A Phase 1b/2 Study of Atezolizumab in Combination with Thiopurine Therapy in Patients with Metastatic Solid Tumors and Intermediate Tumor Mutational Burden.

PURPOSE: The TEMPLE study was a phase 1b/2 trial evaluating the safety, tolerability, and efficacy of atezolizumab combined with thiopurine therapy in patients with metastatic solid tumors, aim-ing to increase tumor mutational burden (TMB) through single-nucleotide mismatching and neoepitope generation. PATIENTS AND METHODS: Phase 1b was an open-label, single-arm dose de-escalation trial conducted to determine the recommended phase 2 dose (RP2D) of 6-mercaptopurine and 6-thioguanine combined with atezolizumab in adult patients with metastatic solid tumors harboring intermediate TMB (5-10 mut/Mb). Phase 2 used Simon's two-stage design to assess objective response per RECIST v1.1. Secondary endpoints included overall survival and progression-free survival. RESULTS: In phase 1b, the initial dose level proved too toxic in this heavily pretreated population. The subsequent dose level (6MP 37.5 mg/m² QD + 6TG 10.0 mg/m² QD + atezolizumab 1200 mg Q3W) was well tolerated and defined as the RP2D. The most common treatment-related ad-verse events were anorexia, nausea, and fatigue. In phase 2 stage 1, 3 of 13 patients achieved stable disease, while the remaining 10 patients experienced progressive disease. No objective responses were observed, and the trial was ter-minated after stage 1. Translational analyses of serial tumor biopsies using whole-genome and RNA sequencing revealed no definitive shifts in tumor mutational burden or neoepitope gen-eration. CONCLUSIONS: A safe and tolerable dose of 6-mercaptopurine and 6-thioguanine combined with atezolizumab was identified in patients with metastatic solid tumors. Although clinical benefit was limited, the TEMPLE study informs future investigations in patients with less advanced disease.