22 Phase II Study of Cemiplimab ± Fianlimab Following SBRT for Oligometastatic Clear-Cell RCC (LAG-BOOST) (NCT07223541)

Abstract

Abstract Background Oligometastatic clear-cell renal cell carcinoma (ccRCC) is a biologically distinct, often indolent state where metastasis-directed therapy, including metastasectomy or SBRT, provides durable local control and delays systemic therapy. Randomized prospective trial evidence demonstrates a survival benefit with adjuvant programmed cell death-1 (PD-1) inhibition following surgical metastasectomy in oligometastatic ccRCC. However, the role of adjuvant PD-1 inhibition following stereotactic body radiation therapy (SBRT) has not been prospectively evaluated. SBRT induces immunogenic tumor cell death, enhances tumor antigen presentation, and promotes T-cell priming, providing a strong biologic rationale for evaluating PD-1 inhibition following SBRT. Beyond PD-1 blockade alone, lymphocyte activation gene-3 (LAG-3) is an inhibitory immune checkpoint expressed on tumor-infiltrating lymphocytes in ccRCC and contributes to T-cell exhaustion and immune evasion. Dual PD-1 and LAG-3 blockade has demonstrated promising anti-tumor activity with acceptable tolerability in early-phase studies, supporting investigation of strategies to enhance the efficacy of adjuvant PD-1 inhibition following SBRT in oligometastatic disease. Methods LAG-BOOST is a 1:1 randomized, prospective, multicenter, investigator-initiated phase II trial. Eligible patients have histologically confirmed oligometastatic ccRCC, defined as ≤ 5 metastatic lesions by RECIST v1.1, all amenable to SBRT. Following SBRT to all visible lesions, patients are randomized to receive one year of adjuvant PD-1 inhibition (cemiplimab) alone or combined PD-1 and LAG-3 inhibition (cemiplimab and fianlimab). Treatment continues for up to one year or until disease progression, unacceptable toxicity, or withdrawal of consent. Patients must be naïve to systemic therapy for metastatic RCC; prior adjuvant therapy for non-metastatic RCC is permitted in the absence of radiographic disease progression within 12 months of treatment completion. Stratification is based on International Metastatic RCC Database Consortium (IMDC) risk and metastatic burden: (1) favorable or intermediate IMDC risk with 3 or fewer metastatic lesions and no brain metastases versus (2) poor IMDC risk or 4–5 metastatic lesions or the presence of brain metastases. The primary endpoint is 1-year progression-free survival (PFS). Secondary endpoints include safety and tolerability (treatment-related adverse events per CTCAE v5.0), objective response rate by RECIST v1.1, duration of response, disease control rate, and overall survival. The study is powered for H0: 65% versus Ha: 85% 1-year PFS (α = 0.05, power=0.8), with an estimated enrollment of 72 patients. ClinicalTrials.gov identifier: NCT07223541. (Figure 1) Results This study addresses a critical gap in the management of oligometastatic clear cell renal cell carcinoma (ccRCC), a biologically distinct subgroup for which optimal treatment strategies remain undefined. Emerging data suggest that SBRT may potentiate systemic antitumor immunity, particularly when all metastatic sites are treated, yet the optimal immunotherapy combination and treatment sequencing remain unclear. Given the established co-expression of PD-1 and LAG-3 in the ccRCC tumor microenvironment and the proven efficacy of dual checkpoint blockade in other malignancies, the LAG-BOOST trial is uniquely positioned to evaluate a novel, mechanism-driven strategy integrating SBRT with dual PD-1/LAG-3 inhibition. Importantly, LAG-BOOST extends beyond a therapeutic investigation to establish a comprehensive translational platform incorporating LAG-3 and PD-L1 immunohistochemistry, multi-omic tumor profiling, and serial circulating tumor DNA analyses. These integrated approaches aim to distinguish predictive from prognostic biomarkers, refine patient selection, and address the heterogeneity of response to immunotherapy. The trial is currently open and actively enrolling patients. Conclusions N/A DOD CDMRP Funding no22 Figure 1 Study Schema