Pryor, David I.

498 Background: Radiotherapy-based metastasis-directed therapy (MDT) has emerged as a viable treatment paradigm for oligometastatic clear cell renal cell carcinoma (ccRCC). However, the optimal integration of MDT with frontline immune checkpoint inhibition (ICI) is unclear, especially in light of the M1 NED subgroup analysis of KEYNOTE-564 suggestive of a larger benefit from adjuvant pembrolizumab. Here, we sought to compare the effects of MDT with or without pembrolizumab on clinical and translational outcomes among patients with oligometastatic ccRCC enrolled on two prospective phase II trials. Methods: We undertook an exploratory cohort study of two prospective, single-arm, investigator-initiated phase II trials. The RAPPORT trial (NCT02855203) assigned 30 patients to radiotherapy-based MDT followed by pembrolizumab 200 mg Q3W for eight cycles (MDT+ICI cohort). The MD Anderson trial (NCT03575611) assigned 121 patients to serial MDT (which was almost exclusively radiotherapy-based) without systemic therapy (MDT cohort). For both trials, eligibility criteria consisted of 1 to 5 ccRCC metastatic lesions amenable to MDT. For the present analysis, the primary endpoint was progression-free survival (PFS), prospectively defined by RECIST v1.1 and analyzed using Cox regression. Peripheral blood flow cytometry obtained at baseline, end of MDT in both cohorts (after 1 cycle of ICI in the MDT+ICI cohort), and after completion of all treatment in both cohorts (3 months in the MDT alone cohort and 12 months in the MDT+ICI cohort) was compared using adjusted linear mixed effect models. Results: A total of 150 patients were included for analysis (MDT+ICI: 30; MDT: 120). Median follow-up time was 34 months (MDT+ICI: 28; MDT: 36). At enrollment, the MDT+ICI cohort had a larger number of metastases (median 3 vs 1). Adjusted for prognostic factors, median PFS was 28 months after MDT+ICI and 17 months after MDT (HR, 0.57; 95% CI: 0.31 to 0.998; P = 0.049). Induction of activated systemic CD8 + T cells (ICOS + ) was observed in both cohorts following MDT; however, this increase was greater in the MDT+ICI cohort. Moreover, there was evidence of decreased systemic CD8 + T cell immunosuppression (CD73 + ) following treatment cessation in the MDT+ICI group. Conclusions: To our knowledge, this is the largest prospective analysis of MDT for ccRCC in the ICI era. The addition of maintenance ICI to MDT may improve clinical outcomes in patients with oligometastatic ccRCC. Greater immunomodulatory signals were observed with MDT+ICI, providing a mechanistic link to the clinical benefits. The ASTROs trial (NCT06004336) randomizing patients with oligometastatic ccRCC to MDT with or without pembrolizumab has been initiated to test the hypotheses generated by the present study. Clinical trial information: NCT02855203 and NCT03575611 .

11504 Background: Surgery & radiation therapy (RT) yield high local control rates for soft tissue sarcoma (STS) of the extremity and limb girdle. However, patients (pts) with high-grade stage III STS are at significant risk for developing metastasis. Median survival for pts with metastatic STS is < 2 years. SARC028 (NCT02301039) evaluated the efficacy of pembrolizumab (pembro) for metastatic STS, showing 20% and 8.7% response rates in undifferentiated pleomorphic sarcoma (UPS) and pleomorphic/dedifferentiated liposarcoma (LPS), respectively. We hypothesized that neoadjuvant pembro with concurrent RT followed by surgery and adjuvant pembro for stage III UPS, including myxofibrosarcoma, or LPS would stimulate an anti-tumor immune response to eliminate micrometastatic disease & improve disease-free survival (DFS). SU2C-SARC032 (NCT03092323) is a multi-institutional, international, randomized phase 2 trial evaluating the safety and efficacy of adding pembro to standard of care (SOC) RT & surgery for pts with stage III UPS or LPS. Methods: Pts aged > 12 yo with stage III (FNCLCC grade 2 or 3) UPS or LPS of the extremity and limb girdle were enrolled. Pts were randomized (1:1, stratified by grade) to neoadjuvant RT (50 Gy/25 fx) then surgery (SOC arm) or neoadjuvant pembro and RT then surgery & adjuvant pembro (EXP arm). Pembro was given 200 mg IV Q3 wk for 3 doses (before, during & after RT) & up to 14 adjuvant cycles. The primary endpoint was 2-yr DFS. Secondary endpoints included local recurrence-free survival (LRFS), distant disease-free survival (DDFS), & overall survival (OS). Target enrollment of 126 evaluable patients (max 144 total) provided 80% power (1-sided α = 0.05) to distinguish between a null hypothesis of 50% 2-yr DFS rate & alternative hypothesis of 75% 2-yr DFS rate by log-rank test, with initial analysis at 45 DFS events. Cox models were stratified by grade; primary analysis was a one-sided stratified log-rank test. Results: Between July 2017-November 2023, 143 patients were enrolled, predominantly with UPS (85%) & grade 3 (64%) histology. Median follow-up for alive patients is 24.1 mo. DFS in the EXP arm is significantly higher than the SOC arm (p = 0.023; HR 0.57, 90% CI: 0.35, 0.91). Estimated 2-yr DFS is 53% (90% CI: 43, 66%) for SOC vs 70% (90% CI: 61, 81%) for EXP arm. Currently, there is no statistically significant difference in LRFS (HR 0.55, 95% CI: 0.21, 1.42), DDFS (HR 0.57, 95% CI: 0.32, 1.01), or OS (HR 0.39, 95% CI: 0.14, 1.12). Pts with grade 3 sarcomas had improved DFS with pembro (HR 0.47, 95% CI: 0.25, 0.89), but no difference in DFS was observed in grade 2 tumors (HR 1.21, 95% CI: 0.35, 4.18). The proportion of patients with grade 3+ adverse events was significantly higher in EXP (52%) vs SOC arm (26%) (p = 0.002). Conclusions: Theaddition of neoadjuvant & adjuvant pembro to RT and surgery significantly improves DFS for pts with stage III UPS and LPS of the extremity and limb girdle. Clinical trial information: NCT03092323 .