3044 - A Phase II Trial of Hepatic Ablation of Metastases to Modulate and Enhance Immunotherapy Response (HAMMER) in Non-Small Cell Lung Cancer

M. T. McMillan¹, D. R. Gomez², M. Reyngold², C. Hajj², D. A. Roth OBrien¹, C. H. Crane², M. Gönen³, M. Bott⁴, A. J. Schoenfeld⁵, and P. B. Romesser²; ¹Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, ²Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ³Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, ⁴Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, ⁵Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Purpose/Objective(s): Anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-[L]1) immunotherapy promotes systemic anti-tumor immunity through expanding neoantigen-specific CD8+ T cells, but it is less effective in patients with liver metastases. Nearly 20% of non-small cell lung cancer (NSCLC) patients develop liver metastases, and these patients are characterized by fewer and less active effector T cells. Preclinical work investigating this phenomenon has shown that liver metastases cause systemic immunosuppression through siphoning neoantigen-specific CD8+ T cells from systemic circulation with subsequent macrophage-mediated intrahepatic death. Preclinical models have shown that liver metastasis-directed radiotherapy can reverse this systemic immunosuppression and sensitize tumors to anti-PD-(L)1 therapy; however, it is unknown whether liver metastasis-directed stereotactic ablative radiotherapy (L-SABR) can sensitize tumors to anti-PD-(L)1 in human NSCLC. This trial is designed to determine if L-SABR, when added to first-line standard-of-care anti-PD-(L)1-based immunotherapy +/- chemotherapy, can improve median progression-free survival (PFS) in patients with metastatic NSCLC involving the liver. Materials/

Methods: The HAMMER-NSCLC Trial is a randomized phase II study planned to enroll 68 patients with newly diagnosed metastatic NSCLC – without known targetable EGFR, ALK, BRAF, or ROS1 alterations – involving the liver and at least one extrahepatic site. Patients will be randomized 1:1 to standard-of-care anti-PD-(L)1 immunotherapy +/- platinum-based chemotherapy (Arm 1) or standard-of-care treatment plus L-SABR (Arm 2). Patients can be enrolled and randomized up to the start of cycle 3 of immunotherapy. For patients in Arm 2, it is preferred that L-SABR be completed prior to initiating standard-of-care anti-PD-(L)1 therapy. L-SABR must be completed prior to the 3rd cycle of anti-PD-(L)1 or within 45 days of anti-PD-(L)1 therapy initiation, whichever is sooner. The primary endpoint is PFS. Secondary endpoints include the safety and tolerability of L-SABR when added to standard-of-care anti-PD-(L)1 immunotherapy, overall survival, and hepatic progression. Correlative objectives include characterizing how L-SABR remodels the liver tumor immune microenvironment and comprehensively profiling how L-SABR remodels the systemic T cell response. The study needs 68 patients combined in the two arms to demonstrate an improvement in PFS with a hazard ratio of 0.6 to provide 80% power with a one-sided alpha of 10%.
Results: Pending full accrual.
Conclusion: Pending full accrual. The HAMMER-NSCLC Trial (NCT05657873) was activated on 12/9/2022 and recruitment is ongoing.