A phase II trial of hepatic ablation of metastases to modulate and enhance immunotherapy response in non-small cell lung cancer (HAMMER-NSCLC).

Background: 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 has shown that liver metastases cause systemic immunosuppression through siphoning neoantigen-specific CD8 + T cells from systemic circulation with subsequent macrophage-mediated intrahepatic death. In preclinical models, 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 (liver SABR) can sensitize tumors to anti-PD-(L)1 in human NSCLC.

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. Patients will be randomized 1:1 to standard-of-care anti-PD-(L)1-based immunotherapy +/- platinum-based chemotherapy (Arm 1) or standard-of-care treatment plus liver 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 liver SABR be completed prior to initiating standard-of-care anti-PD-(L)1 therapy. Liver SABR must be completed prior to the third cycle of anti-PD-(L)1 or within 90 days of anti-PD-(L)1 therapy initiation, whichever is sooner. The primary endpoint is progression-free survival (PFS). Secondary endpoints include the safety/tolerability of liver SABR when added to anti-PD-(L)1-based immunotherapy, overall survival, and hepatic progression. 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%.

Discussion: The HAMMER-NSCLC trial will determine if adding liver SABR to first-line anti-PD-(L)1-based immunotherapy +/- platinum-based chemotherapy can improve median PFS in patients with NSCLC liver metastases.

Trial Registration: NCT05657873, registered 12/12/2022.