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Background: At the last update of the TERAVOLT registry, patients with thoracic malignancies and COVID-19 showed a high mortality rate (35.5% overall and 31% due to COVID-19) compared to the general population and to other solid tumors. Major determinants of mortality were age, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), and previous administration of chemotherapy. No cancer-specific data are available with respect to small-cell lung cancer (SCLC) and other rare thoracic malignancies. Methods: TERAVOLT is an international, multicenter observational registry launched to collect data on patients with thoracic malignancies diagnosed with COVID-19 infection. Risk factors for hospitalization and mortality were identified by Wilcoxon rank sum tests (continuous variables) or χ2 tests (categorical variables). Here we present the subgroup analyses of SCLC and other rare thoracic malignancies, including malignant pleural mesothelioma (MPM), thymic carcinoma/thymoma, and carcinoid/neuroendocrine lung tumors. Results: As of June 4th, 2020, a total of 581 patients with COVID-19 and thoracic cancers have been entered; among them, 66 (11%) were SCLC, 22 (4%) were MPM, 18 (3%) were thymic carcinoma/thymoma, 12 (2%) were carcinoid/neuroendocrine lung tumors, and 442 (76%) NSCLC; 21 were an unknown type. Among SCLC patients, 54% were > 65 years old, 56% were males, 98% were current/former smokers, 31% had an ECOG-PS ≥ 2, 67% had stage IV disease, 82% were on current oncologic treatment at the COVID-19 diagnosis, and 58% were receiving chemotherapy alone or in combination with immune checkpoint inhibitors. Among other non-NSCLC patients, 56% were > 65 years old, 56% were males, 69% were current/former smokers, 24% had an ECOG-PS ≥ 2, 50% had stage IV disease, 52% were on current oncologic treatment at the COVID-19 diagnosis, and 37% were receiving chemotherapy alone or in combination with immune checkpoint inhibitors. Overall, 79.7% of the patients required hospitalization, 15.4% were admitted to an ICU, and 39.8% died (36.2% due to COVID-19). Among SCLC patients, 74.2% required hospitalization, 14.3% were admitted to an ICU, and 42.2% died (37.5% due to COVID-19). Among SCLC patients, age > 65 years old (p=0.81), gender (p=0.71), smoking status (p=1.0), ECOG-PS ≥ 2(p=0.17), disease stage of IV (p=0.37), and having received chemotherapy alone or with checkpoint inhibitors (p=0.84) were not associated with mortality. Conclusions: This analysis confirmed that patients with thoracic malignancies have a high mortality and risk for hospitalization due to COVID-19 overall. SCLC patients showed the highest mortality rate among thoracic cancer patients. Citation Format: Alessio Cortellini, Anne-Marie C. Dingemans, Oscar Arrieta, Javier Baena, Matteo Brighenti, Enriqueta Felip, Marina Chiara Garassino, Pilar Garrido, Carlo Genova, Federica Grosso, Leora Horn, Li-Ching Huang, Jan Van Meerbeeck, Solange Peters, Ernest Nadal, Jacobo Rogado, Yu Shyr, Marcello Tiseo, Valter Torri, Annalisa Trama, Heather Wakelee, Jennifer G Whisenant, Giuseppe Viscardi, Fabrice Barlesi, Sanjay Popat. Thoracic cancers international COVID-19 collaboration (TERAVOLT): Small-cell lung cancer and other rare thoracic malignancies [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S12-03.

Background: HPD was described in ≃10-25% of NSCLC pts upon single-agent ICI and correlated with poor prognosis. High circulating neutrophil count and neutrophils/lymphocytes ratio were associated with shorter survival and HPD in aNSCLC pts. In mouse lung cancer models, interleukin-17 (IL-17) promoted tumor growth upon ICI through increased intratumoral neutrophils. The role of specific circulating and/or tumor-associated neutrophil populations in driving HPD is unknown. Methods: aNSCLC pts treated with ICI and enrolled in a prospective monocentric study were assessed for HPD and circulating neutrophils' phenotype. HPD required 3 tumor measurements (2 before ICI, 1 upon ICI) and was defined as delta tumor growth rate (TGR) TGR (TGR upon ICI - TGR before ICI) >50% and/or TGR ratio (TGR upon ICI/ TGR before ICI) ≥2. Survival curves were estimated by Kaplan Meier and compared by log-rank, correlations with categorical/continuous variables were performed by Fisher/Mann-Whitney tests. The phenotype of circulating low density neutrophils (LDNs) was assessed by flow cytometry (FC) on peripheral blood mononuclear cells from fresh blood samples. Mature and immature LDNs were defined according to the expression of CD10 on CD66b+CD15+ cells, being immature the CD10− neutrophil population. The capacity of immune competent mice to undergo HPD upon anti-PD-1 treatment was further tested in C57BL/6 mice bearing Lewis Lung Carcinoma and treated with anti-murine PD-1. Tumor associated neutrophils' phenotype was assessed by FC analysis. Results: Of 46 aNSCLC, 85% were >65 years, 72% had adenocarcinoma histology, 89% stage IV, 22% had PD-L1 on tumor cells ≥50%, 72% received 1st line ICI. 19 (41%) pts had progression (PD) by RECIST, 4 (9%) pts were HPD by TGR ratio and/or delta-TGR. HPD [4.1 (95% CI 3.1-5) months] correlated with poorer median overall survival compared to non-HPD [6.9 (95% CI 6.1-7.8) months, p=0.03] and to PD pts [4.7 (95% CI 3.2-6.1) months, p=0.8]. Before ICI initiation, the median percentage of circulating immature CD10− CD15+ CD66b+ LDNs was significantly higher in HPD [36.6 (min 29.2; max 64.5)] compared to both non-HPD [8.9 (min 0; max 70.4); p=0.01] and PD non-HPD pts [10.1 (min 0; max 70.4), p=0.04]. HPD defined by TGR ratio and/or delta-TGR occurred in 3 (12.5%) out of 24 immune competent mice treated with anti-murine PD-1. The mean of Gr1highLy6Clow IL-17+ tumor associated neutrophils was significantly higher in HPD compared to non-HPD mice [0.25 (min 0.14; max 0.63) vs 0.06 (min 0.02; max 0.32), p=0.03]. Conclusions: Circulating immature CD10− LDNs and tumor associated IL-17+ neutrophils correlate with HPD upon ICI in aNSCLC pts and in vivo models, respectively. Characterization of neutrophils' functional properties in HPD pts and in vivo models is currently ongoing. Citation Format: Roberto Ferrara, Claudia Proto, Giuseppe Lo Russo, Diego Signorelli, Arsela Prelaj, Giulia Galli, Nicoletta Zilembo, Alessandro De Toma, Giuseppe Viscardi, Riccardo Lobefaro, Marta Brambilla, Monica Ganzinelli, Giuliano Molino, Giovanna Talarico, Marina Chiara Garassino, Mario Colombo, Sabina Sangaletti. Circulating and tumor associated neutrophil subtypes correlate with hyperprogressive disease (HPD) upon immunecheckpoint inhibitors (ICI) in advanced non-small cell lung cancer (aNSCLC) patients (pts) and in vivo models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4480.