Schröeder, Andreas

Abstract Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, leading to durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the tumor immune microenvironment via pepinemab. Here, we present interim results of the Phase 2 portion of the CLASSICAL-Lung study. This phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced stage (IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Dose escalation was successfully completed, presented previously, and no concerning safety signals have been identified to date. Among 29 evaluable IOF patients, 2 experienced confirmed partial response (PR) with 66% and 52% tumor reduction following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease (SD), and at least 7 patients had durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, and 3 patients had clinical benefit ≥ 1 year. The disease control rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, with reduction or elimination of tumor in 10/11 biopsies from subjects with PR or SD. It was notable that 79% of patients who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Enrollment is complete and this interim analysis suggest the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data, as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Citation Format: Jonathan W. Goldman, Terrence L. Fisher, Elizabeth Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Andreas Schröeder, Kevin Chin, Michael Shafique, Thaddeus Beck, Megan A. Baumgart, Ramaswamy Govindan, Nashat Gabrail, Rachel E. Sanborn, Alexander I. Spira, Nagashree Seetharamu, Yanyan Lou, Aaron S. Mansfield, Maurice Zauderer. Interim results from CLASSICAL-Lung, phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC [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 CT191.

Abstract Panel-based germline genetic testing of established breast and ovarian cancer predisposition genes is widely used in high-risk clinics to inform on risks of breast and ovarian cancer. While most protein truncating mutations identified in predisposition genes are associated with moderate to high risks of these cancers, variants of uncertain significance (VUS), in the form of missense and intronic variants, have an undefined relevance to cancer. Many hundreds of VUS in BRCA1 and BRCA2 identified by clinical genetic testing over the last 20 years still have uncertain clinical relevance. In addition, VUS in other known predisposition genes are being identified by current panel-testing in up to 10% of individuals without BRCA1 or BRCA2 mutations. These VUS cause problems in cancer risk estimation and clinical management of patients undergoing clinical genetic testing. In an effort to evaluate the clinical significance of VUS in cancer predisposition genes we have developed functional assays that characterize the impact of the variants on the functions of the proteins encoded by the predisposition genes. In particular, a homology directed repair reporter assay providing a quantitative measure of homologous recombination repair of DNA double strand breaks has been developed for characterization of VUS in homologous recombination associated genes. When applied to 13 known pathogenic and 30 known neutral variants from the DNA binding domain of BRCA2, this assay exhibits 100% specificity and 100% sensitivity. Based on these results a model estimating the probability of pathogenicity of each BRCA2 VUS was developed. The HDR assay and probability model has now been applied to 230 BRCA2 VUS identified through genetic testing. Here we identify 80 BRCA2 variants that are deficient in HDR activity. We further combined these results with prior probabilities of pathogenicity derived from the sequence based Align GVGD in silico prediction model to estimate the posterior probability of pathogenicity for each VUS. Our results suggest that in the absence of family based segregation information, results from the HDR functional assay and in silico prediction models can be used to predict the pathogenicity of BRCA2 VUS. The assay has also been used to characterize VUS in the PALB2 and RAD51C predisposition genes, leading to identification of a subset of missense variants that are deficient in HDR repair activity and may be associated with increased risk of breast and ovarian cancer. These results will prove useful for improved risk assessment of carriers of these BRCA2, PALB2 and RAD51C variants and their family members and for validation of other approaches to mutation classification. Citation Format: Fergus J. Couch, Hermela Shimelis, Andreas Schroeder, Chunling Hu, Emily Hallberg, Gary Lipton, Edwin Iversen, Noralane M. Lindor. Characterization of variants of uncertain significance (VUS) in breast and ovarian cancer predisposition genes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4685. doi:10.1158/1538-7445.AM2015-4685