The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR; is performing a large-scale preclinical study with 39 patient-derived xenograft (PDX) models of rare cancers (including mesothelioma, MPNST, osteosarcoma, Merkel cell carcinoma) treated with 56 novel therapeutic combinations (targeted and cytotoxic agents) in an exploratory, n-of-4 arm, study design. Drug combinations with additive activity may undergo clinical evaluation in patients with rare cancers. PDX tumors are treated with a set of 8 combinations plus relevant vehicle controls while in parallel enough PDXs are serially passaged for the next passage and drug set. Every serial passage undergoes several quality control assessments that serve as go/no-go criteria. Combinations that show promising responses (e.g., regression or durable tumor growth inhibition) are repeated along with the single agent arms to determine if the response is driven by the combination or only one of the agents. We are currently at the half-way point in the overall study and here report interim results for the early combination agents that have single agent data for comparison. In a combination of a VEGFi and EGFRi, 6/37 models achieved a partial regression (30% shrinkage for more than one consecutive time point) and 17/37 had tumor growth inhibition while drug was on board. Single agent studies have been completed for 17/37 models with this combination and 7/9 responses were due to at least an additive effect of the combination. In contrast, while an HDACi + nucleoside analog combination had 16/36 responsive models, response in most of the single agent studies was due to only one of the agents. As part of this study, 3 models have been identified that have responded to at least 50% of the combinations tested possibly indicating a hypersensitive phenotype: two Merkel cell carcinomas (n=28 and 32) and one Neuroendocrine carcinoma (n=27). There is no immediate link between mechanism of action of the agents in the combinations, and the two Merkel cell carcinoma responses only had a moderate overlap. Finally, two Rhabdomyosarcoma models in the study have been the least responsive models to date. Funded by NCI Contract No. HHSN261200800001E

Citation Format: Yvonne A. Evrard, Sergio Y. Alcoser, Suzanne Borgel, Devynn Breen, John Carter, Tiffanie Chase, Alice Chen, Li Chen, Kristen Cooley, Biswajit Das, Emily Delaney, Lyndsay Dutko, Shannon Ecker, Thomas Forbes, Kyle Georgius, Michelle M. Gottholm-Ahalt, Tara Grinnage-Pulley, Sierra Hoffman, Chris Karlovich, Kimberly Klarmann, Shahanawaz Jiwani, Justine Mills, Malorie Morris, Michael Mullendore, Dianne Newton, Gloryvee Rivera, Howard Stotler, Jesse Stottlemyer, Savanna Styers, Cindy R. Timme, Debbie Trail, Shannon Uzelac, Tomas Vilimas, Thomas Walsh, Nikki Walters, P. Mickey Williams, Melinda G. Hollingshead, James H. Doroshow. Single agent response comparisons in a large-scale, preclinical trial of rare cancer PDXs by the National Cancer Institute's patient-derived models repository [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3010.