Journal Article

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

O’Brien, Diana A. Roth, Zinovoy, Melissa, Schoenfeld, Adam J., McMillan, Matthew T., Cuaron, John J., Crane, Christopher H., Gönen, Mithat, Sopka, Dennis M., Williams, Vonetta M., Gomez, Daniel R., Reyngold, Marsha, Kaiser, Adeel, Bott, Matthew, Romesser, Paul B.

2025

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Ablation (Surgery) / Anti-PD-1 / Anti-PD-L1 / Apoptosis / B7-H1 Antigen - antagonists & inhibitors / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Carcinoma, Non-Small-Cell Lung - immunology / Carcinoma, Non-Small-Cell Lung - mortality / Carcinoma, Non-Small-Cell Lung - pathology / Carcinoma, Non-Small-Cell Lung - secondary / Carcinoma, Non-Small-Cell Lung - therapy / Care and treatment / CD8 antigen / Cell death / Chemotherapy / Clinical trial / Clinical Trials, Phase II as Topic / Cytotoxicity / Development and progression / Diagnosis / Effector cells / Health aspects / Health Promotion and Disease Prevention / Humans / Hypotheses / Immune Checkpoint Inhibitors - therapeutic use / Immunosuppression / Immunotherapy / Immunotherapy - methods / Kinases / Liver / Liver cancer / Liver metastasis / Liver Neoplasms - immunology / Liver Neoplasms - secondary / Liver Neoplasms - therapy / Lung cancer / Lung cancer, Non-small cell / Lung Neoplasms - immunology / Lung Neoplasms - mortality / Lung Neoplasms - pathology / Lung Neoplasms - therapy / Lymphocytes / Lymphocytes T / Macrophages / Medical prognosis / Medicine/Public Health / Metastases / Metastasis / Neoantigens / Non-small cell lung cancer / Non-small cell lung carcinoma / Oncology / Patient outcomes / Patients / PD-1 protein / Platinum / Prognosis / Radiation therapy / Radiosurgery - methods / Radiotherapy / Response rates / Small cell lung carcinoma / Standard of care / Study Protocol / Surgical Oncology / Tumors