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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. LIBRETTO-001 is a registrational phase I/II, single-arm, open-label study of selpercatinib in patients with RET (REarranged during Transfection)-activated cancers (ClinicalTrials.gov identifier: NCT03157128). We present long-term safety and efficacy from LIBRETTO-001 in patients with RET -mutant medullary thyroid cancer (MTC; n = 324) and RET fusion-positive thyroid cancer encompassing different histological subtypes (TC; n = 66). At the data cutoff of January 2023, the objective response rate was 82.5% among patients with cabozantinib/vandetanib-naïve MTC and 95.8% among patients with treatment-naïve TC. At a median follow-up time of 42.4 and 44.0 months in patients with cabozantinib/vandetanib-naïve and pretreated MTC, the median progression-free survival (PFS) was not reached and 41.4 months, respectively. At a median follow-up time of 24.9 and 30.4 months in patients with treatment-naïve and pretreated TC, the median PFS was not reached and 27.4 months, respectively. Three-year PFS rates were 75.2% and 87.3% among patients with cabozantinib/vandetanib-naïve MTC and treatment-naïve TC, respectively. Median PFS was similar to median duration of response for each patient group. The safety profile of selpercatinib was consistent with previous reports. With an additional follow-up of 37 months and 228 more patients from the last disclosure, selpercatinib continued to provide durable and robust responses in treatment-naïve and previously treated patients with RET -mutant MTC and RET fusion-positive TC.

This case report describes the efficacy of selpercatinib, a selective RET inhibitor, in an unusual case of large-cell neuroendocrine pancreatic carcinoma (LCNEPAC) harboring a CCDC6::RET fusion. A 56-year-old male with a history of multiple lines of systemic therapies exhibited marked clinical amelioration shortly after initiating selpercatinib within the LOXO-RET-17001 study (ClinicalTrials.gov ID: NCT03157128, first posted: 2017-05-17). Data from the patient's smartwatch suggested early efficacy before conventional methods, such as serum tumor markers and CT imaging confirmed the antitumor activity. This case not only underscores the efficacy of selpercatinib in treating RET fusion-positive rare tumors but also highlights the potential of wearable technology in cancer care. In conclusion, the standard readings from commercially available wearable devices can be useful for the monitoring of treatment response to targeted therapy and may serve as digital biomarkers in clinical trials. This approach marks a significant advancement in patient-centric healthcare, leveraging technology to enhance the effectiveness and precision of treatment evaluation., (© 2024. The Author(s).)

Introduction: Activating RET alterations have been reported in a variety of solid tumors, including pheochromocytoma where they occur both sporadically and as part of familial multiple endocrine neoplasia type 2 (MEN2) syndromes. Selpercatinib is a first-in-class, highly selective, and potent small molecule RET kinase inhibitor that has demonstrated marked and durable anti-tumor activity in diverse RET-activated solid tumors in the LIBRETTO-001 study (NCT03157128)., Methods: We describe the first six pheochromocytoma cases treated with selpercatinib in the LIBRETTO-001 study., Results: Of the six patients (one sporadic and five reported as part of MEN2 syndromes) in this case report, four had a partial response/complete response and two had stable disease per independent review committee. Treatment duration ranged from 9.2 months to more than 56.4 months. The safety profile of treatment was consistent with selpercatinib in other indications., Conclusion: These data support selpercatinib as an effective therapy against RET-mutant pheochromocytoma, adding to the diversity of RET-activated tumor types that may benefit from targeted RET inhibition., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Selpercatinib is indicated for locally advanced/metastatic RET -activated solid tumors after progression or following prior systemic therapies. Until the recently published data from LIBRETTO-431 and LIBRETTO-531, there were limited effectiveness data comparing selpercatinib with other first-line treatments in RET -activated non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and thyroid cancer (TC). This study analyzed patient data from LIBRETTO-001 and compared the outcomes (time to treatment discontinuation {TTD}, time to next treatment or death {TTNT-D}, time to progression {TTP}, and the objective response rate {ORR}) of first-line selpercatinib (selpercatinib arm) use with the outcomes of first-line standard therapies in patients who then received selpercatinib in later lines of treatment (comparator arm). Overall, the first-line selpercatinib arm had a longer TTD, TTNT-D, and TTP versus the first-line comparator arm. The hazard ratios (HRs) for TTD were 0.29 (NSCLC), 0.15 (MTC), 0.08 (TC); for TTNT-D, the HRs were 0.48 (NSCLC), 0.11 (MTC), 0.09 (TC); and for TTP, the HRs were 0.54 (NSCLC), 0.15 (MTC), and 0.12 (TC). The ORR was higher for first-line selpercatinib versus the first-line comparator (NSCLC: 85.3% vs. 39.7%; MTC: 82.6% vs. 15.2%; and TC: 81.8% vs. 31.8%). First-line selpercatinib use is associated with improved outcomes compared to first-line comparator therapies for patients with advanced/metastatic RET -activated cancers.

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.)

Abstract: We present the case of a 60-year-old man with medullary thyroid carcinoma and hepatic, osseous, and lymph node metastases who underwent peptide receptor radionuclide therapy with 177Lu-DOTATOC. After 2 cycles, 68Ga-DOTATOC PET/CT revealed multiple nonavid lesions. To assess whether the patient would be eligible for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, a PSMA PET/CT was conducted. PSMA PET/CT identified increased PSMA expression in both 68Ga-DOTATOC-avid and nonavid lesions. As such, dual-radiotracer PET/CT may allow for insights into the complexities of tumor heterogeneity in patients with medullary thyroid carcinoma, which may pave the way for subsequent therapeutic algorithms., Competing Interests: Conflicts of interest and sources of funding: The authors have no conflicts of interest to declare. This work was supported by the Okayama University “RECTOR” Program (T.H.)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Lymphocyte-activation gene 3 (LAG-3) is an inhibitory immunoreceptor that negatively regulates T-cell activation. This paper presents preclinical characterization of the LAG-3 inhibitor, ieramilimab (LAG525), and phase I data for the treatment of patients with advanced/metastatic solid tumors with ieramilimab ±the anti-programmed cell death-1 antibody, spartalizumab., Methods: Eligible patients had advanced/metastatic solid tumors and progressed after, or were unsuitable for, standard-of-care therapy, including checkpoint inhibitors in some cases. Patients received ieramilimab ±spartalizumab across various dose-escalation schedules. The primary objective was to assess the maximum tolerated dose (MTD) or recommended phase II dose (RP2D)., Results: In total, 255 patients were allocated to single-agent ieramilimab (n=134) and combination (n=121) treatment arms. The majority (98%) had received prior antineoplastic therapy (median, 3). Four patients experienced dose-limiting toxicities in each treatment arm across various dosing cohorts. No MTD was reached. The RP2D on a 3-week schedule was declared as 400 mg ieramilimab plus 300 mg spartalizumab and, on a 4-week schedule (once every 4 weeks; Q4W), as 800 mg ieramilimab plus 400 mg spartalizumab; tumor target (LAG-3) suppression with 600 mg ieramilimab Q4W was predicted to be similar to the Q4W, RP2D schedule. Treatment-related adverse events (TRAEs) occurred in 75 (56%) and 84 (69%) patients in the single-agent and combination arms, respectively. Most common TRAEs were fatigue, gastrointestinal, and skin disorders, and were of mild severity; seven patients experienced at least one treatment-related serious adverse event in the single-agent (5%) and combination group (5.8%). Antitumor activity was observed in the combination arm, with 3 (2%) complete responses and 10 (8%) partial responses in a mixed population of tumor types. In the combination arm, eight patients (6.6%) experienced stable disease for 6 months or longer versus six patients (4.5%) in the single-agent arm. Responding patients trended towards having higher levels of immune gene expression, including CD8 and LAG3 , in tumor tissue at baseline., Conclusions: Ieramilimab was well tolerated as monotherapy and in combination with spartalizumab. The toxicity profile of ieramilimab in combination with spartalizumab was comparable to that of spartalizumab alone. Modest antitumor activity was seen with combination treatment., Trial Registration Number: NCT02460224., Competing Interests: Competing interests: PS reports honoraria and consulting/advisory roles for Deciphera, Blueprint Medicines, and Boehringer Ingelheim; consulting/advisory roles for Ellipses Pharma, Transgene, Exelixis, Medscape, Guided Clarity, Ysios Capital, Adaptimmune, Intellisphere, and Advanced Medicine; research funding for CoBioRes NV, Eisai, GI Therapeutics, Novartis, and PharmaMar; and travel expenses for Boehringer Ingelheim, MSD, and Ipsen. DSWT 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. MigM reports honoraria and consulting/advisory roles for Roche/Genentech, Eli Lilly, Pfizer, Novartis, and Pierre-Fabre; consulting/advisory roles for AstraZeneca, Taiho Pharmaceuticals, and PharmaMar; research funding for Novartis, Roche/Genentech, and Puma; speaker’s bureau for Eli Lilly/ImClone, Roche/Genentech, and Pierre-Fabre; and other relationship with Roche/Genentech. MOdO reports honoraria for MSD. 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. RDC reports consulting/advisory roles and research funding for Merck, Aura Biosciences, Castle Biosciences, Immunocore, PureTech, Sorrento Therapeutics, Chimeron Bio, Regenix, InxMed, Pierre Fabre, TriSalus Life Sciences, Iovance Biotherapeutics, Oncosec, Regeneron, Genzyme, Amgen, Astellas Pharma, AstraZeneca, Bristol-Myer Squib/Medarex, Corvus Pharmaceuticals, Ideya, Mirati Therapeutics, Novartis, Pfizer, Plexxikon, and Roche/Genentech; research funding for Bayer, Bellicum Pharmaceuticals, Eli Lilly, Immunocore, Incyte, Macrogenics, Merck, Mirati Therapeutics, Array BioPharma, IDEAYA Biosciences, and Regeneron; and speaker’s bureau for Bristol-Myer Squib/Medarex.CK reports research funding for Bristol-Myers Squibb, Merus, and Gritstone Oncology. TE reports research funding for Novartis, Astellas Pharma, Sumitomo Group, Eli Lilly, Amgen, Quintiles, Daiichi Sankyo, Bayer, Eisai, IQVIA, MSD, Ono Pharmaceutical, Parexel, Nihonkayaku, and Taiho Pharmaceuticals. AP is an employee of, and reports honoraria for, Novotech; and reports research funding for Roche/Genentech, Bristol-Myers Squibb, Hutchison MediPharma, Merck, Bayer, Macrogenics, Pfizer, Akeso Biopharma, BeiGene, CStone Pharmaceuticals, Five Prime Therapeutics, CBT Pharmaceuticals, Arcus Biosciences, Corvus Pharmaceuticals, Eli Lilly, Henlius, QBiotics, Virogin, GlaxoSmithKline, Theradex, ENB Therapeutics, InxMed, Seattle Genetics, Janssen, Starpharma, and QBiotics. FDB reports honoraria and consulting/advisory roles for Roche, Pfizer, Bristol-Myers Squibb, Merk, MSD, Servier, and Sanofi; consulting/advisory roles for Incyte, Teofarma, EMD Serono, Nerviano Medical Sciences, Sanofi, and Novartis; and research funding for Novartis, Roche, Merck Serono, Pfizer, Servier, Philogen, Loxo Oncology, Tesaro, Nerviano Medical Sciences, and Kymab. RH reports honoraria and consulting/advisory roles for AstraZenca, Bristol-Myers Squibb, Eisai, Eli Lilly, Merck, MSD, Novartis, Oncosec, Pfizer, Roche and Seagen; research funding from AstraZeneca, Eli Lilly, MSD, Roche, Seagen, OncoSec, and Novartis; and travel expenses from Novartis. TZ reports immediate family connections to Capio BioSciences and Archimmume Therapeutics; these relatives also own stock at these companies and at Nanarobotics. TZ reports honoraria for Exelixis, Roche/Genentech, MJH Life Sciences, and Pacific Genuity; consulting/advisory roles for Janssen, Roche/Genentech, Sanofi, Exelixis, AstraZeneca, Pfizer, Bristol-Myers Squibb, Foundation Medicine, Pharmacyclics, Amgen, Merck, Seattle Genetics, Dendreon, and Calithera Biosciences; speaker’s Bureau for Exelixis, Roche/Genentech, Genomic Health, and Sanofi/Aventis; research funding for Astellas Pharma, Janssen, Acerta Pharma, Pfizer, Merrimack, Stem CentRx, Novartis, OmniSeq, Personal Genome Diagnostics, Regeneron, Merck, and Mirati Therapeutics; patents, royalties and other intellectual property for circulating tumor cell novel capture by c-MET technology and prochelators as Targeted Prodrugs for Prostate Cancer; and travel expenses for Acerta Pharma, Genomic Health, and AstraZeneca. RAS reports honoraria and consulting/advisory roles for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Novartis, Pfizer, Roche/Genentech, Takeda, Yuhan, Amgen, Bayer, and Merck; consulting/advisory roles for Taiho Pharmaceutical, Yuhan, Takeda, Amgen, and Merck; and research funding for AstraZeneca and Boehringer Ingelheim. AW reports honoraria for Eisai and Merck; consulting/advisory roles for Merck and Bristol-Myers Squibb; speaker’s bureau for Astellas Pharma and Merck; and travel expenses for Astellas Pharma, Ipsen, and Merck. JK is employed by, and reports receiving leadership fees, patents, royalties or other intellectual property for, Heidelberg ImmunoTherapeutics; and reports research funding for Vaccibody. AL, TS, VA, and EK are employees of Novartis. DG is an employee of Novartis and Mercy BioAnalytics. TS has a spouse who is employed by Teva Pharmaceuticals. NRC is an employee of, and owns stock in, Novartis. CASP was an employee of Novartis and owns stock in, holds patents, royalties, or other intellectual property in Novartis, and is also employed by, and has stock options in, Larkspur Biosciences. RR is an employee of, and holds stock in, Novartis and Takeda. TH is an employee of ViiV Healthcare, owns stock in ViiV Healthcare and Novartis, and holds patents, royalties, or other intellectual property in Novartis. PYR is an employee of, and holds stock in, Novartis. DSH owns stock in MolecularMatch, Presagia, and OncoResponse; reports consulting/advisory roles and research funding for Bayer, Guidepoint Global, Alpha Insights, Axiom Biotechnologies, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD, Infinity Pharmaceuticals, Amgen, Adaptimmune, Boxer Capital, ECOR1, Tavistock, Baxter, COG, Genentech, Group H, Janssen, Acuta, HCW Precision, Infinity, Prime Oncology, and ST Cube; research funding for Daiichi Sankyo, AbbVie, Kite Pharma, MedImmune, Molecular Templates, NCI-CTEP Fate Therapeutics, Novartis, Turning Point Therapeutics, Verstatem, Kyowa, Loxo Oncology, Merck, Eisai, Genmab, Ignyta, Mirati Therapeutics, miRNA, Mologen, Takeda, AstraZeneca, Navier, VM Oncology, Erasca, Inc, Eli Lilly, Bristol-Myers Squibb, EMD Serono, GlaxoSmithKline, Millenium, and Adlai Nortye; and travel expenses for Genmab, SITC, Bayer Schering Pharma, miRNA, Loxo Oncology, Amgen, AstraZeneca, Celgene, Eli Lilly, Genentech, GlaxoSmithKline, Janssen, Pfizer, Philips, and Takeda. MicM, WA, BDB, TL, NP, and AC report no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Aim:  We report results of a first-in-human study of pasotuxizumab, a PSMA bispecific T-cell engager (BiTE ® ) immune therapy mediating T-cell killing of tumor cells in patients with advanced castration-resistant prostate cancer. Patients & methods: We assessed once-daily subcutaneous (SC) pasotuxizumab. All SC patients developed antidrug antibodies; therefore, continuous intravenous (cIV) infusion was assessed. Results:  A total of 47 patients received pasotuxizumab (SC: n = 31, 0.5-172 μg/d; cIV: n = 16, 5-80 μg/d). The SC maximum tolerated dose was 172.0 μg/d. A sponsor change stopped the cIV cohort early; maximum tolerated dose was not determined. PSA responders occurred (>50% PSA decline: SC, n = 9; cIV, n = 3), including two long-term responders. Conclusion: Data support pasotuxizumab safety in advanced castration-resistant prostate cancer and represent evidence of BiTE monotherapy efficacy in solid tumors. Clinical trial registration: NCT01723475 (ClinicalTrials.gov).

Purpose: Third-generation epidermal growth factor receptor ( EGFR ) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes., Methods: Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs., Results: Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor ( MET ) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations)., Conclusion: Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Sebastian MichelsHonoraria: Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Roche Pharma AG Consulting or Advisory Role: Boehringer Ingelheim, Pfizer, Roche Pharma AG Research Funding: Pfizer (Inst), Novartis (Inst), Bristol-Myers Squibb (Inst) Travel, Accommodations, Expenses: NovartisCarina HeydtHonoraria: AstraZeneca, IlluminaNuria PardoOther Relationship: PfizerKim MonkhorstConsulting or Advisory Role: Pfizer, Roche Molecular Diagnostics, MSD, AstraZeneca, AbbVie, Bristol-Myers Squibb Speakers' Bureau: Quadia Research Funding: AstraZeneca, Roche Molecular Diagnostics, Personal Genome Diagnostics Travel, Accommodations, Expenses: Takeda, Pfizer, RocheVanessa RüsselerTravel, Accommodations, Expenses: Ventana Medical SystemsJan StratmannHonoraria: Bristol-Myers Squibb Travel, Accommodations, Expenses: NovartisFrank GriesingerHonoraria: Genentech, Boehringer Ingelheim, Pfizer, AbbVie, MSD, Bristol-Myers Squibb, Ipsen, Novartis Consulting or Advisory Role: AstraZeneca, Genentech, Pfizer, Boehringer Ingelheim, MSD, Bristol-Myers Squibb, Celgene, Takeda, AbbVie, Novartis, Bayer Research Funding: AstraZeneca (Inst), Boehringer Ingelheim (Inst), Bristol-Myers Squibb (Inst), MSD (Inst), Celgene (Inst), Eli Lilly (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Takeda (Inst)Jana FassunkeHonoraria: AstraZenecaRieke FischerHonoraria: Bristol-Myers Squibb, Roche, MSD Research Funding: Bristol-Myers Squibb (Inst), MSD (Inst) Travel, Accommodations, Expenses: MediolanumOliver GautschiOther Relationship: AstraZeneca, PfizerEva GeissingerHonoraria: MSD Sharp & Dohme Consulting or Advisory Role: NovartisHans-Georg KoppHonoraria: MSD Oncology, Boehringer Ingelheim, LEO Pharma, PharmaMar, Roche, Pfizer, Chugai Pharma, Takeda Consulting or Advisory Role: MSD Oncology, Bristol-Myers Squibb, Sanofi, Roche, AstraZeneca Travel, Accommodations, Expenses: Sanofi, Eli Lilly, Amgen, Novartis, PharmaMar, Boehringer Ingelheim, MSD Oncology, Bristol-Myers SquibbAdrianus J. de LangenConsulting or Advisory Role: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), MSD Oncology (Inst), Roche (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst) Research Funding: AstraZeneca (Inst), Bristol-Myers Squibb (Inst), Merck Serono (Inst), MSD Oncology (Inst), Roche (Inst)Alex Martinez-MartiHonoraria: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim Consulting or Advisory Role: Bristol-Myers Squibb, F. Hoffmann-La Roche, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim Speakers' Bureau: F. Hoffmann-La Roche, Bristol-Myers Squibb, Boehringer Ingelheim Research Funding: Merck Serono Travel, Accommodations, Expenses: Bristol-Myers Squibb, F. Hoffmann-La Roche, MSD Oncology, Boehringer IngelheimLucia NogovaHonoraria: Pfizer, Celgene, Novartis, Roche, Boehringer Ingelheim, Janssen, Bristol-Myers Squibb Consulting or Advisory Role: Novartis, Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Janssen, Pfizer Research Funding: Pfizer, (Inst), Bristol-Myers Squibb (Inst), Novartis (Inst), MSD (Inst), Janssen (Inst) Travel, Accommodations, Expenses: Novartis, Pfizer, Celgene, Boehringer IngelheimDennis PlenkerStock and Other Ownership Interests: Roche, Foundation Medicine Patents, Royalties, Other Intellectual Property: A patent of NRG1 fusions has been filedMichael PueskenConsulting or Advisory Role: MSD Travel, Accommodations, Expenses: ShireErnst RodermannConsulting or Advisory Role: Amgen, CelgeneAndreas H. ScheelHonoraria: MSD, Bristol-Myers Squibb, Roche, Dako/Agilent Technologies Consulting or Advisory Role: MSD, Bristol-Myers Squibb, Roche, Dako/Agilent TechnologiesMatthias SchefflerHonoraria: Healthcare Consulting Cologne, Boehringer Ingelheim, Takeda Consulting or Advisory Role: Boehringer Ingelheim, Takeda Travel, Accommodations, Expenses: Boehringer IngelheimRuth Seggewiss-BernhardtHonoraria: Novartis, Celgene, Roche, Bristol-Myers Squibb, Ipsen, Pfizer, AstraZeneca Consulting or Advisory Role: MSD, Pfizer Travel, Accommodations, Expenses: Astellas Pharma, Celgene, IpsenMartin SebastianHonoraria: AstraZeneca, Novartis, Pfizer/EMD Serono, MSD, Takeda, Bristol-Myers Squibb, Eli Lilly, Genentech, Boehringer Ingelheim, AbbVie Consulting or Advisory Role: Genentech, MSD, AstraZeneca, AbbVie, Takeda, Eli Lilly, Boehringer Ingelheim, Novartis, Bristol-Myers Squibb, Pfizer, Celgene Travel, Accommodations, Expenses: Pfizer, TakedaMartin L. SosResearch Funding: Novartis, NovartisLukas C. HeukampEmployment: NEO New Oncology, Hämatopathologie Hamburg Honoraria: Roche Pharma, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim Consulting or Advisory Role: Roche Pharma, Bristol-Myers Squibb, NovartisEnriqueta FelipConsulting or Advisory Role: Pfizer, Roche, Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, Celgene, Guardant Health, Novartis, Takeda, AbbVie, Blueprint Medicines, Eli Lilly, Merck KGaA, Merck Sharp & Dohme Speakers' Bureau: AstraZeneca, Bristol-Myers Squibb, Novartis, Boehringer Ingelheim, Merck Sharp & Dohme, Roche, Pfizer, AbbVie, Eli Lilly, Merck KGaA, Takeda Research Funding: Fundación Merck Salud (Inst), EMD Serono (Inst)Sabine Merkelbach-BruseHonoraria: AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer, Roche Pharma Consulting or Advisory Role: Bristol-Myers Squibb, Novartis, PfizerEgbert F. SmitConsulting or Advisory Role: Eli Lilly, AstraZeneca (Inst), Boehringer Ingelheim (Inst), Genentech (Inst), Bristol-Myers Squibb (Inst), Merck KGaA (Inst), MSD Oncology (Inst), Takeda (Inst), Bayer (Inst) Research Funding: Boehringer Ingelheim (Inst), Bayer (Inst), Genentech (Inst), AstraZeneca (Inst), Bristol-Myers Squibb (Inst)Reinhard BüttnerStock and Other Ownership Interests: Co-founder and CSO for Targos Mol. Pathol. (Kassel/Germany) and TAMP (Atlanta, GA) Honoraria: AstraZeneca, AbbVie, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Serono, MSD, Novartis, Qiagen, Pfizer, Roche Research Funding: Roche (Inst)Juergen WolfHonoraria: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Novartis, Roche Consulting or Advisory Role: AbbVie, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai Pharma, Ignyta, Eli Lilly, MSD Oncology, Novartis, Pfizer, Roche Research Funding: Bristol-Myers Squibb, Novartis, Pfizer No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

The immune oncological treatment approach uses immune checkpoint inhibitors to prevent tumor cells from shutting down the immune system, and thus from escaping immune response. Following the clinical success of immune checkpoint inhibitors, the number of approved immune oncological therapies continues to increase. Response rates and overall survival with anti-PD-1/PD-L1 and CTLA-4 blockade could be further improved by combining both treatment approaches. However, checkpoint inhibition is associated with a unique spectrum of side effects termed immune-related adverse events. These typically occur 3 to 6 months after treatment start and resolve with adequate management procedures if detected early on. Therefore, profound patient education, sensitizing and monitoring are mandatory. We describe in this article selected frequent and rare adverse events that are clinically relevant. Furthermore, using case reports, interdisciplinary experts share their practice-based experience in the management of frequent pneumonic, endocrine, and gastro-intestinal immune-related adverse events., Competing Interests: N. Reinmuth: erhielt Honoraria für Vortragstätigkeiten und Beratungen von Roche, Lilly, Novartis, MSD, BMS, Boehringer-Ingelheim, Astra-Zeneca, Takeda, Celgene und Pfizer.M. Bitzer: Advisory Board für die Firmen Bayer Healthcare, Bristol-Myers Squibb, EISAI, IPSEN und Lilly.B. Deschler-Baier erhielt Vortragshonorare von BMS.J.R. Fischer erhielt Honorare für Beratertätigkeiten und Vorträge von AstraZeneca, Boehringer Ingelheim, Celgene und Hoffmann-La Roche.J. Kuon erhielt Honorare für Beratertätigkeiten und Vorträge von Astrazeneca, Chugai und Roche.J. Leipe erhielt Honorare für Beratertätigkeiten und Vorträge von Abbvie, AstraZeneca, BMS, Celgene, Hospira, Janssen-Cilag, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, UCB; Scientific Support: Novartis, Pfizer.J. Rawluk erhielt Honorare für Beratertätigkeiten und Vorträge von AstraZeneca, Takeda, MSD, BMS, Boehringer Ingelheim und Roche.C. Schulz: Honorare aus Referententätigkeiten: AstraZeneca, Boehringer, Celgene, Lilly, MSD, Novartis, Roche. Honorare aus Beratertätigkeiten: AstraZeneca, AbbVie, BMS, Boehringer, Lilly, MSD, Novartis, Roche. Teilnahme an Klinischen Studien: AstraZeneca, BMS, Boehringer, Lilly, MSD, Novartis, Roche, Pfizer.M. Schultheiß: Beratertätigkeit für Bayer Healthcare und Bristel Myers Squibb.C. Heußel hat Verbindungen mit verschiedenen Firmen, die Immunonkologika herstellen.Die Erstellung dieses Artikels wurde von AstraZeneca GmbH unterstützt., (© Georg Thieme Verlag KG Stuttgart · New York.)

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.)

Introduction: Oral mucositis (OM) is a common and debilitating side effect of chemoradiotherapy in patients awaiting allogeneic hematopoietic stem cell transplantation (aHSCT)., Purpose: The aim of this pilot RCT was to compare an oral care self-management support protocol (OrCaSS) to usual pre-aHSCT care. Feasibility was tested, effect sizes calculated for OM (primary outcome), and patient adherence was measured (secondary outcome)., Methods: Eighteen AML patients awaiting aHSCT and hospitalized between August 2012 and April 2013 were randomized 1:1 to usual care (UCG) and intervention (IG) groups. The OrCaSS protocol consisted of two sessions of educational and behavioral interventions, the first delivered 1 week pre-admission (T1), the second on admission day (T2). Via field notes, practicability and acceptability were evaluated to explore the feasibility of intervention and study procedures. OM data were collected at T1, T2, and daily for 28 days using the WHO scale. The effect size r was calculated (r less than -0.1 ≙ small and greater than or equal to -0.3 ≙ medium). Patients' adherence to the protocol was assessed at T1, T2, and 8-10 days post-HSCT (T3)., Results: Research and intervention procedures were feasible. OM incidence was 100 %. The IG's median highest OM grade was 2.0 (IQR = 2); the UCGs was 3.0 (IQR = 2; r = -0.1). Median OM durations were 12 days in the IG and 14 days in the UCG (r = -0.1). OM onset was 2 days later in the IG than in the UCG (r = -0.1). Over the course of the study, patient adherence decreased in both groups., Conclusions: OrCaSS is a promising intervention to delay and reduce OM. These results can serve to plan a larger RCT.