In a groundbreaking advancement poised to reshape the therapeutic landscape for metastatic non-small cell lung cancer (NSCLC), researchers have launched the HAMMER-NSCLC trial, a phase II study investigating the potential of hepatic stereotactic ablative radiotherapy (SABR) to enhance immunotherapy efficacy. This innovative trial addresses one of the most intractable challenges in oncologic immunotherapy: the systemic immunosuppression engendered by liver metastases, which compromise the responsiveness to immune checkpoint inhibitors, particularly anti-PD-(L)1 therapies.
Non-small cell lung cancer remains a leading cause of cancer-related mortality worldwide, with metastatic dissemination to the liver marking a particularly ominous prognosis. Nearly one-fifth of NSCLC patients develop liver metastases, a subset characterized by diminished quantities and impaired activity of effector CD8+ T cells—key players in tumor immune surveillance and destruction. Prior preclinical research has implicated liver metastases as active agents of systemic immune suppression through mechanisms such as the sequestration of neoantigen-specific cytotoxic T lymphocytes followed by their destruction mediated by intrahepatic macrophages. This immune siphoning results in a systemic depletion of effector cells, thereby attenuating the efficacy of immune checkpoint blockade therapies that rely on robust T cell function.
The novel HAMMER-NSCLC trial emerges directly from these insights by testing a hypothesis borne out in animal models: that targeted ablation of liver metastases using SABR can reverse hepatic-mediated systemic immunosuppression and synergize with anti-PD-(L)1 immunotherapy to improve patient outcomes. SABR is a precision radiotherapeutic approach that delivers ablative doses of radiation to defined extracranial targets with millimetric accuracy, minimizing damage to surrounding normal tissue. In the context of liver metastases, SABR’s capability to induce local tumor destruction while potentially modulating the immune milieu renders it an attractive adjunct to systemic immunotherapy.
This multicenter, randomized phase II trial is designed to enroll 68 patients newly diagnosed with metastatic NSCLC who lack actionable mutations in EGFR, ALK, BRAF, or ROS1 genes—thereby focusing on a population primarily reliant on immunotherapy rather than targeted molecular agents. Eligible participants are randomized evenly to receive either the current standard-of-care anti-PD-(L)1-based immunotherapy with or without platinum-based chemotherapy, or the same systemic regimen combined with liver-directed SABR.
A critical design element of HAMMER-NSCLC is its timing of intervention. For the group receiving SABR, the ablation is ideally completed prior to the initiation of immunotherapy, or at the latest before the third cycle commences, ensuring maximum potential for reversing immunosuppression before systemic therapy intensifies. This temporal sequencing is aligned with preclinical evidence suggesting that immediate disruption of liver metastases dampens the hepatic immune sink effect, allowing for the expansion of neoantigen-specific T cells during immunotherapy.
The primary endpoint of the study, progression-free survival (PFS), was chosen to evaluate whether this combinational approach can significantly delay disease progression compared to immunotherapy alone. With a target hazard ratio of 0.6, the trial aims to demonstrate a meaningful clinical benefit, powered at 80% with a one-sided alpha of 10%. Secondary outcomes include evaluating overall survival, hepatic progression rates, and the safety profile of adding SABR to systemic immunotherapy.
This trial’s scientific premise is deeply rooted in the evolving understanding of the tumor-immune microenvironment and the interplay between metastatic niches and systemic immunity. Liver metastases uniquely modulate systemic immunity because of the liver’s intrinsic immunoregulatory functions, which are essential for maintaining tolerance to gut-derived antigens but unfortunately also create a sanctuary for tumor cells. This immunotolerant environment is manipulated by metastases to promote immune evasion, thereby undermining the systemic anti-tumor immune response.
The integration of SABR represents an attempt to convert this immunosuppressive hepatic environment into one that can facilitate immune reinvigoration. SABR-mediated tumor ablation not only physically destroys metastatic deposits but may also precipitate the release of tumor antigens and pro-inflammatory signals, potentially priming systemic antitumor immune responses. This in situ vaccination effect is hypothesized to amplify the efficacy of anti-PD-(L)1 agents, which act by releasing the brakes on exhausted T cells.
If successful, the implications of HAMMER-NSCLC are far-reaching, potentially redefining the standard of care for NSCLC patients with liver metastases. Current immunotherapy regimens achieve remarkable responses in many patients, yet those with hepatic involvement remain an underserved group with limited complete responses and shortened survival. By demonstrating that targeted liver SABR can rescue the immunotherapeutic response in this subgroup, the study could catalyze a paradigm shift toward multidisciplinary treatment strategies combining localized tumor ablation with systemic immunomodulation.
Moreover, the trial will provide critical data on the safety and tolerability of combining liver SABR with anti-PD-(L)1 treatments, addressing concerns about potential additive toxicities such as radiation-induced liver injury or exacerbated immune-related adverse events. This is especially pertinent given the delicate balance of achieving potent anticancer immunity without provoking deleterious systemic immune activation.
Beyond NSCLC, the biological insights gained from HAMMER-NSCLC could illuminate therapeutic avenues in other malignancies where liver metastases drive immunosuppression, such as colorectal and pancreatic cancers. Understanding how hepatic-directed therapies intersect with immunotherapy could foster novel combinatorial regimens boosting systemic antitumor immunity across cancer types.
The trial’s meticulous design incorporates flexibility to enroll patients up to the initiation of the third immunotherapy cycle, increasing accessibility and feasibility across clinical settings. This pragmatic element enhances the potential for real-world applicability and rapid translation of results into clinical practice.
Importantly, the study excludes patients with targetable mutations to preserve a homogeneous cohort reliant on immunotherapy-based treatments. This ensures that observed outcomes can be attributed primarily to the combination of SABR and immune checkpoint blockade, reducing confounding from targeted therapies known to influence disease course distinctly.
The focus on progression-free survival as the primary endpoint underscores the urgency to extend the time during which patients remain free of disease progression, thereby improving quality of life and possibly providing a window for later therapeutic interventions. Secondary endpoints such as overall survival and hepatic progression rates will further elucidate the durability of responses and the specific impact on liver metastases, which often dictate clinical deterioration.
The trial is registered under NCT05657873, reflecting contemporary standards in clinical transparency and rigor. As recruitment proceeds, clinicians and researchers alike await pivotal data that could validate hepatic SABR as a crucial adjunct in immunotherapy protocols.
In an era where precision oncology increasingly hinges on nuanced understanding of tumor-immune interactions within metastatic niches, HAMMER-NSCLC exemplifies a bold translational leap. Should the hypothesis prove correct, this approach could unlock new therapeutic windows for patients whose disease has hitherto been refractory to immune-based strategies, heralding a new chapter in the fight against metastatic lung cancer.
As the oncology community watches closely, the success of HAMMER-NSCLC may inspire analogous investigations integrating localized ablative modalities with systemic immunotherapies, ultimately transforming metastatic cancer from an incurable disease state to a manageable chronic condition through synergistic multimodal treatment.
Subject of Research:
Enhancing immunotherapy efficacy in metastatic non-small cell lung cancer through hepatic stereotactic ablative radiotherapy targeting liver metastases.
Article Title:
A phase II trial of hepatic ablation of metastases to modulate and enhance immunotherapy response in non-small cell lung cancer (HAMMER-NSCLC).
Article References:
McMillan, M.T., Reyngold, M., Crane, C.H. et al. A phase II trial of hepatic ablation of metastases to modulate and enhance immunotherapy response in non-small cell lung cancer (HAMMER-NSCLC). BMC Cancer 25, 1408 (2025). https://doi.org/10.1186/s12885-025-14779-5
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