pierra Fabre; holds leadership roles in ethics committee of NTEC-CUHK, ESMO Asia 2020 and ESMO 2022 (Track Chair – Paris, Singapore), ASCO 2020 (Session chair), and ESMO Asia 2019 (Co-Chair). CK reports research funding from BMS, Merus, and Gritstone Oncology. DT reports honoraria and consulting/advisory roles for Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, and Takeda; consulting/advisory roles for Bayer, AstraZeneca, Eli Lilly, and GlaxoSmithKline; and research funding for Novartis, AstraZeneca, GlaxoSmithKline, Bayer, Pfizer, and Amgen. PAC reports research funding from AbbVie, Adlai Nortye, Alligator, Amgen, AstraZeneca, Blueprint Medicines, Boston, Bristol Myers Squibb, Celgene, Debio Pharm, Dragonfly, Exelixis, GlaxoSmithKline, Innate Pharma, Janssen, Eli Lilly, Loxo, Molecular Partners, MSD, Novartis, OSE Pharma, Relay, Roche/Genentech, Sotio, Taiho Pharmaceutical, Toray Industries, Transgene, and Turning Point Therapeutics; personal fees from AstraZeneca, Amgen, Merck Serono, Novartis, and Roche/Genentech; nonfinancial research support from AstraZeneca, Debio Pharm, MSD, Novartis, Plexxikon, and Roche/Genentech; and travel accommodation from BMS, MSD, and NETRIS Pharma. JS reports consulting/advisory roles for Astellas Pharma, AstraZeneca/MedImmune, Bayer, Eisai, Roche/Genentech, Pfizer, Immunocore, SeaGen, Novartis, Sun Pharma, EMD Serono, Amgen, Bristol-Myer Squib, Flugent Therapeutics, Exelixis, Merck, Takeda, and Array BioPharma. AW received research grants from Merck and BMS; consulting fees from Ipsen, Astella, BMS; and honoraria from Ipsen, Pfizer, BMS. RDC received research funding from Amgen, Astellis, AstraZeneca, BMS, Corvus, Ideaya, Immunocore, Iovance, Merck, Mirati, Novartis, Pfizer, Plexxikon, Regeneron, Roche/Genentech; consulting fees from Alkermes, BMS, Castle Biosciences, Eisai, Ideaya, Immunocore, InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Sanofi Genzyme, Sorrento Therapeutics, Trisalus; participated in data safety monitoring or advisory board of Aura Biosciences, Chimeron, and Rgenix; and stocks in Aura Biosciences, Chimeron, and Rgenix. TE reports grants for MSD, Novartis, Dainipon Sumitomo, Ono, Daiichi-Sankyo, Astellas, Astellas Amgen Biopharma, Parexel, Chugai, Quintiles, Syneos Health, Pfizer, IQVIA; and honoraria from MSD, Ono, Daiichi-Sankyo, Eli Lilly, Taiho, Chugai, and Sanofi. FR reports consulting fees from BMS and MSD; honoraria from Merck KGaA. FDB reports consulting fees from NMS Nerviano, Menarini, AstraZeneca, Incyte; honoraria from BMS, Merck Group, MDS, Pfizer, Servier, Sanofi, Roche, Amgen, Incyte; travel support from Roche; and participated in advisory board of Pierre Fabre, AstraZeneca, MSD Serono, BMS, Roche, Sanofi, Novartis. LR is employee of Novartis. MicM, JC, JS, WA, BDB reports no conflicts of interest. TS, NRC, DG, EK and VA were employees of Novartis at the time of study conduct. EK and VA report stocks from Novartis., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients harboring activating EGFR mutations. However, resistance mechanisms, particularly the T790 M mutation, hamper longer-term therapeutic success of first and second generation EGFR-TKIs. To address this unmet medical need, EGFR-TKIs of the third generation are under clinical development. Relevant clinical efficacy with mainly mild to moderate class-specific side effects has been shown for third-generation EGFR-TKIs. Molecular testing is of major importance in deciding for treatment with third generation EGFR-TKIs. This article elucidates the developmental state of third generation EGFR-TKIs with its focus on Osimertinib, the first and currently the only compound in this class which is approved in Germany. Additionally, the medical importance of molecular diagnosis using tumor tissue and circulating tumor DNA is discussed., Competing Interests: Beratungs- bzw. Gutachtertätigkeit übte F. Griesinger für Ariad, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Clovis, Lilly, MSD, Novartis, Pfizer und Roche aus. Reisekostenzuschüsse erhielt F. G. von Ariad, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Lilly, MSD, Novartis, Pfizer und Roche. Honorare erhielt F. G. von Ariad, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Clovis, Lilly, MSD, Novartis, Pfizer und Roche. Unterstützung für wissenschaftliche Projekte erhielt F. G. von AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Clovis, Lilly, MSD, Novartis, Pfizer und Roche. B. Deschler-Baier erhielt Referentenhonorare von BMS. M. Kimmich erhielt Beraterhonorare bzw. finanzielle Zuwendungen bei Kongressbesuchen von AstraZeneca, Boehringer-Ingelheim und Novartis. M. Sebastian erhielt Beratung und Honorare von AstraZeneca, Boehringer-Ingelheim und Roche. C. Schulz erhielt Vortrags- und Beraterhonorare von AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Lilly, MSD, Novartis, Roche. W. Brugger ist Mitarbeiter von AstraZeneca und hält Aktien. Davor erhielt er Referentenhonorare von AstraZeneca, Roche, BMS, Boehringer-Ingelheim und Pfizer. R. Wiewrodt erhielt Vortrags- und Beraterhonorare von AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Celgene, CSL, GSK, Hoffmann-La Roche, Lilly, MSD, Novartis und Pfizer. R. Pirker erhielt Referenten und/oder Honorare für Advisory Boards von AstraZeneca, Boehringer-Ingelheim und Clovis. M. Früh erhielt von BMS und AstraZeneca Zuwendungen für Forschungszwecke, die in keinem Zusammenhang mit diesem Artikel stehen. O. Gautschi war Advisory Board Mitglied für AstraZeneca. J. Wolf erhielt Referenten- bzw. Advisory Board Honorare von AstraZeneca, Amgen, BMS, Boehringer-Ingelheim, Clovis, Lilly, MSD, Novartis, Pfizer und Roche. Zudem erhielt er von BMS, MSD, Novartis, Pfizer und Roche Zuwendungen für Forschungszwecke.S. Radke und A. Lüers geben an, dass kein Interessenskonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)