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Abstract Background The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs. Methods We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culture-based antibiotic susceptibilities. Results Of the medications assessed, only antibiotics and corticosteroids significantly associated with shorter OS. The hazard ratios (HRs) for antibiotics and corticosteroids were highest near the start of ICI treatment but remained significant when given prior to ICI. Antibiotics and corticosteroids remained significantly associated with OS even when controlling for multiple factors such as Eastern Cooperative Oncology Group performance status, Charlson Comorbidity Index score, and stage. When grouping antibiotics by class, β-lactams showed the strongest association with OS across all tested cancers. Conclusions The timing and strength of the correlations with antibiotics and corticosteroids after controlling for confounding factors are consistent with the microbiome involvement with the response to ICIs across several cancers.

Abstract Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. Despite high rates of response to first-line chemotherapy and radiotherapy, patients with extensive-stage disease eventually relapse, and very few patients survive more than 5 years from diagnosis. Treatment options for recurrent or refractory disease are limited, and the treatments that do exist are associated with significant treatment-related toxicities. Delta-like ligand 3 (DLL3) is an inhibitory Notch ligand that is highly expressed in SCLC and other neuroendocrine tumors but minimally expressed in normal tissues. It is therefore being explored as a potential therapeutic target in SCLC. Here, we review the preclinical and clinical evidence for targeting DLL3 in SCLC and discuss several DLL3-specific therapies being developed for the treatment of SCLC: the antibody-drug conjugate rovalpituzumab tesirine, the bispecific T cell engager immuno-oncology therapy AMG 757, and the chimeric antigen receptor T cell therapy AMG 119.