Burotto, Mauricio

Abstract Background: In Part 2 of the phase 2 RELATIVITY-104 study of first-line nivolumab (NIVO) plus relatlimab (RELA) with platinum-doublet chemotherapy (PDCT) vs NIVO + PDCT in patients with metastatic NSCLC, NIVO + RELA + PDCT demonstrated improved clinical benefit, including overall survival, in the prespecified subgroup of tumor PD-L1 expression ≥ 1%, which was further enriched in NSQ tumor histology. Baseline lymphocyte-activation gene 3 (LAG-3) expression was associated with enriched efficacy for both NIVO + RELA + PDCT and NIVO + PDCT. In a comparative transcriptomic analysis, NSQ and squamous tumors demonstrated distinct immune signatures, with NSQ tumors exhibiting higher expression of LAG-3 ligands and greater enrichment for combination therapy benefit by PD-L1 expression. To further elucidate the mechanism of action of NIVO + RELA + PDCT, we report additional exploratory translational data in the PD-L1 ≥ 1% NSQ subgroup for Part 2 of RELATIVITY-104. Methods: Patients with untreated metastatic NSCLC were randomized 1:1 to NIVO 360 mg + RELA 360 mg + PDCT or NIVO 360 mg + PDCT Q3W. Exploratory endpoints included translational analyses in the PD-L1 ≥ 1% NSQ subgroup. Gene expression data from pretreatment tumor RNA sequencing were normalized and analyzed for associations with clinical outcomes. Pre- and on-treatment peripheral blood samples were collected for high-dimensional flow cytometry immunophenotyping using a validated 24-marker LAG-3-specific panel that used drug-tolerant, noncompeting clones for LAG-3, PD-1, and CTLA-4. Statistical associations between biomarkers and clinical outcomes were assessed using logistic regression and Cox proportional hazards models. Data are from the May 2, 2025, database lock. Results: In the NIVO + RELA + PDCT arm, immune signatures demonstrated a significantly lower hazard ratio (HR) in the PD-L1 ≥ 1% NSQ subgroup, while stromal signatures demonstrated a significantly higher HR. T exhausted progenitor signature subsets, as well as ICOS+ CD4+ T cells, at baseline were shown to enrich for survival with NIVO + RELA + PDCT. Clinical benefit was observed across all baseline LAG-3 expression levels (< 1% and ≥ 1%); however, on-treatment increases in LAG-3+ T cells were associated with longer progression-free survival and a higher objective response rate with NIVO + RELA + PDCT. In the NIVO + PDCT arm, increases in LAG-3 cell populations were associated with lower response. Conclusions: In the RELATIVITY-104 study, the on-treatment immune dynamics of LAG-3+ T cells correlated with the benefit of NIVO + RELA + PDCT vs NIVO + PDCT in patients with PD-L1 expression ≥ 1% and NSQ NSCLC. Immune signatures including progenitor T exhausted signatures associated with improved outcomes with NIVO + RELA + PDCT. These data support the mechanistic rationale for adding anti-LAG-3 to anti-PD-1 + PDCT in PD-L1 ≥ 1% NSQ NSCLC. Citation Format: Jaclyn Neely, Annie Yu, Nicolas Girard, Manuel Cobo-Dols, Mauricio Burotto, Luis Paz-Ares, Vamsidhar Velcheti, Martin Reck, Srijata Samanta, Anila Qureshi, Priyanka Kasbekar, Charlie Garnett-Benson. RELATIVITY-104 Part 2: translational analyses in the programmed death ligand 1 (PD-L1) ≥ 1% and non-squamous (NSQ) non-small cell lung cancer (NSCLC) subgroup [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB418.

Abstract Lessons Learned Accrual to renal cell carcinoma trials remains a challenge despite the lack of prolonged response to the available treatments. The observation of three responses among the 30 patients with median progression-free survival and overall survival of 8.3 and 15 months, respectively, indicates the combination has some activity, but it is not sufficient for further development. Background Treatment of metastatic renal cell carcinoma (mRCC) remains suboptimal. Preclinical data have previously shown that ixabepilone, a microtubule-stabilizing agent approved for the treatment of breast cancer, is active in taxane-sensitive and -resistant cells. In this single-arm phase II trial, we investigated a combination of ixabepilone plus bevacizumab in patients with refractory mRCC. Methods We enrolled 30 patients with histologically confirmed mRCC, clear cell subtype, who had not been previously treated with ixabepilone or bevacizumab but had received at least one prior U.S. Food and Drug Administration (FDA)-approved treatment for renal cell carcinoma (RCC). The treatment regimen consisted of 6 mg/m2 ixabepilone per day for 5 days and 15 mg/kg bevacizumab every 21 days. After 6 cycles, the treatment interval could be extended to every 28 days. The primary endpoint was the objective response rate according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and the toxicity of the combination. Results The median number of prior therapies was two (range per patient one to five). Patients received a median of 8 cycles of ixabepilone plus bevacizumab (range 2–54). The median follow-up was 36.4 months (range 23.5–96.5). Nineteen patients (63.3%) had stable disease as a best response. Three patients (10%) had a partial response. The median PFS was 8.3 months (95% confidence interval [CI], 4.9–10.6) and the median OS was 15.0 months (95% CI, 11.3–28.8). The total number of cycle for safety evaluation was 289. Grade 3/4 adverse events (>5% incidence) included lymphopenia (16.7%), hypertension (6.7%), and leukopenia (6.7%). Conclusion The combination of ixabepilone and bevacizumab was well tolerated, with modest activity in second - or later-line mRCC, but it is not recommended as a therapy without further clinical development. Alternative combinations with these agents could be explored in future studies.