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Introduction: Brain metastases (BM) are common in patients with advanced EGFR -mutated ( EGFR m+) NSCLC. Despite good BM-related outcomes of osimertinib, several patients still experience intracranial progression. A possible explanation is pharmacologic failure due to low plasma trough levels (C min,SS ) and consequently limited intracranial osimertinib exposure. We investigated the relation between osimertinib C min,SS and BM development or progression., Methods: A prospective multicenter cohort study, including patients receiving osimertinib for advanced EGFR m + NSCLC. At osimertinib start, patients were allocated to the BM or no or unknown BM cohort and were further divided into subgroups based on osimertinib C min,SS (low, middle, and high exposure). Cumulative incidence of BM progression or development and overall survival were determined for each group., Results: A total of 173 patients were included, with 49 (28.3%) had baseline BM. Of these patients, 36.7% experienced BM progression, of which 16.7% in the low (<159.3 ng/mL), 40.0% in the middle, and 47.1% in the high (>270.7 ng/mL) C min,SS subgroups. After 12 months, the cumulative incidence of BM progression for the BM cohort was 20% (95% confidence interval [CI] 2.6-49.0), 31% (95% CI:10.6-53.9), and 31% (95% CI:10.8-54.5) per C min,SS subgroup, respectively. After 20 months, this was 20% (95% CI:2.6-49.0), 52% (95% CI:23.8-74.2), and 57% (95% CI:24.9-79.7), respectively. For the no or unknown BM cohort, 4.0% developed BM without differences within C min,SS subgroups., Conclusions: No relation was found between osimertinib C min,SS and BM development or progression in patients with advanced EGFR m + NSCLC. This suggests that systemic osimertinib exposure is not a surrogate marker for BM development or progression., Competing Interests: Dr. Veerman reports receiving payment or honoraria for lectures from Eli Lilly (payed to the institute). Dr. Steendam reports receiving an unrestricted research grant from AstraZeneca (payed to the institute), payment or honoraria for lectures from Academic Pharmaceutical, supporting for attending meetings from Eli Lilly and Rochte and fullfilling unpaid roles at NVALT and CieBOD. Prof. dr. Mathijssen reports receiving grants of contracts for investigator initiated research from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche, Sanofi and Sevier (all payed to the institute). Prof. dr. Tjan-Heijnen reports receiving grants or contracts from Pfizer, Novartis, Eli Lilly, Gilead, Roche, AstraZeneca and Daiichi Sankyo (all payed to the institute), and receiving consulting fees from Eli Lilly, Novartis and AstraZeneca. Drs. Dursun reports receiving payment or honoraria a presentation at Novartis. Prof. dr. Smit reports receiving grants or contracts from AstraZeneca and Daiichi Sankyo (payed to the institute), receiving consulting fees from AstraZeneca, BMS, Boehringer-Ingelheim, Daiichi Sankyo, Sanofi, Eli Lilly, Roche Genentech, Merck, Novartis, Pfizer, Takeda and Taiho (all payed to the institute), participation on a data safety monitoring board or advisory board from DSI and Taiho and receiving payment of honoraria for lectures from Boehringer-Ingelheim. Prof. dr. Dingemans reports receiving grants or contracts from Amgen, Dutch Cancer Society and HANART (all payed to the institute), receiving consulting fees from AMGEN, Bayer, Boehringer-Ingelheim, Sanofy, Roche, Janssen and AstraZeneca (all payed to the institute), and receiving payment or honoraria for lectures from Janssen, Pfizer, AstraZeneca, Eli Lilly and Takeda (all payed to the institute), participation on a data and safety monitoring board or advisory board from Takeda and Roche and is unpaid char at EORTC LCG. Dr. van Geel reports receiving grants or contracts from Academic Alliance Fund (payed to the institute). Dr. Hendriks reports receiving grants or contracts from Roche Genentech, AstraZeneca, Boehringer-Ingelheim, Takeda, Merck, Pfizer and Novartis (all payed to the institute), receiving payment or honoraria for lectures from MSD, Eli Lilly, Sanofi, GSK and High5oncology (all payed to the institute), and personal payments from Benecke, Medtalks, Medimix, VJOncology, participation on a data safety monitoring board or advisory board from BMS, Eli Lilly, Roche Genetech, Pfizer, Takeda, MSD, Merck, Novartis, Boehringer-Ingelheim, Amgen, Janssen and Anhearts (all payed to the institute), and interview sessions funded by Roche Genentech, Bayer and Eli Lilly (all payed to the institute). All other authors declare no conflict of interest., (© 2024 The Authors.)

Introduction: EGFR tyrosine kinase inhibitor improved the survival of patients with metastatic EGFR mutation-positive ( EGFRm+ ) NSCLC. Despite high response rates, resistance develops inevitably in every patient. In up to 13%, HER2 protein overexpression is found on progression. We hypothesized that dual blockade of EGFR and HER2 by osimertinib combined with trastuzumab-emtansine (T-DM1) could reinduce tumor responses., Methods: In this multicenter, single-arm, phase 1-2 study (NCT03784599), patients with EGFRm+ NSCLC, progressing on osimertinib and HER2 overexpression were included. Patients were treated with T-DM1 3.6 mg/kg (intravenously) every 3 weeks and osimertinib 80 mg once a day. Primary end points were objective response rate (ORR) at 12 weeks and safety. Responses were assessed every 6 weeks (Response Evaluation Criteria in Solid Tumors 1.1). Sample size was calculated using Simon's two-stage minimax design (H0 = 41%, H1 > 55%, 80% power, one-sided type I error 10%: a ORR 16 of 36 was needed to proceed to 58 patients)., Results: From January 2019 to April 2021, 27 patients were enrolled. ORR after 12 weeks of treatment was 4% (1 of 27). Median progression-free survival was 2.8 months (95% confidence interval: 1.4-4.6 mo). Most frequent treatment-related adverse events of any grade were fatigue, diarrhea, and nausea, among these, grade 3 in four patients. There were no grade 4 or 5 therapy-related adverse events., Conclusions: TRAEMOS (Trastuzumab-Emtansine and Osimertinib) is the first trial combining T-DM1 and osimertinib in patients with EGFRm+ NSCLC to target HER2 overexpression at osimertinib resistance. Safety profile was favorable compared with cytotoxic chemotherapy; but treatment revealed limited efficacy. Further clinical evaluation of this regimen is not warranted., (© 2023 The Authors.)

Introduction: With the approval of first-line osimertinib treatment in stage IV EGFR-mutated NSCLC, detection of resistance mechanisms will become increasingly important-and complex. Clear guidelines for analyses of these resistance mechanisms are currently lacking. Here, we provide our recommendations for optimal molecular diagnostics in the post-EGFR tyrosine kinase inhibitor (TKI) resistance setting., Methods: We compared molecular workup strategies from three hospitals of 161 first- or second-generation EGFR TKI-treated cases and 159 osimertinib-treated cases. Laboratories used combinations of DNA next-generation sequencing (NGS), RNA NGS, in situ hybridization (ISH), and immunohistochemistry (IHC)., Results: Resistance mechanisms were identified in 72 first-generation TKI cases (51%) and 85 osimertinib cases (57%). RNA NGS, when performed, revealed fusions or exon-skipping events in 4% of early TKI cases and 10% of osimertinib cases. Of the 30 MET and HER2 amplifications, 10 were exclusively detected by ISH or IHC, and not detected by DNA NGS, mostly owing to low tumor cell percentage (<30%) and possibly tumor heterogeneity., Conclusions: Our real-world data support a method for molecular diagnostics, consisting of a parallel combination of DNA NGS, RNA NGS, MET ISH, and either HER2 ISH or IHC. Combining RNA and DNA isolation into one step limits dropout rates. In case of financial or tissue limitations, a sequential approach is justifiable, in which RNA NGS is only performed in case no resistance mechanisms are identified. Yet, this is suboptimal as-although rare-multiple acquired resistance mechanisms may occur., (© 2021 THE AUTHORS.)