AREN1721, a randomized phase 2 trial of axitinib+nivolumab combination therapy vs. single agent nivolumab for the treatment of TFE/translocation renal cell carcinoma (tRCC) across all age groups, an NCI National Clinical Trials Network (NCTN) phase 2

4521 Background: tRCC accounts for approximately 50% of pediatric RCC and 1-5% of RCC cases overall. tRCC, driven by TFE3 or TFEb fusions or amplifications ( TFEb ), are often aggressive with no existing standard for systemic therapy. Methods: AREN1721 was a prospective randomized COG-led NCTN phase 2 trial of nivolumab/axitinib combination therapy vs. axitinib alone (closed early for feasibility) vs. nivolumab alone in children and adults with advanced unresectable or metastatic tRCC. Prior exposure to anti-PD1/PDL1 therapies or axitinib was prohibited. The primary endpoint was progression-free survival (PFS), defined as the time from randomization to the earliest of disease progression based on immune-modified RECIST criteria or death. The final protocol version targeted enrollment of 28 eligible patients to detect a hazard ratio (HR) of 0.40 for the comparison of nivolumab/axitinib vs. nivolumab alone using a one-sided log-rank test with alpha = 0.15. Results: Despite aggressive approaches for trial recruitment, AREN1721 was closed after enrolling 15 patients (13 eligible) from 2019 to 2023 secondary to poor accrual. Median age 16 years (range 7-42) with 9/13 age &lt; 18 years; 9/13 were male. Six patients were randomized to nivolumab+axitinib, 2 to axitinib alone, and 5 to nivolumab alone. There were no unexpected toxicities. Thirty-three percent of patients randomized to nivolumab+axitinib experienced partial response, compared to 0% in the other arms, and 0% of patients on the combination arm experienced primary disease progression. Addition of axitinib to nivolumab significantly improved PFS (p = 0.0004), extending median PFS from 1.8 to 10.5 months. Overall survival also improved (p = 0.003) with the addition of axitinib. Conclusions: Nivolumab+axitinib combination therapy was statistically more active than nivolumab single agent therapy, which itself was inactive. Whether anti-PD1 pathway inhibitors add benefit to anti-VEGF therapy for tRCC remains to be determined. Optimizing trial recruitment is critical for this rare but aggressive cancer. Clinical trial information: NCT03595124 . Descriptive statistics by arm. Characteristic Arm A: Axitinib/Nivolumab N = 6 Arm B: Axitinib N = 2 Arm C: Nivolumab N = 5 Overall N = 13 p-value 1 Age (Years) 0.715 Mean (SD) 18 (9) 19 (6) 18 (14) 18 (10) Median (Q1, Q3) 16 (10, 21) 19 (15, 23) 15 (12, 16) 16 (12, 21) Min, Max 9, 32 15, 23 7, 42 7, 42 Age Category &gt;0.999 Age &lt; 18 4 (67%) 1 (50%) 4 (80%) 9 (69%) Age 18+ 2 (33%) 1 (50%) 1 (20%) 4 (31%) Prior Anti-VEGF therapy 1 (17%) 0 (0%) 1 (20%) &gt;0.999 No prior systemic therapy 5 (83%) 2 (100%) 4 (80%) 11 (85%) Best Overall Response 0.019 Partial Response 2 (33%) 0 (0%) 0 (0%) 2 (15%) Stable Disease 4 (67%) 2 (100%) 1 (20%)</