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Introduction: Up to 20% of EGFR-mutated NSCLC cases harbor uncommon EGFR mutations, including atypical exon 19 and compound mutations. Relatively little is known about the efficacy of osimertinib in these cases., Methods: Patients treated with first-line osimertinib for NSCLC with rare EGFR exon 19 (non E746_A750del) or compound mutations were included. Response assessment and time to progression were determined using Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Kaplan-Meier analyses were used to estimate progression-free survival (PFS), time to treatment discontinuation (TTD), and overall survival (OS)., Results: Thirty-seven patients with NSCLC harboring an atypical EGFR exon 19 mutation or compound mutation were treated with first-line osimertinib at Johns Hopkins from 2016 to 2021. Overall response rate (ORR) was 76% and median PFS, TTD, and OS were 13 months (95% confidence interval [CI]: 10-15), 22 months (95% CI: 17-32) and 36 months (95% CI, 29-48), respectively. Among atypical exon 19 mutations (n = 25), ORR was 80%, median PFS was 12 months (95% CI: 10-15), median TTD was 19 months (95% CI: 17-38), and median OS was 48 months (95% CI: 25-not reached). Compound mutations (n = 12) had an ORR of 67%, median PFS of 14 months (95% CI: 5-22), median TTD of 26 months (95% CI: 5-36), and median OS of 36 months (95% CI: 20-46). Twelve patients (32%) continued first-line osimertinib after local therapy for oligoprogression., Conclusions: Osimertinib exhibited favorable outcomes for rare EGFR exon 19 and compound mutations. The heterogeneity in outcomes among these groups of tumors with similar mutations underscores the need for continued reporting and further study of outcomes among rare variants to optimize management for each patient., Competing Interests: Dr. Houseknecht has been consulting for AstraZeneca, Aptar Pharma, and has stock ownership with Pfizer. Dr. Feliciano has received research funding direct to the institution from 10.13039/100004325AstraZeneca, 10.13039/100004319Pfizer, 10.13039/100002491Bristol Myers Squibb and was consulting for Regeneron, AstraZeneca, Coherus, Eli Lilly, Genentech, Takeda, Jansen, Daiichi Sankyo. Dr. Hann has received research funding direct to the institution from AstraZeneca, Amgen, Daiichi, Bristol Meyers Squibb, AbbVie; and personal fees from AstraZeneca, Puma BioTechnology, Daiichi, Janssen and Bristol Meyers Squibb. Dr. Lam was consulting for Iovance Biotherapeutics, Anheart Therapeutics, Takeda, Seattle Genetics, Bristol Myers Squibb, AstraZeneca, and Guardant Health; and has received research funding direct to the institution from GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Merck and Seattle Genetics. Dr. Levy has received personal fees from AstraZeneca, Novartis, Eli Lilly, Genentech, Pfizer, Guardant 360, Takeda, Bristol Meyers Squibb, Novocure, Janssen, Daiichi Sankyo, Merck. Dr. Murray has received personal fees from Regeneron, Johnson & Johnson. Dr. Brahmer has received personal fees from 10.13039/100004337Roche, grants and personal fees from Bristol Meyers Squibb, grants from 10.13039/100004334Merck, personal fees from 10.13039/100009857Regeneron, grants and personal fees from AstraZeneca, personal fees from 10.13039/100002429Amgen, personal fees from Summit, personal fees from Mestag, grants and personal fees from RAPT therapeutics, personal fees from 10.13039/100004330GlaxoSmithKline, and personal fees from Sanofi.Dr.Forde has received research funding direct to the institution from AstraZeneca, BMS, Novartis, Regeneron, BioNTech; consulting fees from Ascendis, AstraZeneca, BMS, Curevac, Novartis, Regeneron, G1, Genelux, Genentech, Gritstone, Merck, Janssen, F Star, Sanofi, Amgen, Fosun, Teva, Synthekine, Flame, Iteos, Tavotek, Teva; and has DSMB membership for Polaris. Dr. Marrone has been consulting for AstraZeneca, Amgen, Janssen, Mirati Therapeutics, Daiichi Sankyo/Lilly and Puma Biotechnology; and has received honoraria from AstraZeneca, research funding direct to the institution from Bristol-Myers Squibb and Mirati Therapeutics. Dr. Scott has received research funding direct to the institution from Mirati and Janssen; and has been consulting for AstraZeneca, Foundation Medicine, Genentech, Regeneron, and Tempus. The remaining authors declare no conflict of interest., (© 2024 The Authors.)

Introduction: Increased efforts to optimize outcomes for early stage NSCLC through the investigation of novel perioperative treatment strategies are ongoing. An emerging question is the role of pathologic response and its association with long-term clinical outcomes after neoadjuvant therapy., Methods: To investigate the association of pathologic complete response (pCR) and event-free survival (EFS) and overall survival (OS), we performed a systematic review and meta-analysis identifying studies reporting on the prognostic impact of pCR after neoadjuvant chemotherapy or chemoradiotherapy. To evaluate this prognostic value, an aggregated data (AD) meta-analyses was conducted to estimate the pooled hazard ratios (HRs) of EFS and OS for pCR. Using reconstructed individual patient data (IPD), pooled Kaplan-Meier curves were obtained to estimate this association in a more granular fashion. Subgroup analyses were conducted to further explore the impacts of study-level characteristics., Results: A total of 28 studies comprising 7011 patients were included in the AD meta-analysis, of which, IPD was available for 6274 patients from 24 studies. Results from our AD meta-analysis revealed a pooled pCR rate of 18% (95% confidence interval [CI]: 15%-21%), including significant improvements in OS (HR = 0.50, 95% CI: 0.45-0.56) and EFS (HR = 0.46, 95% CI: 0.37-0.57) on the basis of pCR status. Our IPD analysis revealed a 5-year OS rate of 63% (95% CI: 59.6-67.4) for patients with a pCR compared with 39% (95% CI: 34.5-44.5) for those without a pCR., Conclusions: pCR after neoadjuvant chemotherapy plus or minus radiotherapy is associated with significant improvements in EFS and survival for patients with resectable NSCLC., (© 2022 The Authors.)

Introduction: Given the emergence of combination of programmed cell death protein-1 and CTLA4 pathway blockade as effective treatment options in malignant pleural mesothelioma (MPM), there is interest in the extent to which programmed death-ligand 1 (PD-L1) expression may be prognostic of clinical outcomes and predictive of response to anti-programmed death (ligand) 1 (PD-[L]1) therapies., Methods: MEDLINE and EMBASE electronic databases were searched until November 4, 2020. English-language randomized trials and observational studies that reported clinical outcomes and PD-L1 expression in adult patients (>18 or >20 y) with MPM were included. Forest plots were used to descriptively summarize clinical outcome data across studies., Results: A total of 29 publications were identified providing data on the research question. Among the studies in which anti-PD-(L)1 therapies were not specified to have been used, 63% (10 of 16) found patients with tumors expressing PD-L1 (typically >1%) to have poorer survival than those with tumors expressing lower levels of PD-L1. Among the studies in which anti-PD-(L)1 therapies were used, 83% (five of six) did not reveal an association between survival and PD-L1 tumor expression. The single study directly comparing outcomes between those treated and untreated with anti-PD-(L)1 therapies across different PD-L1 cutoffs did not identify any differences between the groups., Conclusions: The quality and consistency of the existing evidence base are currently insufficient to draw conclusions regarding a prognostic or predictive role of PD-L1 in MPM. Furthermore, high-quality studies on this topic are required to support the use of PD-L1 as a biomarker in MPM., (© 2022 The Authors.)

Introduction: Checkpoint inhibitor pneumonitis (CIP) is a serious toxicity of anti-programmed death-(ligand) 1 immunotherapy. Whether pretreatment differences in pulmonary function exist in patients who develop CIP is unknown. We analyzed the pulmonary function tests (PFTs) of patients with NSCLC treated with immune checkpoint inhibitors (ICIs) to evaluate whether pretreatment lung function was associated with CIP development., Methods: Patients were included if they completed greater than or equal to 1 PFT within 2 years preceding ICI initiation. CIP status (CIP+: developed CIP, CIP-: did not develop CIP) was determined clinically. Generalized estimating equation-based linear regression was used to evaluate the effects of time and CIP on lung function. Primary outcomes included the following: percent-predicted forced expiratory volume in 1 second (FEV1pp), percent-predicted forced vital capacity (FVCpp), and FEV1/FVC., Results: A total of 43 patients (34 CIP-, 9 CIP+) with 79 PFTs (59 CIP-, 20 CIP+) were included. CIP+ patients had a 21.7% lower pretreatment FEV1pp compared with the CIP- group (95% confidence interval: -38.6 to -4.7). No statistically significant differences in FVCpp or FEV1/FVC were observed. The prevalence of obstructive lung disease was similar in both groups at 67% and 62% for the CIP+ and CIP- cohorts, as was the prevalence of current/former smoking at 100% and 93%, respectively., Conclusions: Pretherapy differences in lung function were evident between patients who did and did not develop CIP, though the prevalence of obstructive lung disease was similar. Prospective studies are needed to validate these findings, inform potential risk factors for CIP, and investigate the effects of ICI treatment and CIP on pulmonary function in patients with NSCLC., (© 2021 The Authors.)