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Osimertinib is prescribed to patients with metastatic non‐small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan‐Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR‐mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first‐line (40%), second‐line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4‐19.3), 13.9 (95% CI: 11.3‐16.1) and 8.7 months (95% CI: 4.6‐12.7), respectively. Patients with low BMI (<20.0 kg/m2) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS; >271 ng/mL) had shorter PFS compared to a low Cmin,SS (<163 ng/mL; aHR 2.29; 95% CI: 1.13‐4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45‐0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36‐0.92). A trend towards longer PFS was seen for TP53 wild‐type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib. [ABSTRACT FROM AUTHOR]

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.)

Objectives: In patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung (NSCLC) chemotherapy remains standard of care after progression on EGFR-tyrosine kinase inhibitors (TKIs). With the development of anti-angiogenic agents and immune checkpoint inhibitors the landscape of systemic regimens has changed significantly. This cohort study aims to evaluate the efficacy of chemotherapy regimens after progression on EGFR-TKI in a European population., Material and Methods: All consecutive patients treated with chemotherapy after progression on EGFR-TKI for EGFR-mutated NSCLC, were identified in two tertiary centers in the Netherlands. Data on best response, progression free survival (PFS) and overall survival (OS) were extracted from medical records., Results: In total, 171 lines of chemotherapy were identified: platinum/pemetrexed (PP, n = 95), carboplatin/paclitaxel/bevacizumab/atezolizumab (CPBA, n = 32), paclitaxel/bevacizumab (PB, n = 36) and carboplatin/paclitaxel/bevacizumab (CPB, n = 8). Of the 171 lines, 106 were given as first-line after EGFR-TKI. Median PFS did not differ significantly between the first-line regimens (p = 0.50), with the highest PFS in PP (5.2 months [95% CI 4.5-5.9]) and CPBA (5.9 months [95% CI 3.8-80]). The majority of the PB group (n = 32) received this regimen in a second- or later line with a median PFS of 4.9 months (95% CI 3.3-6.6). First-line regimens had a median OS of 15.3 months (95% CI 11.6-18.9) with no significant difference between regimens (p = 0.85)., Conclusion: After progression on EGFR-TKI, patients with EGFR-mutated NSCLC show substantial benefit on different chemotherapy regimens. In particular, favorable outcomes were seen in patients treated with PP and CPBA as first-line chemotherapy, and PB in further lines of chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C.M.J. Steendam reports receiving institutional fees from Boehringer Ingelheim, Roche and Eli Lilly; outside the current work. S.K. Badrising reports receiving institutional fees from Pfizer; outside the current work. M.S. Paats reports receiving institutional fees from AstraZeneca, Bayer, Eli Lilly, Janssen, Novartis, Pfizer, Roche and Takeda; outside the current work. J.G.J.V. Aerts reports receiving advisory board and speakers fees from Eli-Lilly, BMS, MSD, Astra-Zeneca, Bayer, Amphera and is a stock owner of Amphera; outside the current work. A.J. de Langen reports institutional fees from AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, Merus; outside the current work. A.C Dingemans reports receiving institutional fees from Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Janssen, Chiezi, Amgen, Pfizer, Bayer, Takeda, Pharmamar, Sanofi and Daiichi; outside the current work. S.M. Ernst reports no disclosures., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated ( EGFR m+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFR m+ NSCLC patients., Methods: Patients who started treatment with osimertinib for EGFR m+ NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics., Findings: From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p = 0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p = 0.010)., Interpretation: ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment., Funding: No funding was received for this trial., Competing Interests: G.D.M.V. reports grants from Eli Lilly; outside the submitted work. A.C.D. reports grants from Boehringer-Ingelheim; outside the submitted work (paid to institution). R.H.J.M. reports an unrestricted grant from Boehringer-Ingelheim (paid to institution) and grants from Astellas, Bayer, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Sanofi, and Servier; outside the submitted work (paid to institution). L.E.L.H. has no relationship to disclose in relation to this manuscript. Outside of the current manuscript: research funding Roche Genentech, AstraZeneca, Boehringer Ingelheim, Takeda (all institution, Beigene under negotiation); advisory board: BMS, Eli Lilly, Roche Genentech, Pfizer, Takeda, MSD, Merck, Novartis, Boehringer Ingelheim, Amgen, Janssen (all institution, Roche one time self); speaker: MSD, Lilly (institution); travel/conference reimbursement: Roche Genentech (self); mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars: Benecke, Medtalks, VJOncology (self), high5oncology (institution); interview sessions funded by Roche Genentech, Bayer, Lilly (institution); local PI of clinical trials: AstraZeneca, Novartis, BMS, MSD, Merck, GSK, Takeda, Blueprint Medicines, Roche Genentech, Janssen Pharmaceuticals, Mirati, Abbvie, Gilead. A.J.v.d.W. reports grants and advisory board from AstraZeneca, grants and advisory board from Boehringer-Ingelheim, advisory board from Janssen, advisory board from Novartis, grants and advisory board from Pfizer, grants and advisory board from Roche, grants and advisory board from Takeda, all outside the submitted work; all payment to the UMCG. N.S. provided consultation or attended advisory boards for Boehringer Ingelheim, Cogent Biosciences, Ellipses Pharma, Luszana. N. Steeghs received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, Incyte, InteRNA, Janssen, Kinnate Biopharma, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. All outside the submitted work, all payment to the Netherlands Cancer Institute. E.F.S. has no relationship to disclose in relation to the manuscript. Outside the submitted work (all institutional): research grants from Astra Zeneca, MSD, BMS, Roche Genentech, advisory boards Astra Zeneca, BMS, Boehringer Ingelheim, Bayer, DSI, MSD, Takeda, Roche, Merck, Novartis, Amgen, Janssen. All other authors declare no competing interests., (© 2023 The Author(s).)

Background: Earlier preclinical and phase II research showed enhanced effect of docetaxel plus intercalated erlotinib. The NVALT-18 phase III study was designed to compare docetaxel with docetaxel plus intercalated erlotinib in relapsed metastasized non-squamous (NSQ) non-small cell lung cancer (NSCLC)., Methods: Patients with relapsed Epidermal Growth Factor Receptor (EGFR) wild type (WT) NSQ-NSCLC were randomized 1:1 to docetaxel 75 mg/m 2 intravenously on day 1 every 21 days (control), or docetaxel 75 mg/m 2 intravenously on day 1 plus erlotinib 150 mg/day orally on day 2-16 every 21 days (experimental arm). Progression free survival (PFS) was the primary endpoint, secondary objectives were duration of response, overall survival (OS) and toxicity., Results: Between October 2016 and April 2018 a total of 45 patients were randomized and received treatment in the control (N = 23) or experimental arm (N = 22), the study was stopped due to slow accrual. Median PFS was 4.0 months (95% CI: 1.5-7.1) versus 1.9 months (95% CI 1.4-3.5), p = 0.01 respectively; adjusted hazard ratio (HR) 2.51 (95% CI: 1.16-5.43). Corresponding median OS was 10.6 months (95% CI: 7.0-8.6) versus 4.7 months (95% CI: 3.2-8.6), p = 0.004, with an adjusted HR of 3.67 (95% CI: 1.46-9.27). Toxicity was higher with combination therapy, with toxicity ≥ CTCAE grade 3 in N = 6 (26%) in the control arm and N = 17 (77%) in the experimental arm (p < 0.001), mainly consisting of gastrointestinal symptoms and leukopenia., Conclusions: Our study shows detrimental effects of docetaxel plus intercalated erlotinib, and strongly discourages further exploration of this combination in clinical practice., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To compare the results of plasma cell-free DNA (cfDNA) droplet digital PCR (ddPCR) and next-generation sequencing (NGS) on detection of epidermal growth factor receptor ( EGFR ) primary activating mutations and p.T790M with results of tissue analysis in patients with EGFR mutated non-small-cell lung cancer., Methods: All patients with EGFR mutated non-small cell lung cancer for which a pathology and a plasma specimen were available upon progression between November 2016 and July 2018 were selected. Concordance, Cohen's κ, and intraclass correlation coefficients were calculated., Results: Plasma cfDNA and pathology specimens of 36 patients were analyzed. Agreement between ddPCR and NGS was 86% (κ = 0.63) for the primary activating mutation and 94% (κ = 0.89) for the p.T790M detection. Allele ratios were comparable, with an intraclass correlation coefficient of 0.992 and 0.997, respectively. Discrepancies of some degree were found in 15 patients (41.7%). In six patients (16.7%), no mutations were detected in cfDNA. In three patients (8.3%), p.T790M was detected in plasma but not in the pathology specimen, whereas in three other patients (8.3%), p.T790M was demonstrated in the pathology specimen but not in plasma. Concordance of cfDNA and pathology for the primary activating mutation was 69% for ddPCR and 83% for NGS. For the detection of p.T790M, this was 75% (κ = 0.49) for ddPCR as well as for NGS., Conclusion: Mutual agreement is high between NGS and ddPCR in cfDNA on the level of a specific mutation, with comparable ratio results. Plasma testing of EGFR primary activating mutations and p.T790M shows high concordance with pathology results, for NGS as well as for ddPCR, depending on the extent of the panel used. In NGS, more genetic aberrations can be investigated at once.

Introduction: NSCLC harboring activating mutations of EGFR is highly sensitive to first-line EGFR-tyrosine kinase inhibitors (TKIs), but drug resistance depending on the EGFR mutation p.T790M will occur in about 50-60% of patients. Detailed information on the amount of p.T790M plasmatic level associated with resistance to EGFR-TKIs and guidance to treatment with p.T790M-effective TKI depending on these levels, is lacking., Methods: This study enrolled p.T790M-positive patients (n=49) affected by EGFR-mutated NSCLC at progression to first-line EGFR-TKIs and, in selected cases (n=5), after second-line treatment with osimertinib. Cell-free circulating tumor DNA (cftDNA) was extracted from plasma and the quantitative analysis of EGFR ex19del, p.L858R and p.T790M was performed by digital droplet PCR., Results: The mean amount of mutated alleles at progression to first-line EGFR-TKIs was 108,492 copies/ml for ex19del, 97,336 copies/ml for p.L858R, but only 8,754 copies/ml for p.T790M. There was no significant correlation between progression-free survival and the ratio of p.T790M over EGFR activating mutations. The analysis of cftDNA in 5 patients treated with osimertinib revealed a marked decrease of all EGFR mutant alleles., Conclusions: The amount of p.T790M in plasma can be much lower than activating EGFR mutations. Despite this finding, osimertinib is effective in p.T790M-positive patients. These results indicate that clones driving resistance to EGFR-TKIs represent a minority among cells bearing activating EGFR-mutations. In addition, the identification of a threshold level of p.T790M is not a strict requirement for the selection of patients to be treated with osimertinib, since treatment showed a decrease in all EGFR mutated cells., Competing Interests: CONFLICTS OF INTEREST Authors have nothing to disclose.

Desmopressin is occasionally used to reduce the frequency of nocturnal toilet visits. We describe an 86-year-old woman with nocturnal incontinence due to a urinary tract infection, and a 49-year-old man with frequent toilet visits in the night, known to consume excessive amounts of alcohol. They were admitted to hospital with neurological symptoms due to severe hyponatraemia, 114 and 102 mmol/l respectively, while using desmopressin. After the desmopressin had been discontinued and the fluid balance restored, they recovered completely. Hyponatraemia is inherent to the mechanism of action of desmopressin. Desmopressin should be prescribed only on sound indication, and risk factors for developing severe hyponatraemia should always be taken into consideration. Proper instruction and follow-up are important to prevent severe complications.