PD-1 blockade plus cisplatin-based chemotherapy in patients with small cell/neuroendocrine bladder and prostate cancers

Small cell neuroendocrine cancers share biologic similarities across tissue types, including transient response to platinum-based chemotherapy with rapid progression of disease. We report a phase 1b study of pembrolizumab in combination with platinum-based chemotherapy in 15 patients with stage III-IV small cell bladder (cohort 1) or small cell/neuroendocrine prostate cancers (cohort 2). Overall response rate (ORR) is 43% with two-year overall survival (OS) rate of 86% (95% confidence interval [CI]: 0.63, 1.00) for cohort 1 and 57% (95% CI: 0.30, 1.00) for cohort 2. Treatment is tolerated well with grade 3 or higher adverse events occurring in 40% of patients with no deaths or treatment cessation secondary to toxicity. Single-cell and T cell receptor sequencing of serial peripheral blood samples reveals clonal expansion of diverse T cell repertoire correlating with progression-free survival. Our results demonstrate promising efficacy and safety of this treatment combination and support future investigation of this biomarker. This study was registered at ClinicalTrials.gov ( NCT03582475 ). • Pembrolizumab and chemotherapy show positive efficacy signals • Subset of CD8 + T cells persist and expand over treatment • Highly expanded CD8 + T cells exhibit conserved gene signatures over time • Clonal expansion of T cell repertoire correlates with progression-free survival Gu et al. examine the immunologic basis for clinical responses through single-cell sequencing of serial PBMCs in patients with small cell/neuroendocrine cancers. They show that highly expanded CD8 + T cell clonotypes exhibit a conserved gene signature whose expansion correlates with progression-free survival.