Search

Introduction: Small cell transformation (SCT) is a typical mechanism of adaptive resistance to third generation epidermal growth factor receptor inhibitors (EGFRi) which have become the standard of care for EGFR-driven non-small cell lung cancer (EGFR+ NSCLC). Little is known about the optimal management of SCT patients. This study aimed to compare outcomes under platinum/etoposide chemotherapy alone (chemo) or in combination with EGFR inhibitors (EGFRi+chemo) or immune checkpoint inhibitors (ICI+chemo). In addition, DLL3 expression was explored as potential novel therapeutic target., Methods: We conducted a retrospective study on patients with EGFR+ NSCLC and SCT treated at 19 centers in Europe and the United States. A total of 47 patients were included of whom 17 received chemo, 20 ICI+chemo, and 10 EGFRi+chemo. We analyzed DLL3 expression by immunohistochemistry., Results: In the entire cohort, median overall survival (OS) from start of first SCT therapy was 11 months (95 % confidence interval [95 %CI] 9.1-12.9) and median progression-free survival (PFS) was 5 months (95 %CI 4.2-5.8). Median PFS was similar in all three groups (chemo and ICI+chemo 4 months, EGFRi+chemo 6 months), and 12-months PFS was 12 % (95 %CI 2 %-31 %), 13 % (95 %CI 0 %-43 %), and 0 % for ICI+chemo, EGFRi+chemo, and chemo, respectively. Median OS in the ICI+chemo group was 13 months (95 %CI 5.5-20.5) compared to 10 months (95 %CI 7.6-12.4) with chemo and EGFRi+chemo (95 %CI 8.1-11.9), respectively. Before and after SCT, 0 % and 93 % of tumors were DLL3-positive., Conclusions: Our results suggest that ICI+chemo and DLL3-targeting agents are worth further exploration in EGFR+ NSCLC undergoing SCT., Presented Elsewhere: Part of this work has been presented at ESMO annual meeting in Madrid, Spain in October 2023 (Poster 1336 P)., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Allgäuer, M received speaker fees from Boehringer Ingelheim. Alt, J received speaker fees and/or honoraria for advisory boards by Astra Zeneca, Pfizer, Daichii Sankyo, Roche, Amgen, MSD, Novartis, Janssen, Boehringer Ingelheim, Merck, BMS. Aust, DEA received honoraria from Roche, Astra Zeneca, MSD, Pfizer, Novartis. Christopoulos. P received research funding from Roche, Amgen, Boehringer Ingelheim, Takeda, Merck, AstraZeneca, and Novartis, honoraria from Roche, Takeda, Gilead, AstraZeneca, Merck, Thermo Fisher, Janssen, Pfizer, and Novartis, travel support from AstraZeneca, Pfizer, Janssen, Merck, Gilead, Daiichi Sankyo, Takeda, Novartis, Eli Lilly and compensation for advisory roles for Pfizer, Chugai, Boehringer Ingelheim, Takeda, Janssen, Novartis, astraZeneca, MSD, Roche. Griesinger, F received speaker fees and/or honoraria for advisory boards from AstraZeneca, Boehringer, BMS, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, Abbvie, Tesaro/GSK, Siemens, Tesaro, Amgen, Sanofi, Daiichi-Sankyo, Beigene. Grohé, C received honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Hochmair, M received honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, and Roche, and has had consulting or advisory roles with Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novartis, and Roche. Illini, O received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Menarini, Merck Sharp & Dohme, Pfizer, and Roche and received research grants from Amgen and AstraZeneca outside of the submitted study. Jöhrens, K received compensation for advisory roles for BMS, GSK, Merck Sharp & Dohme, honoraria from AstraZeneca, Agilent, Boehringer Ingelheim, and DSO, and serves as medical advisor for QuIP. Kauffmann-Guerrero received speaker fees and/or honoraria for advisory boards from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Novartis, Pfizer, Roche, Takeda. Kirfel, J received speaker fees and/or honoraria for advisory boards, from AstraZeneca, Bristol-Myers Squibb, Novartis, Pfizer and Roche. König, D received a personal grant from Geistlich-Stucki-Stiftung, consulting fees from AstraZeneca, Merck, MSD, Novartis, PharmaMar, honoraria for presentations from Amgen, BMS, Mirati, Sanofi, Swiss Oncology in Motion, support for attending meetings from Amgen, Roche, Sanofi, honoraria for advisory boards from AstraZeneca, BMS, Merck, MSD, PharmaMar, Roche. Michels, S received research grants from Novartis and Pfizer, personal fees from Eli Lilly, Janssen, and Astra Zeneca as well as support for attending meetings and/or travel from Eli Lilly, and Janssen. Overbeck, T received speaker fees and/or honoraria for advisory boards by AstraZeneca, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen-Cilag, Merck, MSD, Novartis, Roche, Takeda, Tesaro/GSK, Lilly, Roche, travel reimbursement by AstraZeneca, Boehringer-Ingelheim, Janssen-Cilag, Lilly, and Roche. Rohde, G received personal fees from Astra Zeneca, Atriva, Boehringer Ingelheim, GSK, Insmed, MSD, Sanofi, Novartis and Pfizer for consultancy during advisory board meetings and personal fees from Astra Zeneca, Berlin Chemie, BMS, Boehringer Ingelheim, Chiesi, Essex Pharma, Grifols, GSK, Insmed, MSD, Roche, Sanofi, Solvay, Takeda, Novartis, Pfizer and Vertex for lectures. Rothschild, S received honoraria (institutional) from, Roche, AstraZeneca, BMS, Boheringer Ingelheim, MSD Oncology, Novartis, Amgen, Lilly, Eisai, Merck serono, Pfizer, Takeda, Bayer, Janssen Oncology, Otsuka, PharmaMar, and Sanofi, compensation for advisory roles for AstraZeneca, Boerhinger Ingelheim, BMS, Pfizer, Eisai, Eli Lilly, Merck Serono, MSD Oncology, Novartis, Roche Pharma AG, Takeda, Amgen, Otsuka, PharmaMar, serves for the speakers bureau of Roche Pharma AG, Sanodi/Aventis, Amgen, AstraZeneca, Takeda, received research funding from Abbvie, BMS, AstraZeneca, Boerhinger Ingelheim, Merck Serono, Roche Pharma AG, and travel support, accomodation, expenses from Sanofi, Roche Pharma AG, BMS, MSD Oncology, AstraZeneca, Takeda, Boehringer Ingelheim, Amgen. He serves at the Federal Drug Comission of the Federal Office of Public Health and the Swiss Group for Clinical Cancer Research (SAKK). Saalfeld, F received research funding from Roche, consultancy fees from Boehringer Ingelheim, honoraria for lectures from AstraZeneca, Janssen, Takeda, Pfizer, Novartis, Thieme, and GWT-TUD, travel support from Janssen and Eli Lilly, and compensation for advisory meetings with BMS, Pfizer, AstraZeneca, Janssen, MSD, and Roche. Stenzinger, A received research grants from Bayer, BMS, Chugai, Incyte, and MSD, and compensation for advisory boards/speaker’s bureau: Agilent, Aignostics, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Qlucore, QuiP, Roche, Sanofi, Seagen, Servier, Takeda, Thermo Fisher. Syrigos, K received honoraria for advisory boards from Merck Sharp & Dohme, AstraZeneca, BMS Amgen. Thomas, M received research funding (institution) from AstraZeneca, BMS, Merck, Roche, Takeda, speaker fees and/or honoraria for advisory boards by Amgen, AstraZeneca, Beigene, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen Oncology, Lilly, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Takeda. Veluswamy, R served on advisory boards for Bristol-Myers Squibb, Astrazeneca, Merck, Boehringer Ingelheim, Merus, Novocure, Regeneron, BerGenBio, and Serna Bio, on unbranded speaker’s bureau of Astrazeneca and EMD Serono, received consulting honorarium from Beigene, received research funding from Bristol-Myers Squibb, Onconova, Astrazeneca, Boehringer Ingelheim, Lung Cancer Research Foundation, Stand Up 2 Cancer. Wenzel, C received speaker fees from Astra Zeneca. Wermke, M received honorary from Lilly, Boehringer-Ingelheim, SYNLAB, Janssen, Merck Serono, GWT, Amgen, Novartis, Pfizer, BMS and has/had paid consulting or advisory positions for BMS, Novartis, Lilly, Boehringer-Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, ImCheck, AstraZeneca, Tacalyx, Regeneron, Daiichi, Zymeworks, PharmaMar. He receive research funding (instution) from Roche and travel support from Pfizer, BMS, AstraZeneca, Amgen, Gemoab, Sanofi-Aventis, Merck Serono, Immatics, Janssen, Iovance, Daiichi-Sankyo. Wesseler, C received speaker fees and/or honoraria for advisory boards from Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, MSD, Novartis, Takeda, AstraZeneca, Chugai, BMS. Wiesweg, M received honoraria and Advisory Role: Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Janssen, Novartis, Pfizer, Roche, Takeda, and travel costs from Amgen, Janssen, Daiichi Sankyo, and research funding from Bristol-Myers Squibb, Takeda. Klimova, A, Kulhvay, J, Möller, J, Pelusi, N, Rasokat, A, Schubart, C, Schütz, M, Wang, A, and Vathiotis, J have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib., Methods: This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics., Results: Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAF non-V600 -mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively., Conclusions: Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect., Clinicaltrials: gov identifier: NCT02974725., Competing Interests: Declaration of competing interest David Planchard reports consulting, advisory role or lectures for AstraZeneca, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati and Seagen; clinical trials research as principal investigator or co-investigator (institutional financial interests) for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Abbvie, Janssen, Pierre-fabre, Takeda, ArriVent, Mirati and Seagen; and travel, accommodation and expenses from AstraZeneca, Roche, Novartis and Pfizer. Jürgen Wolf reports grants from BMS, Janssen, Pharmaceutica, Novartis and Pfizer (payment to institution); and consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and/or travel, and participation on a data safety monitoring board or advisory board from Amgen,  AstraZeneca, Bayer, BluePrint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda and Turning Point. Benjamin Solomon reports fees for advisory boards from Pfizer, AstraZeneca, Janssen, Takeda, Bristol Myers Squibb, Meck, Roche-Genentech, Beigene and Amgen; payment or honoraria for lectures and presentations from AstraZeneca, Pfizer, Glaxo Smith Klein, Merck and Roche; and is a board director of Thoracic Oncology Group of Australasia, Cancer Council Victoria and International Association for the Study of Lung Cancer. Martin Sebastian reports grants or contracts to institution from AstraZeneca; consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer lngelheim, Amgen, Takeda, Merck-Serono, Pfizer, Pierre-Fabre and DaiIchi- Sankyo; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer lngelheim, Amgen, Takeda, Merck, GSK, Daiichi and Pfizer; and support for attending meetings and/or travel from Pfizer, Merck and BMS. Martin Wermke reports research funding for institution from Roche; consulting fees from Bristol Myers Squibb, Novartis, Lilly, Boehringer Ingelheim, Immatics, Bayer and ImCheck Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly, Boehringer Ingelheim, SNYLAB, Merck Serono, GWT, Amgen and Novartis; support for attending meetings and/or travel from Pfizer, Bristol Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics and Merck Serono; and participation on a data safety monitoring board or advisory board for ISA Pharmaceuticals. Rebecca S. Heist reports grants to institution from Abbvie, Agios, Daichii Sankyo, Lilly, Novartis, Mythic, Mirati, Symphogen, Turning Point and Erasca; consulting fees from Novartis, EMD Serono, Daichii Sankyo, Abbvie, Regeneron, Sanofi, Lilly, Claim Therapeutics, AstraZeneca, Amgen and Gilead; and receiving medical writing services from Daichii Sankyo, Novartis, Lilly and Mirati. Jong-Mu Sun has no conflicts of interest to declare. Tae Min Kim reports consulting fees from AstraZeneca, Janssen, Regeneron, Samsung Bioepis, Takeda and Yuhan; participation on Advisory Board for AstraZeneca/Medimmune, Janssen and Regeneron; and other financial or non-financial interests received by the institution from ABBVIE, AstraZeneca, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, F. Hoffmann-La Roche Ltd/Genentech, Inc, Hanmi, Janssen, Novartis, Regeneron, Sanofi, Takeda and Yuhan. Noemi Reguart has received speaker’s honoraria or sponsorship to attend international scientific meetings from Bayer, MSD, BMS, Roche, Boehringer Ingelheim, Janssen, Pfizer, AbbVie, Novartis, Astrazeneca, Lilly, Takeda, Amgen and Merck; and research grants from Novartis, MSD and Pfizer (all for Institution). Miguel F. Sanmamed received research grants from Roche; consulting fees from Numab; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD; support for attending meetings and/or travel from Roche; and participation on advisory board for Numab. Enriqueta Felip reports consulting fees from Abbvie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point and Daiichi Sankyo; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda and Touch Oncology; and support for attending meetings and/or travel from AstraZeneca, Janssen and Roche. Pilar Garrido received personal fees for lectures, presentations, speakers bureaus or educational events from Janssen, MSD, Novartis, Medscape, Takeda, TouchTime and Medscape; support for attending meetings and/or travel from Astra Zeneca, Roche and Janssen; personal fees for advisory role from Abbvie, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda, and personal fees for steering committee from Novartis and IO Biotech IO102-Janssen. Armando Santoro received consultancy fees from Sanofi and Incyte; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Takeda, BMS, Roche, Abbvie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD and BeiGene; and participation on a data safety monitoring board or advisory board for BMS, Servier, Gilead, Pfizer, Eisai, Bayer and MSD. Douglas Bootle is a Novartis employee. Xuân-Mai Couillebault is a Novartis employee. Anil Gaur is a Novartis employee. Christina Mueller is a Novartis employee and Novartis stockholder. Teresa Poggio is a Novartis employee. Jie Yang is a Novartis employee and Novartis stockholder. Michele Moschetta is a previous Novartis employee, Novartis stockholder and has one patent issued relating to naporafenib. Christophe Dooms has no conflicts of interest to declare. All authors received medical writing support funded by Novartis Pharmaceuticals Corporation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Oligometastatic (OMD) non-small cell lung cancer (NSCLC) is a distinct but heterogeneous entity. Current guidelines recommend systemic therapy and consolidation with local ablative therapy (LAT). However, evidence regarding the optimal choice of multimodal treatment approaches is lacking, in particular with respect to the integration of immunotherapy. This real-world study identified 218 patients with OMD NSCLC (2004-2023, prespecified criteria: ≤5 metastases in ≤2 organ systems) from three major German comprehensive cancer centers. Most patients had one (72.5%) or two (17.4%) metastatic lesions in a single (89.9%) organ system. Overall survival (OS) was significantly longer with a single metastatic lesion (HR 0.54, p = .003), and female gender (HR 0.4, p < .001). Median OS of the full cohort was 27.8 months, with 29% survival at 5 years. Patients who had completed LAT to all NSCLC sites, typically excluding patients with early progression, had a median OS of 34.4 months (37.7% 5-year OS rate) with a median recurrence-free survival (RFS) of 10.9 months (13.3% at 5 years). In those patients, systemic treatment as part of first-line therapy was associated with doubling of RFS (12.3 vs. 6.4 months, p < .001). Despite limited follow-up of patients receiving chemo-immunotherapy (EU approval 2018/2019), RFS was greatly improved by adding checkpoint inhibitors to chemotherapy (HR 0.44, p = .008, 2-year RFS 51.4% vs. 15.1%). In conclusion, patients with OMD NSCLC benefitted from multimodality approaches integrating systemic therapy and local ablation of all cancer sites. A substantial proportion of patients achieved extended OS, suggesting a potential for cure that can be further augmented with the addition of immunotherapy., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and MET amplification as a mechanism of resistance to first-line osimertinib have few treatment options. Here, we report the primary analysis of the phase 2 INSIGHT 2 study evaluating tepotinib, a highly selective MET inhibitor, combined with osimertinib in this population., Methods: This open-label, phase 2 study was conducted at 179 academic centres and community clinics in 17 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and advanced or metastatic EGFR-mutated NSCLC of any histology, with MET amplification by tissue biopsy fluorescence in-situ hybridisation (FISH; MET gene copy number of ≥5 or MET-to-CEP7 ratio of ≥2) or liquid biopsy next-generation sequencing (MET plasma gene copy number of ≥2·3), following progression on first-line osimertinib. Patients received oral tepotinib 500 mg plus oral osimertinib 80 mg once daily. The primary endpoint was independently assessed objective response in patients with MET amplification by central FISH treated with tepotinib plus osimertinib with at least 9 months of follow-up. Safety was analysed in patients who received at least one study drug dose. This study is registered with ClinicalTrials.gov, NCT03940703 (enrolment complete)., Findings: Between Feb 13, 2020, and Nov 4, 2022, 128 patients (74 [58%] female, 54 [42%] male) were enrolled and initiated tepotinib plus osimertinib. The primary activity analysis population included 98 patients with MET amplification confirmed by central FISH, previous first-line osimertinib and at least 9 months of follow-up (median 12·7 months [IQR 9·9-20·3]). The confirmed objective response rate was 50·0% (95% CI 39·7-60·3; 49 of 98 patients). The most common treatment-related grade 3 or worse adverse events were peripheral oedema (six [5%] of 128 patients), decreased appetite (five [4%]), prolonged electrocardiogram QT interval (five [4%]), and pneumonitis (four [3%]). Serious treatment-related adverse events were reported in 16 (13%) patients. Deaths of four (3%) patients were assessed as potentially related to either trial drug by the investigator due to pneumonitis (two [2%] patients), decreased platelet count (one [1%]), respiratory failure (one [1%]), and dyspnoea (one [1%]); one death was attributed to both pneumonitis and dyspnoea., Interpretation: Tepotinib plus osimertinib showed promising activity and acceptable safety in patients with EGFR-mutated NSCLC and MET amplification as a mechanism of resistance to first-line osimertinib, suggesting a potential chemotherapy-sparing oral targeted therapy option that should be further investigated., Funding: Merck (CrossRef Funder ID: 10.13039/100009945)., Competing Interests: Declaration of interests Y-LW reports receiving institute grants from AstraZeneca, Bristol Myers Squibb, and Pfizer; consulting fees from AstraZeneca, Boehringer Ingelheim, Merck, and Roche; and speaker fees from AstraZeneca, Eli Lilly, Hengrui, Pfizer, Roche, and Sanofi. VG reports receiving personal fees for advisory board membership from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, MSD, Novartis, Pfizer, and Olema Oncology; speaker fees from Amgen, AstraZeneca, Eli Lilly, Exact Sciences, Gilead, GSK, and Novartis; fees for expert testimony for Eli Lilly; and travel support from Gilead, AstraZeneca, and PharmaMar. PJV reports receiving personal fees for advisory board membership from Amgen, AstraZeneca, BeiGene, Ipsen, MSD, Novartis, Pfizer, and Roche. MWi reports receiving personal advisory board fees, consulting fees, speaker fees, and institute grants from AstraZeneca. CKL reports receiving research grants from AstraZeneca and Boehringer Ingelheim; honoraria for lectures from AstraZeneca, Boehringer Ingelheim, Janssen, MSD, Novartis, Pfizer, Roche, and Zuellig Pharma; travel support from AstraZeneca, Boehringer Ingelheim, Merck, MSD, Novartis, Pfizer, and Roche; and personal fees for advisory board membership from AstraZeneca, Janssen, MSD, Novartis, Pfizer, and Roche. JM reports receiving advisory board fees from Roche, Bristol Myers Squibb, AstraZeneca, Pfizer, Novartis, Merck, Daiichi Sankyo, and MSD, and research funding to his institution from Roche, AstraZeneca, and Pierre Fabre. LMT reports receiving advisory board fees from AstraZeneca, Janssen, Merck, Novartis, Pfizer, and Roche; personal honoraria fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Merck, Novartis, Pfizer, and Roche; and travel support from AstraZeneca, Merck, Novartis, Pfizer, and Roche. HH reports receiving honoraria fees from AstraZeneca, Ono Pharmaceutical, Bristol Myers Squibb, Eli Lilly, Boehringer Ingelheim, Sysmex Corporation, 3H Medi Solution, Chugai Pharmaceutical, Pfizer, Novartis, Merck Biopharma Co, Tokyo, Japan, an affiliate of Merck, Amgen, Daiichi Sankyo/UCB Japan, Takeda, and MSD; research funding from IQVIA, Syneos Health Clinical, EPS Corporation, Nippon Kayaku, Takeda, MSD, Amgen, Taiho Pharmaceutical, Bristol Myers Squibb, Janssen, CMIC, Pfizer R&D, LabCorp, Kobayashi Pharmaceutical, Pfizer, Eisai, EP-CRSU, Shionogi & Co, Otsuka Pharmaceutical, GSK, Sanofi, Chugai Pharmaceutical, Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Astellas Pharma, Ascent Development Services, and Bayer; and financial support for the present manuscript from Guardant Health. PLC reports receiving advisory board fees from AstraZeneca, Merck, and Pfizer, and honoraria fees from AstraZeneca. JR reports receiving personal honoraria from Bristol Myers Squibb, speaker fees (to their institution) from Merck, and advisory board fees (to their institution) from Merck. GF reports receiving personal fees for speaker engagements with AstraZeneca, Bristol Myers Squibb, and MSD, and travel support from Roche. TK reports receiving honoraria from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Takeda; receiving research funding for their institution from AbbVie, Amgen, AstraZeneca, BeiGene, BluePrint, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Haihe Biopharma, Merck, MSD, Novartis, Pfizer, Regeneron, Takeda, and TurningPoint; receiving advisory board fees from AstraZeneca, BeiGene, Daiichi Sankyo, Janssen, Merck, MSD, Novartis, and Pfizer; and their spouse as an employee of Eli Lilly. EN reports receiving research funding from Roche, Pfizer, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and Bristol Myers Squibb; consulting fees from Roche, Bristol Myers Squibb, MSD, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Sanofi, Pfizer, Eli Lilly, Amgen, Janssen, Daiichi Sankyo, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Janssen, Pierre Fabre, Qiagen, and Bayer; personal honoraria for lectures from Roche, Bristol Myers Squibb, MSD, Sanofi, Pfizer, Eli Lilly, Amgen, Janssen, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi, Janssen, Qiagen, Mirati, and Bayer; travel support from Takeda, MSD, AstraZeneca, and Roche; and fees for participation in data safety meetings from Apollomics. HSH reports receiving research grants for their institution from AstraZeneca, Merck, Janssen, Novartis, and Boehringer Ingelheim; honoraria and fees for lectures and advisory board meetings from AstraZeneca, MSD, Novartis, Pfizer, Roche, and Janssen; and travel support from AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Pfizer, and Roche. EFS reports receiving advisory or consultancy fees to their institution from Eli Lilly, AstraZeneca, MSD, Boehringer Ingelheim, Bristol Myers Squibb, Takeda, and Daiichi Sankyo; personal speaker fees from Boehringer Ingelheim; and advisory board fees from Merck and Daiichi Sankyo. MWe reports holding a consulting or advisory role for Bristol Myers Squibb, Novartis, Eli Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, and ImCheck therapeutics; honoraria fees from Eli Lilly, Boehringer Ingelheim, SYNLAB, Janssen, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, GWT, Amgen, and Novartis; travel support from Pfizer, Bristol Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics, and EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck; and research funding to his institution from Roche. DT reports receiving consulting fees for their institution from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, DKSH, GSK, Merck, Novartis, Roche, Pfizer, and Takeda; research funding from ACM Biolabs, Amgen, AstraZeneca, Bayer, and Pfizer; and speaker fees for their institution from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, and Takeda. MM reports receiving research funding from Boehringer Ingelheim and Eli Lilly; personal honoraria fees from Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical; and other clinical trial support from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Pfizer, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Kissei, Taiho, and Novartis. AO’B, SA, BMP, CS, DJ, RS, BE-L, and NK report being employees of Merck. KB reports being an employee of Merck at the time of the study and manuscript preparation. KG reports being an employee of EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck. XL reports receiving consulting fees from EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, AstraZeneca, Spectrum Pharmaceuticals, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Janssen Oncology, Daiichi Sankyo, Blueprint Medicines, Sensei Biotherapeutics, AbbVie, Arrivent, and Regeneron; travel support from Spectrum Pharmaceuticals and EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and research funding to their institution from Eli Lilly, Boehringer Ingelheim, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, and Regeneron. TMK reports receiving grants for their institution from AstraZeneca; consulting fees from AstraZeneca, Janssen, Regeneron, Samsung Bioepis, Takeda, and Yuhan; honoraria for lectures from AstraZeneca, IMBDx, Janssen, Takeda, and Yuhan; advisory board fees from AstraZeneca, Janssen, Regeneron, and Takeda; and clinical trial funding to their institution from AbbVie, Amgen, AstraZeneca/Medimmune, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, Dizal, EMD Serono Research & Development Institute, Billerica, MA, USA, an affiliate of Merck, Roche/Genentech, Hanmi, Genmab, Janssen, Novartis, RAPT Therapeutics, Regeneron, Sanofi, Takeda, and Yuhan. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Non-small cell lung cancer (NSCLC) is characterized by high recurrence rates in the early stages. In a German cohort, recurrence-free survival after 5 years was 62% (stage IA1), 40.7% (stage IIA) and 28% (stage IIIA). In addition to the perioperative use of immune checkpoint inhibitors, targeted tumor therapy is also making inroads as an innovation from the palliative setting into the early stages. Of particular relevance is the use of the EGFR inhibitor osimertinib, which has been shown to improve overall survival in the adjuvant setting. In this practice-oriented review, we briefly describe the current status of adjuvant targeted therapy and the associated testing and provide an outlook on further developments., Competing Interests: Bezahlte Vorträge und Advisory Boards: MSD, AstraZeneca ; BMS, Novocure, (Thieme. All rights reserved.)

Rationale of the Trial: Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors., Trial Design: The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of 16 patients. IMA202 consists of autologous genetically modified cytotoxic CD8 + T cells expressing a T cell receptor (TCR), which is specific for a nine amino acid peptide derived from MAGEA1. Eligible patients underwent leukapheresis, T cells were isolated, transduced with lentiviral vector carrying MAGEA1-specific TCR and following lymphodepletion (fludarabine/cyclophosphamide), infused with a median of 1.4×10 9 specific T cells (range, 0.086×10 9 -2.57×10 9 ) followed by interleukin 2. SAFETY OF IMA202: No DLT was observed. The most common grade 3-4 adverse events were cytopenias, that is, neutropenia (81.3%), lymphopenia (75.0%), anemia (50.0%), thrombocytopenia (50.0%) and leukopenia (25.0%). 13 patients experienced cytokine release syndrome, including one grade 3 event. Immune effector cell-associated neurotoxicity syndrome was observed in two patients and was grade 1 in both. EFFICACY OF IMA202: Of the 16 patients dosed, 11 (68.8%) patients had stable disease (SD) as their best overall response (Response Evaluation Criteria in Solid Tumors V.1.1). Five patients had initial tumor shrinkage in target lesions and one patient with SD experienced continued shrinkage in target lesions for 3 months in total but had to be classified as progressive disease due to progressive non-target lesions. IMA202 T cells were persistent in peripheral blood for several weeks to months and were also detectable in tumor tissue. Peak persistence was higher in patients who received higher doses., Conclusion: In conclusion, IMA202 had a manageable safety profile, and it was associated with biological and potential clinical activity of MAGEA1-targeting genetically engineered TCR-T cells in a poor prognosis, multi-indication solid tumor cohort., Trial Registration Numbers: NCT04639245, NCT05430555., Competing Interests: Competing interests: MBH, AM, AS, MK, KP, ASM, DK, and SW were employees of Immatics US in the course of this work and may have securities from Immatics. SG-G, KA, SS, JH, MAK, AA, LB, MB, SB, CW, OS, AM-M, NH, and CMB were employees of Immatics Biotechnologies in the course of this work and may have securities from Immatics. AMT: Clinical trial research funding (received through the institution): OBI Pharma USA, Immatics, Parker Institute for Cancer Immunotherapy, Agenus, Tempus, Tvardi, Boston Biomedical, Karus Therapeutics; Consulting or advisory role: Vincerx, Diaccurate, BrYet, Nex-I, Macrogenics, BioEclipse. BSA: Two patents sold to GreenJay Therapeutics, privately held. IIW’s ASCO COI form is up to date. JJL: Data and safety monitoring board: Abbvie, Agenus, Amgen, Immutep, Evaxion; Scientific advisory board: (no stock) 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc. AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest; Consultancy with compensation: Abbvie, Agenus, Alnylam, Atomwise, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic, Synthekine; Research support: (all to institutions for clinical trials unless noted) AbbVie, Astellas, Astrazeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; Patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). MW: Honoraria: Amgen, Bayer, Boehringer Ingelheim, GWT, Janssen, Lilly, Merck Serono, Novartis, SYNLAB; Consulting or advisory role: Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, ImCheck therapeutics, Immatics, ISA Pharmaceuticals, Lilly, Novartis; Research funding: Roche; Travel, accommodations, expenses: Amgen, AstraZeneca, Bristol-Myers Squibb, GEMoaB, Immatics, Merck Serono, Pfizer, Sanofi/Aventis; TAWH: Honoraria: Amgen, Bristol-Myers-Squibb, GlaxoSmithKline, Jazz; Consulting or advisory role: Amgen, Jazz, Kite/Gilead, Novartis, Sanofi, Bristol-Myers-Squibb, Pfizer, GlaxoSmithKline; Travel, accommodation, expenses: Janssen, Jazz, Abbvie, Bristol-Myers-Squibb, Amgen, Kite/Gilead, Astellas, Neovii, GlaxoSmithKline, Sanofi. VKM: Consulting or advisory role: Axiom Healthcare Strategies, Bicara Therapeutics, BioMedical Insights, Boehringer Ingelheim, Incyte; Research funding: Bicara Therapeutics, BioNTech, Bristol-Myers Squibb, EMD Serono, Immatics, Pfizer. WHA: Consulting or advisory role: Janssen; Research funding (received through institution): Affimed, BioNTech; Travel, accommodation, expenses: Immatics, Janssen, BioNTech; Honoraria: GSK, Janssen, AstraZeneca, Astellas. All other authors have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor T-cell therapy, was approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) based on the results from pivotal Cohorts 1+2 of ZUMA-1 (NCT02348216). ZUMA-1 was expanded to investigate safety management strategies aimed at reducing the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs). Prospective safety expansion Cohort 5 evaluated the impact of debulking therapy, including rituximab-containing immunochemotherapy regimens and radiotherapy, in axi-cel-treated patients; the CRS and NE management strategy paralleled those in Cohorts 1+2. Among the 50 patients in Cohort 5 who received axi-cel, 40% received ≥3 prior lines of chemotherapy, and 40% had disease that progressed while on the most recent chemotherapy. Forty-eight patients (96%) received debulking therapy, 14 (28%) radiotherapy only, and 34 (71%) systemic immunochemotherapy. Median decrease in tumor burden (per sum of product of diameters of target lesions) relative to screening was 17.4% with R-ICE/R-GDP, 4.3% with other debulking chemotherapies, and 6.3% with radiotherapy only. All patients were followed for ≥8 months. CRS was reported in 43 patients (86%), with 1 patient (2%) experiencing grade ≥3. NEs were reported in 28 patients (56%), with 6 (12%) experiencing grade ≥3. Cytopenias were the most frequent grade ≥3 adverse event (AE); 19 (38%) and 18 (36%) treated patients had any and grade ≥3 prolonged thrombocytopenia, respectively, and 25 (50%) and 24 (48%) patients had any and grade ≥3 prolonged neutropenia, respectively. Overall, patients who received debulking chemotherapy had higher incidences of serious treatment-emergent AEs than those who received radiotherapy only. At the 24-month analysis, objective response rate was 72%, and complete response rate was 56%. Median duration of response, progression-free survival, and overall survival were 25.8, 3.1, and 20.6 months, respectively. These results from exploratory Cohort 5 demonstrate the feasibility of debulking prior to axi-cel, and together with current real-world evidence, suggest that debulking regimens may help minimize the frequency and severity of CRS and NEs in patients with R/R LBCL. The incidence of other AEs observed in Cohort 5 suggest the risk/benefit profile was not improved via the debulking regimens studied here., Competing Interests: TvM: honoraria from Kite, a Gilead Company, Gilead Sciences, Celgene/Bristol Myers Squibb; consulting/advisory role for Janssen, Lilly, and Kite; and research funding from Celgene/Bristol Myers Squibb, Siemens, and Genentech. JK: honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche, and Seattle Genetics; consulting/advisory role for AbbVie, Antengene, Bristol Myers Squibb, Gilead Sciences, Karyopharm, Medison Ventures, Merck, Roche, and Seattle Genetics; research funding from AstraZeneca, Merck, and Roche; and other relationship with DSMB, Karyopharm, and Chair of Scientific Advisory Board Lymphoma Canada. KWS: honoraria from Amgen, Bristol Myers Squibb, Janssen, and Kite, a Gilead Company. CT: consulting or advisory role for Amgen, Bristol Myers Squibb, Incyte, Kite, a Gilead Company, Novartis, Roche, and Takeda; research funding from Roche; and travel, accommodations, and expenses from Bristol Myers Squibb, Incyte, Kite, Novartis, Roche, and Takeda. MCM: consulting or advisory role for Bristol Myers Squibb, CDR-life, GSK, and Janssen-Cilag (institution); speaker’s bureau participation for WebMD (institution); and research funding from BeiGene (institution). EF: consulting or advisory role for Novartis; speakers’ bureau participation for Alexion, Astellas, Gilead Sciences, GSK, Novartis, and Sanofi; and travel support from Alexion, Gilead Sciences, MSD, and Novartis. SDG: honoraria from and consulting/advisory role for AbbVie, Gilead Sciences, and Janssen. MJK: honoraria from and consulting/advisory role for Adicet Bio, Celgene/Bristol Myers Squibb, Kite, a Gilead Company, Miltenyi Biotec, Novartis, and Roche; research funding from Kite (all to institution); and travel support from Kite, Miltenyi Biotec, Novartis, and Roche. PGNJM: no relevant financial relationships to disclose. MW: honoraria from AstraZeneca, Bristol Myers Squibb, Merck, Novartis, and Pfizer; consulting/advisory role for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genmab, Kite, a Gilead Company, Merck, Novartis, and Pfizer; and travel support from AstraZeneca, Bristol Myers Squibb, and Novartis. YZ: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. AX: Stock or other ownership in Amgen, Biogen, and Kite, a Gilead Company. JNW: employment with and research funding from Kite, a Gilead Company, and stock or other ownership in Gilead. JN: employment with and stock or other ownership in Kite, a Gilead Company. RRS: employment with and stock or other ownership in Kite, a Gilead Company; and patents, royalties, and other intellectual property from Atara and Kite. CS: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. FN: employment with Kite, a Gilead Company; and stock or other ownership in Gilead Sciences. JJK: employment with and stock or other ownership in Kite, a Gilead Company. MST: consulting/advisory role for AstraZeneca, Bristol Myers Squibb, Genmab, Kite, a Gilead Company, and Roche; research funding from Kite, Regeneron, Roche, and Takeda; and travel support from Janssen and Kite., (AJCR Copyright © 2024.)

We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m 2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m 2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

The search for target antigens for CAR-T cell therapy against multiple myeloma defined the B-cell maturation antigen (BCMA) as an interesting candidate. Several studies with BCMA-directed CAR-T cell therapy showed promising results. Second-generation point-of-care BCMA.CAR-T cells were manufactured to be of a GMP (good manufacturing practice) standard using the CliniMACS Prodigy ® device. Cytokine release in BCMA.CAR-T cells after stimulation with BCMA positive versus negative myeloma cell lines, U266/HL60, was assessed via intracellular staining and flow cytometry. The short-term cytotoxic potency of CAR-T cells was evaluated by chromium-51 release, while the long-term potency used co-culture (3 days/round) at effector/target cell ratios of 1:1 and 1:4. To evaluate the activation and exhaustion of CAR-T cells, exhaustion markers were assessed via flow cytometry. Stability was tested through a comparison of these evaluations at different timepoints: d0 as well as d + 14, d + 90 and d + 365 of cryopreservation. As results, (1) Killing efficiency of U266 cells correlated with the dose of CAR-T cells in a classical 4 h chromium-release assay. There was no significant difference after cryopreservation on different timepoints. (2) In terms of endurance of BCMA.CAR-T cell function, BCMA.CAR-T cells kept their ability to kill all tumor cells over six rounds of co-culture. (3) BCMA.CAR-T cells released high amounts of cytokines upon stimulation with tumor cells. There was no significant difference in cytokine release after cryopreservation. According to the results, BCMA.CAR-T cells manufactured under GMP conditions exerted robust and specific killing of target tumor cells with a high release of cytokines. Even after 1 year of cryopreservation, cytotoxic functions were maintained at the same level. This gives clinicians sufficient time to adjust the timepoint of BCMA.CAR-T cell application to the patient's course of the underlying disease.

Background: The national Network Genomic Medicine (nNGM) Lung Cancer provides comprehensive and high-quality multiplex molecular diagnostics and standardized personalized treatment recommendation for patients with advanced non-small cell lung cancer (aNSCLC) in Germany. The primary aim of this study was to investigate the effectiveness of the nNGM precision medicine program in terms of overall survival (OS) using real-world data (RWD)., Methods: A historical nationwide cohort analysis of patients with aNSCLC and initial diagnosis between 04/2019 and 06/2020 was conducted to compare treatment and OS of patients with and without nNGM-participation. Patients participating within the nNGM (nNGM group) were selected based on a prospective nNGM database. The electronic health records (EHR) of the prospective nNGM database were case-specifically linked to claims data (AOK, German health insurance). The control group was selected from claims data of patients receiving usual care without nNGM-participation (non-nNGM group). The minimum follow-up period was six months., Findings: Overall, n = 509 patients in the nNGM group and n = 7213 patients in the non-nNGM group met the inclusion criteria. Patients participating in the nNGM had a significantly improved OS compared to the non-nNGM group (median OS: 10.5 months vs. 8.7 months, p  = 0.008, HR = 0.84, 95% CI: 0.74-0.95). The 1-year survival rates were 46.8% (nNGM) and 41.3% (non-nNGM). The use of approved tyrosine kinase inhibitors (TKI) in the first-line setting was significantly higher in the nNGM group than in the non-nNGM group (nNGM: 8.4% (43/509) vs. non-nNGM: 5.1% (366/7213), p  = 0.001). Overall, patients receiving first-line TKI treatment had significantly higher 1-year OS rates than patients treated with PD-1/PD-L1 inhibitors and/or chemotherapy (67.2% vs. 40.2%, p  < 0.001)., Interpretation: This is the first study to demonstrate a significant survival benefit and higher utilization of targeted therapies for aNSCLC patients participating within nNGM. Our data indicate that precision medicine programs can enhance collaborative personalized lung cancer care and promote the implementation of treatment innovations and the latest scientific knowledge into clinical routine care., Funding: The study was funded by the AOK Federal Association Germany., Competing Interests: AKä, nvdB, KM, and WH declare financial support from the Federal Association of the AOK, Berlin, Germany (e.g., for performing the analyses and writing the manuscript), as stated in the manuscript. MSche received institutional grants from Amgen, Bristol Myers Squibb, Dracen Pharmaceuticals Inc., Janssen, Novartis, Siemens Healthineers, personal consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Novartis, Pfizer, Roche, Sanofi-Aventis, Siemens Healthineers and Takeda, honoraria or payment for educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Novartis, Pfizer, Sanofi-Aventis and Takeda; received support for attending meetings and/or travel from Boehringer Ingelheim, Janssen, Pfizer, AstraZeneca; and reports participation on a Data Safety Monitoring Board at Boehringer Ingelheim, a leadership or fiduciary role (unpaid) at the ESMO Lung Cancer Faculty, ESMO Climate Change Task Force and the EORTC Lung Cancer group. DTR received payment or honoraria from Roche (Bristol Myers Squibb), Bayer and Lilly for lectures, presentations, speakers’ bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Bayer. MSchu received institutional grants from AstraZeneca and Bristol Myers Squibb, consulting fees from Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi-Aventis and Takeda, payment or honoraria from Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Novartis, Roche, Sanofi-Aventis for lectures, presentations, speakers’ bureaus, manuscript writing or educational events; received support for attending meetings and/or travel from Janssen, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Novartis, Amgen; and participated in Data Safety Monitoring Boards or Advisory Boards at Amgen, Bristol-Myers Squibb, Novartis, Sanofi-Aventis, Janssen, Tacalyx, Abalos and GlaxoSmithKline. MW received institutional grants from Roche, personal consulting fees from Bristol Myers Squibb, Novartis, Lilly, Boehringer Ingelheim, Amgen, Immatics, Bayer and ImCheck Therapeutics, payment or honoraria for educational events from Lilly, Boehringer Ingelheim, SYNLAB, Janssen, Merck Serono, GWT-TUD GmbH, Amgen and Novartis; he received support for attending meetings and/or travel from Pfizer, Bristol Myers Squibb, AstraZeneca, Janssen, Amgen, GEMoaB, Sanofi-Aventis, Immatics, Merck Serono and Daiichi Sankyo and honoraria for participation in a Data Safety Monitoring Board or Advisory Board of ISA Pharmaceuticals. FK received payment or honoraria from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Lilly, Agilent, Bayer, Merck and Trillium for lectures, presentations, speakers’ bureaus, manuscript writing or educational events and is a board member at the National Pathologists’ Association Germany; and received personal honoraria for lectures by AstraZeneca and Novartis and participated in an advisory board by AstraZeneca. MSe received grants from AstraZeneca and consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, Merck-Serono and GSK; received payment or honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer Ingelheim, Amgen, Takeda, Johnson, CureVac, BioNTech, Merck-Serono, GSK, Daiichi and Pfizer for lectures, presentations, speakers’ bureaus, manuscript writing or educational events; and received support for attending meetings and/or travel from Pfizer, Bristol-Myers Squibb and participated in a Data Safety Monitoring Board at Amgen. CB received consulting fees from the AOK NRW-Hamburg, and honoraria for participation in a Data Safety Monitoring Board or Advisory Board of AstraZeneca, Bayer Healthcare, Bristol Myers Squibb, Janssen-Cilag, Merck Serono and Sanofi-Aventis; received payment or honoraria for lectures given for Bristol Myers Squibb, Roche Pharma and Sanofi-Aventis; and received support for attending meetings and/or travel from Sanofi-Aventis, Janssen-Cilag and has an unpaid leadership or fiduciary role at DGHO, DKG-Zertifizierungskommission and CCC Netzwerk. RB received payment or honoraria for lectures and participation in advisory boards for AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Illumina, Janssen, Lilly, Merck Serono, Merck Sharp & Dohme, Novartis, Qiagen, Pfizer, Roche and Targos MP Inc.; and reports a leadership or fiduciary role as co-founder and co-owner of Gnothis Inc (SE) and Timer Therapeutics Inc (GE). JW received funding from Amgen, AstraZeneca, Bayer, Blueprint, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, Merck Sharp & Dohme, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda and Turning Point. The remaining authors declare no conflict of interest., (© 2023 The Author(s).)

In no other cancer is clinical practice as close to the ideals of personalized oncology as in the treatment of non-small cell lung cancer (NSCLC). Here, we briefly outline the basic principles of molecular analysis. The focus of the article is on the clinical utility of targeted therapy. Finally, we highlight the challenges for medical staff and structural solutions reflecting the situation in Germany., Competing Interests: Wermke, M Honorare: Lilly, Boehringer Ingelheim, SYNLAB, Janssen, Merck Serono, GWT TUD, Amgen, Novartis. Beratung: Bristol-Myers Squibb, Novartis, Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, Amgen, Immatics, Bayer, ImCheck Therapeutics. Forschungsförderung: Roche. Reisekosten/Unterbringung: Pfizer, Bistol-Myers Suqibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics, Merck Serono Aust, DE Honorare: Roche, Astra Zeneca, MSD, Pfizer, Novartis Saalfeld, FC Honorare: AstraZeneca, Novarits, Pfizer, Takeda. Beratung: AstraZeneca, Janssen. Reisekosten/Unterbringung: Lilly, Takeda, (Thieme. All rights reserved.)

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog ( NRAS )-mutant melanoma is currently available., Patients and Methods: In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF -mutant non-small-cell lung cancer (escalation arm) or NRAS -mutant melanoma (escalation and expansion arms)., Results: Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily., Conclusion: Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS -mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

Background: Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC., Patients and Methods: Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS)., Results: At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab., Conclusions: Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors., Competing Interests: Disclosure EG reports research funding to the institution for clinical studies from Merck Sharp & Dohme (MSD), Novartis, AstraZeneca/MedImmune, Roche, Thermo Fisher Scientific, Taiho Oncology, 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 Kgga, S.A – Peptomyc, Ribon Therapeutics, Roche Farma SA, Seattle Genetics Inc., Symphogen A/S, fees for consulting and advisory roles from Roche, Ellipses Pharma, NeoMed, Janssen, Boehringer Ingelheim, Seattle Genetics, TFS, Alkermes, Thermo Fisher Scientific, Bristol Myers Squibb (BMS), mAb Discovery, Anaveon, fees for speakers bureau from MSD, Roche, Thermo Fisher Scientific, Lilly, reimbursement for travel from BMS, Menarini, Glycotope GmbH, MSD; AS reports research funding to the institution from MSD, stock in BMS, Merck, fee for speakers bureau from Merck, Eisai; NJL, AP, YYL, TG report research funding to the institution for clinical studies from MSD; SAI reports research funding to the institution for clinical studies from MSD, AstraZeneca, Eisai, Boryung Pharm, Daewon Pharm, Roche, Pfizer, fees for consulting or advisory role from AstraZeneca, Daiichi Sankyo, Eisai, GlaxoSmithKline, Lilly, MSD, Novartis, Pfizer, Roche; RG reports research funding to the institution for clinical studies from MSD, Novartis, honoraria from BMS, Lilly, Medison, Roche, Novartis, Janssen, Takeda, MSD, Pfizer, Merck, fees for consulting or advisory role from Eisai, AstraZeneca, Bayer, MSD, Novartis, Boehringer Ingelheim, BOL Pharma, Roche, reimbursement for travel from Merck, Bayer, BMS, Medison; MDM reports research funding to the institution from MSD, Roche, Sanofi, PharmaMar, AbbVie, Janssen, Faron, Genentech, MacroGenics, Menarini, Nektar, Novartis; MW reports research funding to the institution for clinical studies, fees for consulting or advisory roles from BMS, Novartis, Kite, Heidelberg Pharma, Roche, Boehringer Ingelheim, honoraria from BMS, Merck, Roche, Novartis, Kite, Boehringer Ingelheim, AstraZeneca, reimbursement for travel from Glenmark, BMS, AstraZeneca; JP, SJ, MC, AA, JH are employees of MSD LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) and hold stock in Merck & Co., Inc., Rahway, NJ, USA; GSF reports research funding to the institution for clinical studies from 3-V Biosciences, Abbisko, AbbVie, ABL Bio ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, BeiGene, BioAtla, BioInvent, Biothera, Bicycle, Boehringer Ingelheim, Celldex, Celgene, CicloMed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, IGM Biosciences, Ignyta, ImmunoGen/MacroGenics, Incyte, Jacobio, Jounce, Kolltan, Loxo/Bayer, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, RasCal, Regeneron, Rgenix, Ribon, Samumed, Sapience, Silicon, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, Vegenics, Xencor, fees for consulting or advisory role from Fujifilm, Silicon, Navire, Turning Point, Predicine, EMD Serono, reimbursement for travel from BMS, EMD Serono, Fujifilm, Millenium, Sarah Cannon Research Institute, speakers honoraria from Total Health Conferencing, Rocky Mountain Oncology Society., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Patients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate (ORR) of 36% in 66 patients who progressed after ICI and targeted therapy. Herein, we report independent review committee (IRC)-assessed outcomes of 153 patients treated with lifileucel in a large multicenter Phase 2 cell therapy trial in melanoma., Methods: Eligible patients had advanced melanoma that progressed after ICI and targeted therapy, where appropriate. Melanoma lesions were resected (resected tumor diameter ≥1.5 cm) and shipped to a central good manufacturing practice facility for 22-day lifileucel manufacturing. Patients received a non-myeloablative lymphodepletion regimen, a single lifileucel infusion, and up to six doses of high-dose interleukin-2. The primary endpoint was IRC-assessed ORR (Response Evaluation Criteria in Solid Tumors V.1.1)., Results: The Full Analysis Set consisted of 153 patients treated with lifileucel, including longer-term follow-up on the 66 patients previously reported. Patients had received a median of 3.0 lines of prior therapy (81.7% received both anti-programmed cell death protein 1 and anti-cytotoxic lymphocyte-associated protein 4) and had high disease burden at baseline (median target lesion sum of diameters (SOD): 97.8 mm; lactate dehydrogenase (LDH) >upper limit of normal: 54.2%). ORR was 31.4% (95% CI: 24.1% to 39.4%), with 8 complete responses and 40 partial responses. Median duration of response was not reached at a median study follow-up of 27.6 months, with 41.7% of the responses maintained for ≥18 months. Median overall survival and progression-free survival were 13.9 and 4.1 months, respectively. Multivariable analyses adjusted for Eastern Cooperative Oncology Group performance status demonstrated that elevated LDH and target lesion SOD >median were independently correlated with ORR (p=0.008); patients with normal LDH and SOD 30); and being on the speaker’s bureau for Bristol-Myers Squibb, Regeneron, and Castle Biosciences. ST reports honoraria, consulting or advisory role, research funding, speaker’s bureau, and travel, accommodations, expenses with Bristol-Myers Squibb, Merck, Pfizer, Ipsen, Amgen, Genentech, and Foundation One. MW reports receiving honoraria from Novartis, Pfizer, and Roche; consulting or advisory role with Bristol-Myers Squibb, Novartis, Pfizer, Cellex GmbH, Eli Lilly, Boehringer Ingelheim, ISA Pharmaceuticals, GEMoaB, Roche, MSD, AstraZeneca, Amgen, and Immatics; research funding from Roche; and travel, accommodations, and expenses from Pfizer, Bristol-Myers Squibb, AstraZeneca, Roche, Amgen, and GEMoaB. MC reports speaker’s bureau participation with Sirtex Medical. ED-M reports receiving honoraria from Castle Biosciences; consulting or advisory role and speaker’s bureau with Regeneron; and research funding from Clinigen. GQP reports honoraria from IBSA; consulting or advisory role with Acella, Amneal, and Terns; and patents, royalties, or other intellectual property with Virginia Commonwealth University. JMK reports consulting role with Amgen, Ankyra Therapeutics, Applied Clinical Intelligence, Axio Research, Becker Pharmaceutical Consulting, Bristol-Myers Squibb, Cancer Network, Checkmate Pharmaceuticals, DermTech, Fenix Group International, Harbour BioMed, Immunocore, Iovance Biotherapeutics, IQVIA, Istari Oncology, Merck, Natera, Novartis, Oncocyte, OncoSec, Pfizer, Replimune, Scopus BioPharma, SR One Capital Management LP, Takeda Development Center Americas, and Takeda Pharmaceutical Company; and research trial support to institution from Amgen, Bristol-Myers Squibb, Checkmate Pharmaceuticals, Harbour BioMed, ImmVira, Immunocore, Iovance Biotherapeutics, Novartis, Takeda, and Verastem. JCH reports honorarias for talks from Almirall, Amgen, Bristol-Myers Squibb, GSK, JSD Pharma, Novartis, Pierre Fabre, Roche, Sanofi, and Sun Pharma; advisory boards for GSK, MSD, Pierre Fabre, Sun Pharma (personal), and Bristol-Myers Squibb, Immunocore, Nektar, Novartis, and Philogen (institution); research funding from Bristol-Myers Squibb, Sun Pharma, and Sanofi; and travel, accommodations, and expenses from Sun Pharma. MO reports consulting or advisory role with TriSalus, Immunocore, Ideaya, and Delcath, and her husband is an employee of GSK. JL reports receiving honoraria from Eisai, Novartis, Incyte, Merck, touchIME, touchEXPERTS, Royal College of Physicians, Cambridge Healthcare Research, Royal College of General Practitioners, VJOncology, Agence Unik, and Bristol-Myers Squibb; consulting or advisory role with iOnctura, Apple Tree, Merck, Bristol-Myers Squibb, Eisai, Debiopharm, and Incyte; research funding from Bristol-Myers Squibb, MSD, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar, Covance, Immunocore, Pharmacyclics, and Aveo; and travel, accommodations, and expenses from Pierre Fabre, Roche, and GSK. JW reports stock or other ownership with Biond, Instil Bio, OncoV4, and Evaxion; honoraria and consulting or advisory role with Bristol-Myers Squibb, GSK, Pfizer, Sellas, Biond, OncoC4, ImCheck, Genentech, AstraZeneca, Regeneron, Instil Bio, Iovance Biotherapeutics, Evaxion, and Ultimovacs; research funding from Bristol-Myers Squibb, Moderna, Merck, Incyte, and Genentech; patents, royalties, or other intellectual property with Moffitt Cancer Center and Biodesix. AJSF reports consulting or advisory role with Immunocore and GSK; speaker’s bureau participation with Bristol-Myers Squibb, Ipsen, and Eisai; and travel, accommodations, and expenses from ESMO. NIK reports stock and other ownership interest with Bellicum Pharmaceuticals, Amarin Corporation, and Asensus Surgical; consulting or advisory role with Bristol-Myers Squibb, AstraZeneca, Regeneron, Array BioPharma, Immunocore, Merck, Incyte, Jounce Therapeutics, Iovance Biotherapeutics, NCCN/Pfizer, Genzyme, Novartis, Nektar, Castle Biosciences, and InstilBio; research funding from Bristol-Myers Squibb, Merck, Novartis, GSK, HUYA Bioscience International, Amgen, Regeneron, Celgene, and Replimune; and other relationships with Nektar, Regeneron, Bristol-Myers Squibb/Celgene, and Replimune. TM reports consulting or advisory role with Merck, Bristol-Myers Squibb, Iovance Biotherapeutics, Moderna, Nektar, Regeneron, Exicure, Checkmate Pharmaceuticals, BioAtla, Xencor, Replimune, Day One Biopharmaceuticals, Pfizer, and Taiga. MEE reports consultant or advisory role with Iovance Biotherapeutics and receiving research funding from SkylineDx. FGF, MJ, PH, GS, WS, and XW are employees of Iovance Biotherapeutics and hold stock and/or stock options. Further, FGF is in a leadership position at Iovance Biotherapeutics; owns stocks from Adverum Biotechnologies, Roche, Bristol-Myers Squibb, and Johnson & Johnson; and holds patents, royalties, or other intellectual property rights with Bristol-Myers Squibb. PH additionally reports receiving honoraria from Janssen, Amgen, Karyopharm, Bristol-Myers Squibb, and Sanofi; has been paid for a consultant or advisory role by Janssen, Amgen, Karyopharm, Bristol-Myers Squibb, and Allogen; and received travel, accommodations, and expenses from Johnson & Johnson, Bristol-Myers Squibb, and Sanofi. AS reports honoraria and consulting or advisory role with Iovance Biotherapeutics, Guidepoint, Defined Health, Huron Consulting Group, KeyQuest Health, Istari, Gerson Lehrman Group, Physicians’ Educational Resource, Medscape and MedStar Health; and holds patents, royalties, or other intellectual property rights with Moffitt Cancer Center, Iovance Biotherapeutics, and Provectus., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We evaluated MK-4621, an oligonucleotide that binds and activates retinoic acid-inducible gene I (RIG-I), as monotherapy (NCT03065023) and in combination with the anti-programmed death 1 antibody pembrolizumab (NCT03739138)., Patients and Methods: Patients were ≥ 18 years with histologically/cytologically confirmed advanced/metastatic solid tumors with injectable lesions. MK-4621 (0.2‒0.8 mg) was administered intratumorally as a stable formulation with jetPEI™ twice weekly over a 4-week cycle as monotherapy and weekly in 3-week cycles for up to 6 cycles in combination with 200 mg pembrolizumab every 3 weeks for up to 35 cycles. Primary endpoints were dose-limiting toxicities (DLTs), treatment-related adverse events (AEs), and treatment discontinuation due to AEs., Results: Fifteen patients received MK-4621 monotherapy and 30 received MK-4621 plus pembrolizumab. The only DLT, grade 3 pleural effusion that subsequently resolved, occurred in a patient who received MK-4621/jetPEI™ 0.8 mg plus pembrolizumab. 93% of patients experienced ≥ 1 treatment-related AE with both monotherapy and combination therapy. No patients experienced an objective response per RECIST v1.1 with MK-4621 monotherapy; 4 (27%) had stable disease. Three (10%) patients who received combination therapy had a partial response. Serum and tumor biomarker analyses provided evidence that MK-4621 treatment induced an increase in gene expression of interferon signaling pathway members and associated chemokines and cytokines., Conclusions: Patients treated with MK-4621 monotherapy or in combination with pembrolizumab experienced tolerable safety and modest antitumor activity, and there was evidence that MK-4621 activated the RIG-I pathway. At the doses tested, MK-4621 did not confer meaningful clinical benefit., Trial Registration: ClinicalTrials.gov, NCT03065023 and NCT03739138., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Functional impairment of the bone marrow (BM) niche has been suggested as a major reason for prolonged cytopenia and secondary graft failure after allogeneic hematopoietic cell transplantation (alloHCT). Because mesenchymal stromal cells (MSCs) serve as multipotent progenitors for several niche components in the BM, they might play a key role in this process. We used collagenase digested trephine biopsies to directly quantify MSCs in 73 patients before (n = 18) and/or after alloHCT (n = 65). For the first time, we demonstrate that acute graft-versus-host disease (aGvHD, n = 39) is associated with a significant decrease in MSC numbers. MSC reduction can be observed even before the clinical onset of aGvHD (n = 10). Assessing MSCs instantly after biopsy collection revealed phenotypic and functional differences depending on the occurrence of aGvHD. These differences vanished during ex vivo expansion. The MSC endotypes observed revealed an enhanced population of donor-derived classical dendritic cells type 1 and alloreactive T cells as the causing agent for compartmental inflammation and MSC damage before clinical onset of aGvHD was ascertained. In conclusion, MSCs endotypes may constitute a predisposing conductor of alloreactivity after alloHCT preceding the clinical diagnosis of aGvHD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Krüger, Wehner, Herbig, Kräter, Kramer, Middeke, Stölzel, List, Egger-Heidrich, Teipel, Oelschlägel, Wermke, Jambor, Wobus, Schetelig, Jöhrens, Tonn, Subburayalu, Schmitz, Bornhauser and von Bonin.)

Poorly differentiated neuroendocrine carcinomas such as small-cell lung cancer (SCLC) have poor survival and high relapse rates. DLL3 is found on these carcinomas and has become a target of increasing interest in recent years. The bispecific DLL3/CD3 T-cell engager BI 764532 has been shown to induce complete tumor regression in a human T cell-engrafted mouse model. Here, we describe the study design of a first-in-human, phase I, multicenter, open-label, non-randomized, dose-escalation study in patients with SCLC or other DLL3-positive neuroendocrine carcinomas. The study will determine the maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics and preliminary efficacy of BI 764532 monotherapy.

Background: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce., Patients and Methods: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases., Results: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, ≈7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p < 0.05). Overall survival (OS) was not dependent on the choice of first-line treatment, but related to more lines of systemic therapy (p < 0.05). TP53 mutations and brain metastases were associated with shorter PFS under platinum doublets and EGFR inhibitors (HR 3.3-6.1, p < 0.01), and shorter OS for patients receiving both treatments (p < 0.05). More tumour CD8 + and less Th1 cells were associated with longer OS independent of brain and TP53 status (p < 0.01). No difference in outcome was noted according to the ex20ins site and use of pemetrexed (vs. other cytotoxics) or bevacizumab. Long-lasting responses (>1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants., Conclusions: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival., Competing Interests: Conflict of interest statement PC: research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Roche, Takeda, and advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Gilead, Novartis, Pfizer, Roche, Takeda. JR: lecture fees from AstraZeneca, Boehringer Ingelheim. FCS: research funding from Roche; non-financial support from Lilly; personal fees from Takeda, and Pfizer, outside the submitted work. BH: advisory board/lecture fees from AstraZeneca, Boehringer Ingelheim, BMS, MSD, Roche, Pfizer. JK: research funding from AstraZeneca and Celgene. MJ: speaker's honoraria from Roche, Boehringer, and travel grants from Daiichi Sankyo. DK: advisory boards/speakers honoraria from AstraZeneca, BMS, Boehringer Ingelheim, GSK, MSD, Novartis, Pfizer, Roche, Takeda. FE: speaker's honoraria from Roche. FB: research funding from AstraZeneca, BMS and Roche, and travel grants from BMS and MSD. RS: research funding from BMS, and speaker's honoraria from AstraZeneca and Roche. AT: research funding from BMS. MW: research funding from Roche; Personal fees from Roche, AstraZeneca, Boehringer, Kite, Novartis, Merck, BMS, Heidelberg Pharma; Non-financial support from AstraZeneca, BMS, Glenmark; outside the submitted work. SL: advisory board, speaker's honoraria and travel support from BerGenBio, Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AstraZeneca, Sanofi, as well as research funding from Roche, BMS, BerGenBio. WB: consulting fees from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche, Sanofi, honoraria for lectures from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, MSD, Pfizer, Roche, Sanofi. Travel grants from AstraZeneca, Boehringer Ingelheim, MSD, Roche. CS: advisory board honoraria from AstraZeneca, Boehringer Ingelheim, BMS, MSD, Novartis, Roche, Pfizer, Takeda. Speaker's honoraria from AstraZeneca, Boehringer, Lilly, Roche, MSD, Takeda. DM: advisory board/lecture fees from AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Novartis, Roche, Sanofi and Takeda (no personal honoraria) NF: advisory board/lecture fees from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Pfizer, Roche, MSD, Takeda. JK: advisory board member without receiving any personal fees for Roche Pharma, Boehringer Ingelheim, BMS, MSD, Amgen, Lilly and Takeda. MR: advisory board/lecture fees from Amgen, AstraZeneca, BMS, Boehringer, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Samsung. FG: grants and personal fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, Takeda, as well as personal fees from AbbVie, Tesaro/GSK, Blueprint Medicines, Amgen. CG: advisory board/lecture fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Takeda, MSD, Novartis, Pfizer, Roche, AbbVie, Tesaro/GSK and Blueprints Medicines. AS: advisory board honoraria from BMS, AstraZeneca, ThermoFisher, Novartis, speaker's honoraria from BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche, and research funding from Chugai and BMS. MT: advisory board honoraria from Novartis, Eli Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer Ingelheim, Pfizer, speaker's honoraria from Eli Lilly, MSD, Takeda, Pfizer, research funding from AstraZeneca, BMS, Celgene, Novartis, Roche, Takeda, and travel grants from BMS, MSD, Novartis, Boehringer. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Although the treatment and prognosis of many solid tumor types in the metastatic situation could be considerably improved during the last decade, for a long time no significant progress in the treatment of small cell lung cancer (SCLC) could be achieved., Objective: The aim of this article is to describe the current treatment standard for SCLC and to discuss potential approaches for further improvement., Methods: A selective literature search was carried out in PubMed and abstract lists of relevant conferences., Results: Given the recent approval of two immunochemotherapy regimens based on the combination of anti-PD-L1 antibodies with platinum-etoposide, the therapeutic standard in the first line treatment of metastasized SCLC has finally been improved for the first time in three decades; however, the overall survival benefit has been modest with an improvement of just 2-3 months. In advanced lines of treatment no new approaches could so far show improved outcome compared with established chemotherapy protocols, such as topotecan and combinations of anthracycline, cyclophosphamide and vincristine. The slow progress in SCLC compared to non-SCLC, has been attributed to the complex biology, the exceptionally high proliferation rate and rapid development of resistance to chemotherapy. Increasing knowledge on the molecular and immunological principles of SCLC is increasingly opening up novel treatment approaches., Conclusion: There has finally been a slow but clinically meaningful progress in the treatment of SCLC. Patients should be included in clinical trials at the latest after second line treatment, in order to accelerate the speed of the expansion of treatment options., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but deficiency of environmental signals and insufficient tumor recognition may limit their activity. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to a spliced isoform of the extracellular matrix (ECM) glycoprotein tenascin-C would potentiate NK-cell-mediated antibody-dependent cellular cytotoxicity against leukemic blasts. In this novel-novel combination, dose-escalation, phase 1 trial, we enrolled patients with posttransplant acute myeloid leukemia (AML) relapse to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of the antibody-cytokine fusion F16IL2 (10 × 106 to 20 × 106 IU IV; days 1, 8, 15, and 22 of each 28-day cycle) in combination with the anti-CD33 antibody BI 836858 (10-40 mg IV, 2 days after each F16IL2 infusion). Among the 15 patients (median [range] age, 50 [20-68] years) treated across 4 dose levels (DLs), 6 (40%) had received 2 or 3 prior transplantations. The most frequent adverse events were pyrexia, chills, and infusion-related reactions, which were manageable, transient and of grade ≤2. One dose-limiting toxicity occurred at each of DLs 3 (pulmonary edema) and 4 (graft-versus-host disease). Three objective responses were observed among 7 patients treated at the 2 higher DLs, whereas no responses occurred at the 2 starting DLs. Combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcγRIIIA/CD16 receptor. ECM-targeted IL-2 combined with anti-CD33 immunotherapy represents an innovative approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. This trial was registered at EudraCT as 2015-004763-37., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date., Patients and Methods: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions)., Results: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1., Conclusions: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations., Competing Interests: Disclosure MJ: speaker’s honoraria and/or advisory board from Roche, Boehringer, Amgen, AstraZeneca, Novartis. AT: honoraria, consulting and/or travel support from Lilly, Pfizer, Boehringer, Celgene, MSD, BMS, Amgen, Roche, Takeda, GSK. JLVR: consulting and/or travel support from Roche, Lilly. MR: research funding from BMS. AJ: speaker honoraria, advisory board and/or travel support from Amgen, Archer, Astra Zeneca, Bayer, Biocartis, Boerhinger Ingelheim, BMS, Merck, MSD, Novartis, Pfizer, QuiP GmbH, Roche, Thermo Fisher. IB: honoraria, consulting and/or travel support from AstraZeneca, Novartis, BMS, Bayer. HDH: travel, accommodations or other expenses from Johnson & Johnson, Boehringer Ingelheim, Bristol-Myers Squibb and Amgen. JAS: honoraria, consulting and/or travel support from AstraZeneca, Novartis, Amgen, Roche; research funding from AstraZeneca. JA: consulting and/or travel support from AstraZeneca, Boehringer Ingelheim, BMS, Roche. JB: honoraria from Novartis. FCS: honoraria from Pfizer, Takeda; research funding from Roche; travel support from Lilly. MW: research funding from Roche; honoraria and/or advisory board fees from Roche, AstraZeneca, Boehringer, Kite, Novartis, Merk, BMS, Heidelberg Pharma; non-financial support from AstraZeneca, BMS, Glenmark. SMB: honoraria and/or advisory board from Amgen, AstraZeneca, Roche, Novartis, GSK, MSD, Targos Molecular Health, Merck, Onkowisse, QuIP GmbH and advisory board honoraria, speaker fees and non-financial support from Janssen and BMS. CB: honoraria and/or advisory board from AstraZeneca, Bayer, Berlin Chemie, BMS, Merck, Roche, Novartis, Sanofi, Lilly/ImClone and travel expenses from BMS, Merck, Pfizer and Sanofi. RB: employment with Targos Molecular Path Inc, Kassel, Germany, leadership role as Chief Scientific Officer at Targos Molecular Path Inc, stock from Targos Molecular Path Inc. JW: consulting and/or travel support from Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda; research funding from BMS, Janssen Pharmaceutica, Novartis, Pfizer. SL: advisory board, speaker honoraria and travel support from Lilly, Sanofi, BerGenBio, Novartis, Boehringer Ingelheim, BMS, Roche, Astra Zeneca, MSD, Sanofi-Aventis, Janssen, Takeda, Daiichi-Sankyo and research funding from Roche, BMS and BerGenBio. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This report summarizes three phase I studies evaluating volasertib, a polo-like kinase inhibitor, plus azacitidine in adults with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, or acute myeloid leukemia., Methods: Patients received intravenous volasertib in 28-day cycles (dose-escalation schedules). In Part 1 of 1230.33 (Study 1; NCT01957644), patients received 250-350 mg volasertib on day (D)1 and D15; in Part 2, patients received different schedules [A, D1: 170 mg/m 2 ; B, D7: 170 mg/m 2 ; C, D1 and D7: 110 mg/m 2 ]. In 1230.35 (Study 2; NCT02201329), patients received 200-300 mg volasertib on D1 and D15. In 1230.43 (Study 3; NCT02721875), patients received 110 mg/m 2 volasertib on D1 and D8. All patients in Studies 1 and 2, and approximately half of the patients in Study 3, were scheduled to receive subcutaneous azacitidine 75 mg/m 2 on D1-7., Results: Overall, 22 patients were treated (17 with MDS; 12 previously untreated). Across Studies 1 and 2 (n = 21), the most common drug-related adverse events were hematological (thrombocytopenia [n = 11]; neutropenia [n = 8]). All dose-limiting toxicities were grade 4 thrombocytopenia. The only treated patient in Study 3 experienced 18 adverse events following volasertib monotherapy. Studies 1 and 2 showed preliminary activity (objective response rates: 25 and 40%)., Conclusions: The safety of volasertib with azacitidine in patients with MDS was consistent with other volasertib studies. All studies were terminated prematurely following the discontinuation of volasertib for non-clinical reasons by Boehringer Ingelheim; however, safety information on volasertib plus azacitidine are of interest for future studies in other diseases., (© 2022. The Author(s).)

Purpose of Review: Treatment outcome of relapsed or refractory AML patients remains dismal and new treatment options are needed. Adoptive cell therapy using CAR-T cells is a potentially interesting approach in this., Recent Findings: Several potentially interesting AML targets are being investigated with CAR-T therapy with over 60 clinical trials listed on clinicaltrials.gov. The first clinical data are only just emerging with mixed results, once more proving that further research is needed., Summary: Adoptive cell therapy using chimeric antigen receptor T cells is being investigated in AML through many clinical trials. So far, no AML-specific antigen has been identified, requiring additional strategies to mitigate on-target off-tumor toxicity and to increase efficacy. Focus point is to acquire control over the CAR T cells once administered. Strategies to do so include biodegradable CARs, inducible CARs, suicide-switch containing CARs and two-component modular CARs. Limited and mixed results are available, confirming the risk of lasting toxicity for nonswitchable CARs. Initial results of modular CARs suggest toxicity can be mitigated whilst maintaining CAR activity by the use of modular CAR concepts that allows for 'ON' and 'OFF' switching., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Allogeneic hematopoietic cell transplantation (HCT) during chemotherapy-induced aplasia may offer long-term survival in acute myeloid leukemia (AML) with otherwise poor prognosis including ELN adverse risk, relapsed or refractory disease. However, the value of residual morphologic disease prior HCT in this context has not been conclusively settled until yet. Therefore, we aimed to investigate variables predicting outcome in this unique setting of sequential conditioning therapy, with a focus on pretreatment morphologic blast count. In contrast to the most popular FLAMSA-RIC protocol, we used a melphalan-based conditioning regimen during aplasia., Methods: We retrospectively analyzed data from 173 AML patients who underwent a sequential melphalan-based conditioning therapy between 2003 and 2015 at our centre. All patients participated either in the prospective Phase 2 BRIDGE trial (NCT01295307), the Phase 3 AML2003 study (NCT00180102) or were treated according to this protocol and underwent allogeneic HCT after melphalan-based conditioning in treatment-induced aplasia., Results: Median bone marrow blast count prior to conditioning was 10% (range, 0-96%). Four year probabilities of EFS and OS were 34% (95% CI, 28-43%) and 43% (95% CI, 36-52%), respectively. In multivariate analysis, blast count >20% was associated with worse EFS (HR = 1.93; p = 0.009) and OS (HR = 1.80; p = 0.026). This effect was not significant anymore for HCT during 1st line therapy., Conclusion: Allogeneic HCT in aplasia with a melphalan-based conditioning regimen has the potential to cure a subset of adverse risk AML patients, even with persistent morphological disease prior HCT. However, a high pre-transplant blast count still indicates patients with a dismal prognosis, especially in the relapsed patient group, for whom post-transplant strategies should be considered to further optimize post HCT outcome., Competing Interests: Dr Martin Wermke reports personal fees, grants, and/or non-financial support from Novartis, Pfizer, Roche, Lilly, Bristol Myers Squibb, Cellex, Boehringer Ingelheim, ISA Pharmaceuticals, Gemoab, AstraZeneca, Immatics, and Amgen, outside the submitted work. The authors declare no other potential conflicts of interest for this work., (© 2022 Sockel et al.)

Introduction: The advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood., Methods: We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles., Results: While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC =  - 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC =  - 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine-cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors., Conclusion: Targeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors., (© 2021. The Author(s).)

Objectives: Immune checkpoint inhibitors (ICI) have significantly improved outcome of patients with advanced NSCLC and recently also showed benefit in early-stage disease. Patients with oligometastatic disease (OMD) harbor limited metastases, resectable primary tumors and derive benefit from treatment with multimodal locally ablative and systemic therapy approaches. Nothing is known about feasibility and efficacy of neoadjuvant ICI in this setting., Material and Methods: We here provide data from a multicenter retrospective study comprising 13 patients with NSCLC and OMD (≤3 distant metastases) from 5 university medical centers in Germany who have been treated with neoadjuvant ICI alone (n = 4) or in combination with chemotherapy (CT) (n = 9) prior to resection of the primary tumor. We analyzed complete (pCR) and major pathological remission (MPR) rates., Results: These data show that neoadjuvant immunotherapy applied mostly in combination with CT results in high rates of pCR and MPR (54 and 69%, respectively). Up to now, 85% of patients are free of progression with a median follow-up of 9 months (3-28 months). Single cell RNASeq analysis of tumor tissue from one patient treated with CT-ICI indicates a strong predominance of adaptive immune cell populations over a small minority of epithelial (tumor) cells., Conclusion: Neoadjuvant ICI with or without CT is a promising therapeutic concept in patients with OMD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Chimeric-antigen-receptor (CAR)-T-cell therapy is already widely used to treat patients who are relapsed or refractory to chemotherapy, antibodies, or stem-cell transplantation. Multiple myeloma still constitutes an incurable disease. CAR-T-cell therapy that targets BCMA (B-cell maturation antigen) is currently revolutionizing the treatment of those patients. To monitor and improve treatment outcomes, methods to detect CAR-T cells in human peripheral blood are highly desirable. In this study, three different detection reagents for staining BCMA-CAR-T cells by flow cytometry were compared. Moreover, a quantitative polymerase chain reaction (qPCR) to detect BCMA-CAR-T cells was established. By applying a cell-titration experiment of BCMA-CAR-T cells, both methods were compared head-to-head. In flow-cytometric analysis, the detection reagents used in this study could all detect BCMA-CAR-T cells at a similar level. The results of false-positive background staining differed as follows (standard deviation): the BCMA-detection reagent used on the control revealed a background staining of 0.04% (±0.02%), for the PE-labeled human BCMA peptide it was 0.25% (±0.06%) and for the polyclonal anti-human IgG antibody it was 7.2% (±9.2%). The ability to detect BCMA-CAR-T cells down to a concentration of 0.4% was similar for qPCR and flow cytometry. The qPCR could detect even lower concentrations (0.02-0.01%). In summary, BCMA-CAR-T-cell monitoring can be reliably performed by both flow cytometry and qPCR. In flow cytometry, reagents with low background staining should be preferred.

We conducted a phase I clinical trial of H3B-8800, an oral small molecule that binds Splicing Factor 3B1 (SF3B1), in patients with MDS, CMML, or AML. Among 84 enrolled patients (42 MDS, 4 CMML and 38 AML), 62 were red blood cell (RBC) transfusion dependent at study entry. Dose escalation cohorts examined two once-daily dosing regimens: schedule I (5 days on/9 days off, range of doses studied 1-40 mg, n = 65) and schedule II (21 days on/7 days off, 7-20 mg, n = 19); 27 patients received treatment for ≥180 days. The most common treatment-related, treatment-emergent adverse events included diarrhea, nausea, fatigue, and vomiting. No complete or partial responses meeting IWG criteria were observed; however, RBC transfusion free intervals >56 days were observed in nine patients who were transfusion dependent at study entry (15%). Of 15 MDS patients with missense SF3B1 mutations, five experienced RBC transfusion independence (TI). Elevated pre-treatment expression of aberrant transcripts of Transmembrane Protein 14C (TMEM14C), an SF3B1 splicing target encoding a mitochondrial porphyrin transporter, was observed in MDS patients experiencing RBC TI. In summary, H3B-8800 treatment was associated with mostly low-grade TAEs and induced RBC TI in a biomarker-defined subset of MDS., (© 2021. The Author(s).)

Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory large B-cell lymphoma (R/R LBCL). To reduce axi-cel-related toxicity, several exploratory safety management cohorts were added to ZUMA-1 (NCT02348216), the pivotal phase 1/2 study of axi-cel in refractory LBCL. Cohort 4 evaluated the rates and severity of cytokine release syndrome (CRS) and neurologic events (NEs) with earlier corticosteroid and tocilizumab use. Primary endpoints were incidence and severity of CRS and NEs. Patients received 2 × 10 6 anti-CD19 CAR T cells/kg after conditioning chemotherapy. Forty-one patients received axi-cel. Incidences of any-grade CRS and NEs were 93% and 61%, respectively (grade ≥ 3, 2% and 17%). There was no grade 4 or 5 CRS or NE. Despite earlier dosing, the cumulative cortisone-equivalent corticosteroid dose in patients requiring corticosteroid therapy was lower than that reported in the pivotal ZUMA-1 cohorts. With a median follow-up of 14·8 months, objective and complete response rates were 73% and 51%, respectively, and 51% of treated patients were in ongoing response. Earlier and measured use of corticosteroids and/or tocilizumab has the potential to reduce the incidence of grade ≥ 3 CRS and NEs in patients with R/R LBCL receiving axi-cel., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: In contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting., Methods: We retrospectively evaluated outcomes of patients with HER2mu NSCLC treated with ICI alone or in combination with chemotherapy within the German National Network Genomic Medicine Lung Cancer consortium by means of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS)., Results: ICI either in combination with chemotherapy or as monotherapy was applied as first-line treatment in 27 patients, whereas 34 received single-agent ICI in second or subsequent lines. Patient characteristics were in line with previously published data. In treatment-naive patients receiving ICI in combination with chemotherapy, the ORR, median PFS, and OS rate at 1 year were 52%, 6 months, and 88%, respectively. In second or subsequent lines, ICI monotherapy was associated with an ORR of 16%, a median PFS of 4 months, and a median OS of 10 months., Conclusions: ICIs are effective as monotherapy and in combination with platinum-doublet chemotherapy. Therefore, ICI-based treatments may be found as the current standard of care and benchmark for targeted therapies in HER2mu NSCLC., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)