Dual immune checkpoint inhibition in advanced incurable radioidine-refractory differentiated thyroid carcinoma (RAIR DTC), anaplastic (ATC), and medullary thyroid carcinoma (MTC): Long-term survival results from phase II clinical trial.

6105 Background: Immunoprofiling and preclinical studies with patient derived organotypic tumor spheroids supported therapeutic targeting of programmed death (PD)-1 and cytotoxic T lymphocyte antigen (CTLA)-4 pathways in thyroid tumors. We previously presented initial results of a phase 2 clinical trial evaluating dual immune checkpoint inhibition with nivolumab (N) and ipilimumab (I) in advanced incurable thyroid carcinoma (TC) (ASCO 2020, PMID: 39446365) with data cutoff at 24 months (mo) follow up. Methods: This nonrandomized phase 2 clinical trial evaluated N (3 mg/kg every 2 weeks) + I (1 mg/kg every 6 weeks) in the primary patient population of RAIR DTC, with exploratory cohorts in ATC and MTC. Primary endpoints were objective response rate (ORR), with secondary endpoints of safety, progression-free survival (PFS), and overall survival (OS). Here, we present long term results (data cutoff 12/27/24), with median follow up of 75.3 mo for the overall population. Results: 49 patients (32 RAIR DTC, 10 ATC, and 7 MTC) were evaluable, 51% female, with median age of 65 years (range 30-88). Median duration of follow up (by cohorts) for this analysis was 74.9 mo (range 12.7 - 82.1) for RAIR DTC, 67.6 mo (29.9 - 84.4) for ATC and 81.1 mo (75 - 82.1) for MTC. ORR was 9.4% (in RAIR DTC), 30% (ATC), and 0% (MTC), all partial responses. Previously unreported, median duration of response (DoR) was 30 mo (range: 18.1 – 69.7) for RAIR DTC, and 23.2 mo (9.1 - 73.1) for ATC. Updated median PFS was 4.9 mo (95% CI 2.1, 17.0) for RAIR DTC, 4.3 mo (0.5, NA) for ATC, and 2.1 mo (0.9, 4.0) for MTC. 5-year PFS rates were 14.6% (95% CI 4.3%, 30.9%) for RAIR DTC, and 26.7% (4.8%, 56.3%) for ATC. Updated median OS was 44.6 mo (95% CI 24.6, NA) for RAIR DTC, 13.8 mo (1.2, NA) for ATC, and 46.1 mo (12.2, NA) for MTC. 5-year OS rates were 39.0% (95% CI 22.2%, 55.4%) for RAIR DTC, 30.0% (7.1%, 57.8%) for ATC, and 42.9% (9.8%, 73.4%) for MTC. Conclusions: Exceptionally durable responses were observed in the exploratory cohort of ATC (median DoR: 23.2 mo). To the best of our knowledge, this is the longest follow up reported for patients with aggressive thyroid carcinoma treated with immunotherapy. 5-year OS rate of 30% in incurable ATC is congruent with one prior report of 25.7% at another large volume cancer center (PMID: 3597734), but compares favorably with the historical rates reported for ATC in the SEER database (8% for all stages and 4% for distant metastatic disease). Biomarker studies are currently underway to identify exceptional responders and long-term survivors. Clinical trial information: NCT03246958 . RAIR DTC(N=32) ATC(N=10) Median PFS (95% CI), mo 4.9 (2.1, 17.0) 4.3 (0.5, NA) 5 year PFS (95% CI) 14.6% (4.3%, 30.9%) 26.7% (4.8%, 56.3%) Median OS (95% CI), mo 44.6 (24.6, NA) 13.8 (1.2, NA) 5 year OS (95% CI) 39.0% (22.2%, 55.4%) 30.0% (7.1%, 57.8%)