Nivolumab plus ipilimumab in advanced salivary gland cancer: a phase 2 trial

• Published in: Nature medicine Vol. 29; no. 12; pp. 3077 - 3089
• Main Authors: Vos, Joris L., Burman, Bharat, Jain, Swati, Fitzgerald, Conall W. R., Sherman, Eric J., Dunn, Lara A., Fetten, James V., Michel, Loren S., Kriplani, Anuja, Ng, Kenneth K., Eng, Juliana, Tchekmedyian, Vatche, Haque, Sofia, Katabi, Nora, Kuo, Fengshen, Han, Catherine Y., Nadeem, Zaineb, Yang, Wei, Makarov, Vladimir, Srivastava, Raghvendra M., Ostrovnaya, Irina, Prasad, Manu, Zuur, Charlotte L., Riaz, Nadeem, Pfister, David G., Klebanoff, Christopher A., Chan, Timothy A., Ho, Alan L., Morris, Luc G. T.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-12-2023; Nature Publishing Group
• Subjects: 692/699/67/1059/2325; 692/699/67/1536; 692/699/67/1857; 692/699/67/580; 692/699/67/69; Adenoid; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer Research; Carcinoma; CTLA-4 protein; Effectiveness; Exocrine glands; Flow cytometry; Gene sequencing; Histology; Humans; Immune system; Infectious Diseases; Ipilimumab - therapeutic use; Lymphocytes; Lymphocytes T; Metabolic Diseases; Metastases; Metastasis; Molecular Medicine; Neoantigens; Neurosciences; Nivolumab - adverse effects; Oral cancer; Patients; PD-1 protein; Peripheral blood; Receptors, Antigen, T-Cell; Salivary gland; Salivary Gland Neoplasms - chemically induced; Salivary Gland Neoplasms - drug therapy; Salivary Gland Neoplasms - genetics; Salivary glands; T cell receptors; Tumors
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-023-02518-x

Salivary gland cancers (SGCs) are rare, aggressive cancers without effective treatments when metastasized. We conducted a phase 2 trial evaluating nivolumab (nivo, anti-PD-1) and ipilimumab (ipi, anti-CTLA-4) in 64 patients with metastatic SGC enrolled in two histology-based cohorts (32 patients each): adenoid cystic carcinoma (ACC; cohort 1) and other SGCs (cohort 2). The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 (5/32, 16%) but not in cohort 1 (2/32, 6%). Treatment safety/tolerability and progression-free survival (PFS) were secondary endpoints. Treatment-related adverse events grade ≥3 occurred in 24 of 64 (38%) patients across both cohorts, and median PFS was 4.4 months (95% confidence interval (CI): 2.4, 8.3) and 2.2 months (95% CI: 1.8, 5.3) for cohorts 1 and 2, respectively. We present whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumors and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumors universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding ACCs harbored neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo. This study shows that nivo+ipi has limited efficacy in ACC, albeit with infrequent, exceptional responses, and that it could be promising for non-ACC SGCs, particularly salivary duct carcinomas. ClinicalTrials.gov identifier:
NCT03172624
.
Treatment of patients with metastatic salivary gland cancer with anti-PD-1 and anti-CTLA-4 led to encouraging clinical benefit in certain histologic subtypes, with translational analyses showing pre-existing T cell clonal expansion in responding tumors.