Hussein A. Tawbi

Purpose: Postoperative stereotactic radiation (SRT) is the standard-of-care for resected brain metastases. Implantation of cesium-131 collagen tiles (tile-based radiation therapy [TBRT]) initiates focal radiation immediately after resection, potentially offering therapeutic and logistical advantages. Radiation One and Done Study, a randomized, open-label, noninferiority, phase III trial (ClinicalTrials.gov identifier: NCT04365374 ), compared the safety and efficacy of resection with TBRT (R + TBRT) with resection with SRT (R + SRT) for patients with a newly diagnosed brain metastasis indicated for surgical resection. Methods: Across 32 US centers, patients were preoperatively randomly assigned 1:1 to R + TBRT or R + SRT. Any nonresected brain metastases received SRT postoperatively. Co-primary outcomes were time-to-surgical bed recurrence (SBR) and surgical bed recurrence-free survival (SB-RFS). Outcomes were analyzed using Cox proportional hazards models with stratification factors as covariates. Multiplicity was controlled by hierarchical testing. Analyses used the prespecified modified intention-to-treat (mITT) population (patients who underwent surgery, had pathologic confirmation of brain metastasis, and had follow-up information). Results: From April 2021 to August 2025, 230 patients were randomly assigned (115 per arm), 204 of whom (103 R + TBRT, 101 R + SRT) comprised the mITT population. The median follow-up was 12.9 months. The median time-to-SBR was not reached in R + TBRT versus 17.4 months in R + SRT (hazard ratio [HR]: 0.06 [95% CI, 0.01 to 0.46]; P = .0070). SB-RFS was improved with R + TBRT, with a median of not reached versus 10.9 months in R + SRT (HR, 0.48 [95% CI, 0.30 to 0.76]; P = .0021). Overall adverse events did not appear to differ: 83 patients (79.0% [95% CI, 70.0 to 86.4]) in R + TBRT versus 67 patients (80.7% [95% CI, 70.6 to 88.6]) in R + SRT. Conclusion: For patients with newly diagnosed brain metastases requiring resection, R + TBRT significantly improved SBR and SB-RFS, demonstrating both noninferiority and superiority.

B cells and their cellular neighborhoods, i.e., lymphoid aggregates (LA) and tertiary lymphoid structures (TLS), have not been extensively studied in melanoma brain metastases (BM) or lung adenocarcinoma BM, despite their prognostic value and role in immunotherapeutic responses. In this study, we evaluated the prognostic benefit and heterogeneity of B-cell infiltration and LA formation in more than 200 patients with melanoma BM or lung adenocarcinoma BM. We found that LAs were associated with increased intratumoral CD8+ T cells in melanoma BM compared with lung adenocarcinoma BM. Moreover, the presence of LAs was associated with an increased survival benefit in patients with melanoma BM but not in those with lung adenocarcinoma BM. Despite lacking canonical TLS hallmarks, LAs in BM contained proliferating B and T cells with the potential for effector function. Our work has solidified the need for the mechanistic investigation of intracranial B cells and the immune neighborhoods in which they reside. Significance: Among tumor metastases, patients with BM are considered to have the greatest mortality and very limited therapeutic options. This study uncovers immunologically active LAs as potential orchestrators of CD8+ T cell–mediated antitumor immunity in melanoma BM, emphasizing their potential as a therapeutic target within the unique tumor microenvironment of the brain.

Nivolumab plus relatlimab is approved for advanced melanoma based on the RELATIVITY-047 trial; however, long-term data are needed. Here, we report data from RELATIVITY-047 with the longest follow-up at present. In this phase 2–3, double-blind trial, patients with metastatic/unresectable melanoma were randomized 1:1 to nivolumab 480 mg plus relatlimab 160 mg (n = 355) or nivolumab 480 mg (n = 359) intravenously every 4 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints were overall survival (OS), response, and safety. Additional post-hoc analyses such as melanoma-specific survival (MSS), and exploratory biomarker analyses are also reported. This analysis shows clear separation in survival curves with the largest absolute differences to date in PFS, OS, and MSS. In this prespecified 5-year analysis, with a minimum follow-up of 57.3 months, nivolumab plus relatlimab demonstrated continued clinically significant benefit versus nivolumab for PFS (hazard ratio = 0.77; 95% confidence interval: 0.65–0.92), OS (hazard ratio = 0.78; 95% confidence interval: 0.64–0.95), and MSS (hazard ratio = 0.71; 95% confidence interval: 0.57–0.88). The safety profile remained consistent with prior reports. Among biomarker-evaluable patients in the programmed death ligand 1 ≥1% subgroup, analyses revealed an association between worse outcomes with nivolumab and high peripheral or tumor lymphocyte activation gene 3 (LAG-3)⁺ CD8 cell levels. The addition of relatlimab to nivolumab was associated with a lower prevalence of primary resistance than nivolumab alone. These data support the hypothesis that relatlimab can overcome LAG-3–mediated resistance to nivolumab and provides evidence for differential efficacy patterns observed across biomarker subgroups linked to primary versus acquired resistance states. ClinicalTrials.gov identifier: NCT03470922.

Neoadjuvant immune checkpoint inhibitors (ICIs) are standard of care for resectable stage IIIB–D melanoma, but knowledge gaps remain regarding optimal treatment type, long-term survival, postsurgical management and clinical, histopathological or molecular subgroups. We analyzed 1,038 patients treated with neoadjuvant ICIs ( n = 735), BRAF and MEK inhibitors (BRAF/MEKis; n = 119) or ICI plus any targeted therapy (ICI + TT; n = 184) from 26 international sites in both trial (755, 72.7%) and nontrial (283, 27.3%) settings. ICI regimens included anti-programmed cell death protein 1 (PD-1) alone (PD-1 alone; n = 242) and anti-PD-1 plus other immuno-oncology agent(s) (PD-1 + IO; n = 489). Outcomes included major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). An MPR was achieved in 57.8% of patients with ICIs, 51.4% with BRAF/MEKis and 44.6% with ICI + TT. PD-1 + IO elicited higher MPR rates than PD-1 alone (61.4% versus 49.5%). The 5-year RFS rate was 61.0% with PD-1 alone, 73.9% with PD-1 + IO, 37.4% with BRAF/MEKis and 76.4% with ICI + TT; the 5-year OS rates were 83.3%, 87.5%, 69.8% and 83.9%, respectively. ICI-treated patients with MPR had 5-year OS rates of 98.8% with PD-1 alone and 97.9% with PD-1 + IO and gained no benefit from continuing ICIs into the adjuvant setting. Neoadjuvant ICIs were active in BRAF -mutant melanoma (MPR, 46.3%), acral melanoma (38.1%), in-transit metastases (66.7%) and oligometastases (41.2%), although subgroup sizes and relative effectiveness varied. Survival outcomes were excellent with neoadjuvant ICIs, particularly in patients achieving MPR, but poor with BRAF/MEKis and mixed with ICI + TT. Predictive biomarker-driven trials, effective adjuvant strategies and subgroup-specific research are needed for nonresponders.

The COMBI-I trial (ClinicalTrials.gov identifier: NCT02967692 ) evaluating spartalizumab plus dabrafenib and trametinib (sparta-DabTram, n = 267) versus placebo plus dabrafenib and trametinib (placebo-DabTram, n = 265) for BRAF V600–mutant unresectable or metastatic melanoma failed to reach its primary end point of progression-free survival at 24 months. This final analysis reports overall survival (OS) during at least 5 years of extended follow-up. At the end of the trial (August 21, 2024), the median duration of follow-up was 76.9 months (range, 73.7-83.3 months). The median OS was 61.5 months (95% CI, 41.6 to not evaluable) for the sparta-DabTram arm and 41.6 months (95% CI, 30.6 to 56.9) for the placebo-DabTram arm (hazard ratio, 0.760 [95% CI, 0.598 to 0.966]). The safety findings were consistent with the known safety profile for sparta-DabTram. The most common treatment-related adverse event (TRAE) was pyrexia (65.9% v 46.2%, respectively, in the two study arms). Grade ≥3 TRAEs were reported in 57.3% and 36.7% of patients in the two arms, respectively. The combination of sparta-DabTram appears to improve OS compared with dabrafenib and trametinib alone in patients with BRAF V600–mutant metastatic melanoma.

Peripheral blood lymphocyte, monocyte, and platelet dynamics following sotigalimab and pembrolizumab combination treatment

The combination of sotigalimab and pembrolizumab induces broad innate and adaptive immune activation in injected and non-injected tumors

Immunological changes in injected tumors induced by sotigalimab in combination with pembrolizumab, compared to anti-PD-1 monotherapy.

Clinical responses to the combination of sotigalimab and pembrolizumab do not require MHC class II expression or IFN-g–mediated immune activation at baseline