PT-112 + avelumab

PT-112 + avelumab is a combination therapy being investigated for the treatment of advanced solid tumors. This combination pairs PT-112, a novel platinum-pyrophosphate conjugate that induces immunogenic cell death, with avelumab, an anti-PD-L1 immune checkpoint inhibitor. ## Mechanism of Action PT-112 works by causing immunogenic cell death in cancer cells, leading to the emission of danger signals that initiate anticancer immunity. These signals include calreticulin exposure on dying cell surfaces, as well as ATP and HMGB1 secretion[4]. This process creates an immunostimulatory environment that can enhance the effectiveness of immune checkpoint inhibitors like avelumab. Avelumab is a PD-L1 inhibitor that blocks the interaction between PD-L1 on tumor cells and PD-1 on T cells, preventing the suppression of T cell activity and allowing the immune system to recognize and attack cancer cells. The combination aims to leverage PT-112's ability to induce immunogenic cell death while simultaneously removing immune suppression through PD-L1 blockade with avelumab. ## Clinical Development The combination has been evaluated in a Phase 1b/2a clinical trial (NCT03409458) for patients with advanced solid tumors[1][3][5]. This open-label, multi-center, non-randomized study was conducted in two parts: 1. **Dose Escalation Phase**: Determined the Maximum Tolerated Dose (MTD) and recommended Phase 2 dose (RP2D) of PT-112 when combined with avelumab (administered at a flat dose of 800 mg)[1]. 2. **Dose Confirmation Phase**: Evaluated the combination in patients with non-small cell lung cancer or urothelial carcinoma at or below the MTD[1][5]. Results from the Phase 1b dose escalation study presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 showed that the combination was safe and well-tolerated in 36 heavily pre-treated solid tumor patients who had exhausted standard therapy options[2]. Common treatment-related adverse events included nausea (47%), fatigue (31%), thrombocytopenia (28%), and decreased appetite (28%)[2]. Grade 3-4 treatment-related adverse events occurred in 44% of patients, with thrombocytopenia (17%) being the most frequent[2]. Clinical benefit was observed in patients treated with PT-112 doses ranging from 150 to 360mg/m²[2]. No dose-limiting toxicities occurred during the study[2]. ## Recent Developments While the PT-112 + avelumab combination continues in development, PT-112 as a monotherapy has recently made progress. In May 2025, Promontory Therapeutics announced a successful End of Phase 2 meeting with the FDA regarding PT-112 monotherapy for metastatic castration-resistant prostate cancer (mCRPC)[6][8]. This has paved the way for a registrational Phase 3 study of PT-112 as a standalone treatment for mCRPC. Additionally, immune response biomarker data for PT-112 presented at the 2025 American Association for Cancer Research Annual Meeting demonstrated strong immune activity, showing statistically significant changes such as increases in proliferative and NKp46-positive Natural Killer cells, proliferative CD4+ and CD8+ T cells, and PD-L1-positive monocytes[6]. PT-112 is also being studied as a monotherapy in patients with thymic epithelial tumors, where preliminary results have shown disease stabilization in 89% of evaluable patients[10].