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Introduction: Esophageal adenocarcinoma (EAC) remains a devastating disease and second line treatment options in the metastatic space are limited. Homologous recombination (HR) defects have been described in EAC in up to 40% of patients. Poly (ADP-ribose) polymerase (PARP)1 and PARP2 inhibitors have shown efficacy in HR defective prostate and ovarian cancers. Here, we describe the activity of the PARP inhibitor niraparib in metastatic EAC with HR defects., Methods: In this single arm Simon two-stage Phase II study, we assessed the safety and efficacy of niraparib in patients with metastatic EAC previously treated with platinum containing chemotherapy harboring defective HR. Defective HR was defined as deleterious alterations in the following HR genes: BRCA1/2, PALB2, ATM, BARD1, BRIP1, CDK12, CHEK2, FANCA, RAD51, RAD51B, RAD51C, RAD51D, RAD54L, NBN, ARID1A and GEN1., Results: 14 patients were enrolled in this study. The trial was stopped early due to slow accrual. 3 patients did not have post-treatment scans because of rapid clinical decline. The overall response rate (ORR) (95% exact CI) was 0/11 = 0% (0%, 28.49%). The disease control rate (DCR) (95% exact CI) was 2/11 = 18.2% (2.3%, 51.8%). The median PFS was 1.8 months (95% CI = 1.0-3.7). The median OS for evaluable patients was 6.6 months (95% CI =2.7-11.4) and 5.7 months for all patients (95% CI =2.7-10.1). The most common adverse events seen were anemia, fatigue, and thrombocytopenia., Conclusion: In patients with metastatic EAC, single agent niraparib as second line therapy is not an effective option., 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 © 2024 Khalid, Fountzilas, Burney, Mamdani, Schneider, Fausel, Perkins and Jalal.)

Background: The incidence of lung cancer in the US has been decreasing but a bigger decline has been observed in men despite similar declines in tobacco use between men and women. Multiple theories have been proposed, including exposure to exogenous estrogens. Our study seeks to understand the relationship between hormone receptors (HR), gender, and the genomic landscape of non-small lung cancer (NSCLC)., Methods: 3,256 NSCLC tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified and assessed for HR expression. Hormone receptor (HR+) was defined as ≥ 1% nuclear staining of estrogen receptor-alpha (ER-a) or progesterone receptor (PR) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n=2753) and Illumina NextSeq 592 gene panel (n=503). An adjusted p-value (q-value) <0.05 was determined significant., Results: HR+ was identified in 18.3% of NSCLC. HR+ occurred more commonly in women compared to men (19.6% vs 11.4%, p <0.0001, q <0.0001). EGFR mutations occurred more commonly in HR+ NSCLC than HR- NSCLC (20.2% vs. 14.6%, p = 0.002, q=0.007). Overall, men with EGFR mutations were affected by HR status with a higher prevalence in HR+ NSCLC while such differences were not seen in women. However, in women ages ≤45, there was a trend towards greater prevalence HR+ NSCLC (25.25% vs. 11.32%, q= 0.0942) and 10/25 (40.0%) of HR+ cases in young women were found to be EGFR mutated. KRAS mutations and ALK+ IHC expression occurred more in HR+ NSCLC whereas TP53 mutations occurred more in HR- NSCLC., Conclusions: Women were more likely to have HR+ NSCLC than men and EGFR and KRAS mutations occurred more commonly in HR+ NSCLC. Additional studies with more strict inclusion criteria for HR+ are warranted to see if there is benefit to targeting HR in these subgroups., Competing Interests: RH is a consultant for Targeted Oncology and received honorarium from DAVA Oncology and The Dedham Group outside of the submitted work. BX is an employee of Janssen Pharmaceuticals. RF is an employee of Caris Life Sciences. L.E.R. reports research funding from Genentech/Roche, Merck Serono, Boehringer Ingelheim, Novartis, Pfizer, Syndax, Loxo, Merck, Bristol Myers Squibb, Guardant Health, Heat Biologics, Amgen, Calithera Biosciences, Daiichi Sankyo/UCB Japan, NantHealth outside of the submitted work. HB consulting fees and advisory board involvement from BMS, Lilly, Genentech, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Amgen, Axiom, PharmaMar, Takeda, Mirati, Daiichi, Guardant, Natera, Oncocyte, Beigene, iTEO, Jazz, Janssen, Da Volterra, Puma, BerGenBio, Bayer, and Iobiotech; reports being on the data and safety monitoring board of Takeda, Incyte, Novartis, Springworks, and University of Pennsylvania CAR-T program; reports stock options in Sonnetbio, Inspirna, and Nucleai; reports honoraria from Amgen, Pfizer, Daiichi, Regeneron; reports research support from BMS, Lilly, and Amgen; reports travel support from Amgen, BMS, Merck, Lilly, EMD-Serono, Genentech, and Regeneron outside of the submitted work. CK reports grants from AstraZeneca, BMS, Regeneron, Tesaro, Karyopharm, Debiopharm, Mirati, Genentech, Spectrum, and Merck; grants and personal fees from Novartis and Janssen; and personal fees from PierianDx, Sanofi, Diffusion, Mirati, Jazz Pharmaceuticals outside the submitted work. MN reports personal fees from AstraZeneca, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Janssen, Pfizer, Caris Life Sciences, Blueprint Medicines, Regeneron, Mirati, and Lilly, and non-financial support from An Heart outside of the submitted work. H.M. reports personal fees from AstraZeneca and Genentech and research funding from AstraZeneca outside of the submitted work. AMV reports employment from Caris Life Sciences, personal fees from Bristol Myers Squibb, Caris Life Sciences, Compugen, ConcertoHealthAI, Elsevier, and Inivata; non-financial support from Roche/Genentech and AstraZeneca; and grants from Amgen, Merck, Replimune, EMD Serono, Immunomedics/Gilead outside the submitted work. GL reports stock in Lucence Diagnostics, Xilis, honoraria from Boehringer Ingelheim, Blueprint Medicines, AstraZeneca, Merck, consulting fees from Pfizer, AstraZeneca, research funding from Merck, EMD Serono, AstraZeneca, Blueprint Medicines, Tesaro, Bavarian Nordic, Novartis, G1 Therapeutics, Adaptimmune, BMS, GlaxoSmithKline, AbbVie, Rgenix, Pfizer, Roche, Genentech, Lilly, Janssen, Lucence, Silis, E.R. Squibb Sons, LLC, and non-financial support from Boehringer Ingelheim, Pfizer, E.R. Squibb Sons, LLC, Janssen, Seattle Genetics, Celgene, Ipsen, Pharmacyclics, Merck, AstraZeneca outside of the submitted work. M.A.S reports grants and personal fees from Genentech, AstraZeneca, Merck, and Novartis; personal fees from Jazz, Lilly, Mirati, Regeneron, Guardant, AbbVie, Blueprint, and Janssen; grants from Spectrum, BeiGene, and Daiichi Sankyo during the conduct of the study; grants and personal fees from Genentech, AstraZeneca, Merck, and Novartis outside of the submitted work. AJW reports personal fees from Premier, Beigene, Incyte, Novocure, Janssen, GlaxoSmithKline, Regeneron, and AstraZeneca; other support from BeyondSpring and Odronate outside the submitted work. AIS reports grants and personal fees from Amgen and Mirati; personal fees from Novartis, Pfizer, Merck, and AstraZeneca outside the submitted work. SVL reports personal fees from AstraZeneca, Beigene, Daiichi Sankyo, G1 Therapeutics, Guardant Health, Inivata, Janssen, Jazz Pharmaceuticals, PharmaMar, Regeneron, Takeda, Novartis, Eisai, Sanofi, Catalyst Pharmaceuticals, Candel Therapeutics, MSD Oncology, and Amgen; grants and personal fees from Blueprint, Bristol Myers Squibb, Genentech, Lilly, Merck, Pfizer, Elevation Oncology, Gilead Sciences, and Turning Point Therapeutics; grants from Alkermes, Bayer, Merus, Rain Therapeutics, and RAPT outside of the submitted work. JJN reports personal fees from AstraZeneca, Naveris, AADi, Bioatla, Mindmed, stock in Epic Sciences, Cansera, Quantgene, Indee P/L, and research funding from Merck and Genentech outside of the submitted work. The remaining 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 © 2023 Hsu, Chen, Xia, Feldman, Cozen, Raez, Borghaei, Kim, Nagasaka, Mamdani, Vanderwalde, Lopes, Socinski, Wozniak, Spira, Liu and Nieva.)

Background: Most patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients., Methods: We conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population., Results: Thirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56-84%) with median RFS of 21 months (95% CI, 14-40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs . 66.7%, p = 0.1551) and ≥1 (84.2% vs . 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05-0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15-0.93, p = 0.0351, respectively)., Conclusions: Adjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS., Competing Interests: The authors report following relationships with the companies, none of which has resulted in an actual or potential conflict of interest with regard to this manuscript. HM: Consulting/Advisory board – AstraZeneca, Zentalis; Travel Accommodations: AstraZeneca (IITpresentation at Immuno-oncology conference). BS: Clinical trials funding to the institution – Merck. P. Kasi: Consultancy/advisory board: Taiho (to institution), Ipsen (to institution), Foundation Medicine, Bayer, Axiom, Natera, Roche, IPBA, Merck, QED, Tempus Labs, Daiiche Sankyo, Boston Health Care, Delcath, Eli Lily; Research/Grant Funding: BMS (institution), Advanced Accelerator Applications (institution), Array Biopharma (institution), Tesaro (institution), Boston Scientific (institution), Celgene (institution); Travel Accommodations: AstraZeneca (IITpresentation at Immuno-oncology conference). SJ: Consulting/Advisory board – Adaptimmune; Clinical trials funding to the institution- AstraZeneca, Tesaro, Astex. The remaining 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 © 2021 Mamdani, Schneider, Perkins, Burney, Kasi, Abushahin, Birdas, Kesler, Watkins, Badve, Radovich and Jalal.)