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Clinical Trial
. 2024 Dec 1;10(12):1663-1671.
doi: 10.1001/jamaoncol.2024.4019.

Dual Immune Checkpoint Inhibition in Patients With Aggressive Thyroid Carcinoma: A Phase 2 Nonrandomized Clinical Trial

Kartik Sehgal  1   2   3   4 , Theodora Pappa  1   2   3   4 , Kee-Young Shin  5 , Julia Schiantarelli  1   3 , Mofei Liu  5 , Cora Ricker  1   3 , Naomi R Besson  6 , Stephanie M Jones  6 , Emma L Welsh  6 , Kathleen L Pfaff  6 , Justine A Barletta  3   7 , Jihye Park  1   3 , Brendan Reardon  1   3 , Gerard M Doherty  2   3   8 , Erik K Alexander  2   3   4 , Scott J Rodig  3   6   7 , David A Barbie  1   3   4 , Anne O'Neill  5 , Eliezer Van Allen  1   3   4 , Robert I Haddad  1   2   3   4 , Jochen H Lorch  1   2   9
Affiliations
Clinical Trial

Dual Immune Checkpoint Inhibition in Patients With Aggressive Thyroid Carcinoma: A Phase 2 Nonrandomized Clinical Trial

Kartik Sehgal et al. JAMA Oncol. .

Abstract

Importance: Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition.

Objective: To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma.

Design, setting, and participants: This phase 2 nonrandomized clinical trial enrolled patients with RAIR DTC in a single center from October 2017 to May 2019, with exploratory cohorts in MTC and ATC. The data were analyzed between June 2021 and September 2023.

Intervention: Intravenous nivolumab, 3 mg/kg, every 2 weeks and ipilimumab, 1 mg/kg, every 6 weeks until disease progression, intolerable adverse events, or a maximum duration of 2 years.

Main outcomes and measures: The primary end point of the study was objective response rate (ORR) in RAIR DTC, which was scored according to RECIST (Response Evaluation Criteria in Solid Tumours), version 1.1. Key secondary end points included safety, progression-free survival, overall survival, and biomarker analyses.

Results: A total of 51 patients were registered, and 49 patients were evaluable for analysis. The median (range) age was 65 years (30-88 years), and 25 participants (51%) were female. ORR in the DTC cohort was 9.4% (3/32 [95% CI, 2.8%-28.5%]), with all partial responses in either oncocytic carcinoma (2/6 [33.0%]) or poorly differentiated thyroid carcinoma (1/5 [20.0%]). Clinical benefit rates were 62.5% (20/32) in the overall DTC cohort, including 83.3% (5/6) in oncocytic carcinoma and 40% (2/5) in poorly differentiated thyroid carcinoma. ORR in the exploratory ATC cohort was 30.0% (3/10 [95% CI, 6.7%-65.2%]), with a clinical benefit rates of 50.0% (5/10). No responses were observed in the exploratory MTC cohort. The safety profile was similar to prior reports with dual immune checkpoint inhibition (pruritus, rash, diarrhea, fatigue, and elevation of lipase and liver enzymes). The presence of NRAS tumor genetic sequence variations, but not BRAF V600E, was associated with worse outcomes.

Conclusions and relevance: This phase 2 nonrandomized clinical trial reported clinical activity of dual immune checkpoint inhibition in aggressive thyroid cancer. The study did not meet its end point in the primary population of RAIR DTC and does not support further investigation in non-biomarker-selected DTC. However, the signal observed in ATC may merit further evaluation.

Trial registration: ClinicalTrials.gov Identifier: NCT03246958.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Sehgal reported consulting fees from Scholar Rock, AmeriSourceBergen, Guidepoint Global, and Equinox Group, Inc; personal fees for consulting or advisory board participation from Exelixis Inc, Pfizer, and MedScape; research funding to the institution from Merck; and honoraria from Merck, Gilead, Pri-Med, and BinayTara Foundation. Dr Pappa reported grants from the National Institutes of Health (5K12AR084230-21 and 5K12HD051959-19), Harvard Catalyst, Sperling Family Fellowship, and American Thyroid Association during the study. Dr Reardon reported a pending institutional patent for methods of clinical interpretation. Dr Alexander reported personal fees from Veracyte, Pink Dx, and Roche Diagnostics during the study. Dr Van Allen reported personal fees from Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa Therapeutics, Novartis Institute for Biomedical Research, Riva Therapeutics, and Serinus Bio; grants from BMS, Sanofi, Janssen, and NextPoint, outside the submitted work; and a pending institutional patent on chromatin variants, immunotherapy response, and methods for clinical interpretation. Dr Haddad reported grants from BMS during the study; personal fees from Merck, BMS, Hookipa, Nerus, Galera, ALX, ISA, EMD Serono, Genentech, Pfizer, Incyte, Celgene, Eisai, Nanobiotix, Boehringer Ingelheim, AstraZeneca, and Bayer, outside the submitted work. Dr Lorch reported grants from the Dana-Farber Cancer Institute and Lurie Cancer Center of Northwestern University for financial and drug support for investigator-sponsored trials during the study; and personal fees from Bayer and Adlai Norteye, outside the submitted work. No other disclosures were reported.

Comment in

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