Work

A Phase Ib/II Study of Atezolizumab in Combination with Thiopurine Therapy in Patients with Metastatic Solid Tumors and Intermediate Tumor Mutational Burden

Year: 2026

Type: article

Abstract: PURPOSE: The Thiopurine Enhanced Mutations for PD-1/Ligand-1 Efficacy (TEMPLE) study was a phase Ib/II trial evaluating the safety, tolerability, and efficacy of atezolizumab combined with thiopurine therapy in patients with metastatic solid tumors, aiming to increase tumor mutational burden (TMB) through single-nucleotide mismatching and neoepitope generation. PATIENTS AND METHODS: Phase Ib was an open-label, single-arm dose de-escalation trial conducted to determine the recommended phase II dose (RP2D) of 6-mercaptopurine (6MP) and 6-thioguanine (6TG) combined with atezolizumab in adult patients with metastatic solid tumors harboring intermediate TMB (5-10 mutations per megabase). Phase II used a Simon two-stage design to assess objective response per RECIST v1.1. Secondary endpoints included overall survival and progression-free survival. RESULTS: In phase Ib, the initial dose level proved too toxic in this heavily pretreated population. The subsequent dose level (6MP 37.5 mg/m2 every day + 6TG 10 mg/m2 every day + atezolizumab 1,200 mg every 3 weeks) was well tolerated and defined as the RP2D. The most common treatment-related adverse events were anorexia, nausea, and fatigue. In phase II stage 1, 3 of 13 patients achieved stable disease, whereas the remaining 10 patients experienced progressive disease. No objective responses were observed, and the trial was terminated after stage 1. Translational analyses of serial tumor biopsies using whole-genome and RNA sequencing revealed no definitive shifts in TMB or neoepitope generation. CONCLUSIONS: A safe and tolerable dose of 6MP and 6TG 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. SIGNIFICANCE: The TEMPLE study investigated a novel translational strategy aimed at increasing tumor immunogenicity through thiopurine-induced single-nucleotide mismatching, thereby enhancing neoepitope generation and potentially sensitizing tumors to PD-L1 blockade. A safe and tolerable combination treatment regimen was established; however, no objective responses were observed in this heavily pretreated and heterogeneous patient population.

Source: Cancer Research Communications

DOI: 10.1158/2767-9764.crc-26-0210