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Limited Efficacy of Nivolumab plus Ipilimumab in Adenoid Cystic Carcinomas, but Promising for Salivary Duct Carcinomas

Findings from a phase II study
11 Sep 2023
Head and Neck Cancers

A phase II study of nivolumab plus ipilimumab in patients with recurrent or metastatic salivary gland carcinomas met its primary endpoint in cohort 2 (non-adenoid cystic carcinoma histologies) with a 16% objective response rate (ORR), but not in cohort 1 (adenoid cystic carcinoma) with ORR of just 6%. Efficacy appeared enriched in salivary duct carcinomas with ORR of 25%. These responses highlight the therapeutic potential of immune checkpoint blockade in salivary duct carcinomas and the need for novel strategies to bring this benefit to more patients with other salivary gland carcinoma subtypes.

However, 48% of patients experienced progressive disease (PD) as best of response, and 20% (13 of whom 2 with simultaneous PD) discontinued treatment due to toxicity underlining the need for biomarkers to limit immune checkpoint blockade to those who may experience efficacy and spare others from the toxicities of ineffective treatment. The findings are reported by Dr. Luc G. T. Morris of the Head and Neck Service and Immunogenomic Oncology Platform, Department of Surgery, Memorial Sloan Kettering Carcinoma Center (MSKCC) in New York, NY, US, and colleagues on 24 August 2023 in the Nature Medicine. Drs. Alan L. Ho and Luc G. T. Morris jointly supervised this work.

Salivary gland carcinomas are rare, aggressive malignancies comprising approximately 5% of all head and neck carcinomas and less than 0.5% of carcinomas overall. The World Health Organization recognises 24 histologic subtypes of salivary gland carcinomas, including adenoid cystic carcinoma and salivary duct carcinoma. Upon recurrence or distant metastasis, salivary gland carcinoma is incurable, and patients are treated with palliative intent. Understanding of biology of salivary gland carcinomas is limited and there is paucity of preclinical models.

Immune checkpoint blockade with antibodies targeting the PD1 or PD-L1 has activity in multiple recurrent or metastatic tumour types. However, ORRs in patients with salivary gland carcinomas have been low (4–12% across four studies), perhaps due to the low rate of PD-L1 positivity (23%). In some solid tumours, concurrent blockade of the PD1 and CTLA4 checkpoints yields durable responses. The ORR of 55% observed upon dual immune checkpoint blockade in patients with PD-L1-negative melanoma is notable, considering the low PD-L1 expression in most salivary gland carcinomas. The study team hypothesised that anti-PD1/anti-CTLA4 dual immune checkpoint blockade would be efficacious in patients with recurrent or metastatic salivary gland carcinomas.

The study investigators performed a phase II study evaluating nivolumab and ipilimumab in patients with recurrent or metastatic salivary gland carcinomas enroled in two histology-based cohorts. A total of 32 patients with adenoid cystic carcinoma (cohort 1) and 32 with non-adenoid cystic carcinoma (cohort 2) were included and analyzed in two cohorts, given the distinct clinical behaviour and immunological and genomic profiles of different histologies of salivary gland carcinomas. The primary endpoint was objective response per RECIST version 1.1. Secondary endpoints were safety/tolerability and progression-free survival (PFS).

A key aim of this study was the serial collection of pre-treatment and on-treatment tumour and peripheral blood biospecimens to investigate the mechanistic basis for immune checkpoint blockade efficacy in salivary gland carcinomas. This approach allowed the study team to conduct a comprehensive, integrated analysis linking the clinical efficacy of nivolimuab plus ipiliumab with immunogenomic features, patient-specific neoantigens and T cell dynamics.

The primary efficacy endpoint (≥4 objective responses) was met in cohort 2 among 5 of 32 patients (16%), but not in cohort 1 (2 of 32 patients, 6%). Treatment-related adverse events grade ≥3 occurred in 24 of 64 patients (38%) 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.

The authors presented whole-exome, RNA and T cell receptor (TCR) sequencing data from pre-treatment and on-treatment tumours and immune cell flow cytometry and TCR sequencing from peripheral blood at serial timepoints. Responding tumours universally demonstrated clonal expansion of pre-existing T cells and mutational contraction. Responding adenoid cystic carcinomas harboured neoantigens, including fusion-derived neoepitopes, that induced T cell responses ex vivo.

The authors concluded that together, these results shed light on the clinical and molecular determinants of response to nivolumab plus ipilimumab for patients with salivary gland carcinomas and may help guide the rational development of more effective therapies for this orphan disease. The results show that meaningful responses to nivolumab plus ipilimumab, although uncommon in salivary gland carcinomas, can be profound and durable, even in poorly immune-infiltrated and TMB-low adenoid cystic carcinomas. Other salivary gland carcinoma histologies, particularly salivary duct carcinoma seems more susceptible, justifying further development of immune checkpoint blockade approaches in these histologies.

Empirically testing all potential immune checkpoint blockade combinations is not a feasible drug development strategy for this rare disease. The ability to use data presented herein to prioritise the most biologically rational approaches will enhance the likelihood of improving immunotherapy strategies for this understudied carcinoma.

This study was supported, in part, by US National Institutes of Health (NIH) grants, the Geoffrey Beene Carcinoma Research Center, the Jayme and Peter Flowers Fund, the Sebastian Nativo Fund, Congressionally Directed Medical Research Programs Award and the MSK Population Science Research Program, the Overman Fund, and NIH/NCI Carcinoma Center Support Grant (institutional to MSKCC). Bristol Myers Squibb provided the study drugs and funding (institutional to MSKCC) to support conduct of the clinical study, including research biopsies. In addition, the authors acknowledge using the MSKCC Integrated Genomics Operation Core, funded by NCI Carcinoma Center Support Grant, Cycle for Survival and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.


Vos JL, Burman B, Jain S, et al. Nivolumab plus ipilimumab in advanced salivary gland cancer: a phase 2 trial. Nature Medicine; Published online 24 August 2023. DOI: https://doi.org/10.1038/s41591-023-02518-x

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