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

Autor:	Sehgal K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Thyroid Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Pappa T; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Thyroid Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Shin KY; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Schiantarelli J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Liu M; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Ricker C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Besson NR; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Jones SM; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Welsh EL; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Pfaff KL; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Barletta JA; Harvard Medical School, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Park J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Reardon B; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts., Doherty GM; Thyroid Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts., Alexander EK; Thyroid Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Rodig SJ; Harvard Medical School, Boston, Massachusetts.; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts., Barbie DA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., O'Neill A; Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts., Van Allen E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Haddad RI; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Thyroid Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts.; Harvard Medical School, Boston, Massachusetts.; Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts., Lorch JH; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Thyroid Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts.; Head and Neck/Thyroid Program, Robert H. Lurie Cancer Center of Northwestern University, Chicago, Illinois.
Jazyk:	angličtina
Zdroj:	JAMA oncology [JAMA Oncol] 2024 Oct 24. Date of Electronic Publication: 2024 Oct 24.
DOI:	10.1001/jamaoncol.2024.4019
Abstrakt:	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.
Databáze:	MEDLINE
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