Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and overall survival and performed correlative studies with PDL-1 and combined positive score, CD8+ T cell infiltration and tumor mutational burden. A total of 50 patients were screened and 36 were enrolled with 33 evaluable for response. The primary end point was met, with 17 out of 33 patients having a partial response (52%) and 13 (39%) stable disease with an overall clinical benefit rate of 91%. Median and 1-year overall survival were 22.3 months (95% confidence interval (CI) = 11.7–32.9) and 68.4% (95% CI = 45.1%–83.5%), respectively. Median and 1-year progression-free survival were 14.6 months (95% CI = 8.2–19.6) and 54% (95% CI = 31.5%–72%), respectively. Grade 3 or higher treatment-related adverse events included increased aspartate aminotransferase (n = 2, 5.6%). In 16 patients (44.4%), the dose of cabozantinib was reduced to 20 mg daily. The overall response rate correlated positively with baseline CD8+ T cell infiltration. There was no observed correlation between tumor mutational burden and clinical outcome. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC. Further investigation of similar combinations are needed in RMHNSCC. The trial is registered at ClinicalTrials.gov under registration no. NCT03468218.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author upon written request and clarification from the requesting party as to how the data will be used. Requests for data sharing will be responded to within 2 weeks. The WES data has been submitted to the SRA. The full study protocol is available as SupplementaryInformation.
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This research was supported by a grant from Exelixis to N.F.S. The research reported in this publication was supported in part by the Biostatistics Shared Resource of Winship Cancer Institute of Emory University and National Institutes of Health (IH)/NCI under award no. P30CA138292. The computational resources used were partially funded by the NIH Shared Instrumentation grant no. 1S10OD021644-01A1; this research was partially supported by a Huntsman Cancer Institute at the University of Utah Cancer Center Support grant no. P30CA042014, the National Institute of Dental and Craniofacial Research (no. R01DE030508 to A.C.T. and C.H.C.) and the James and Esther King Biomedical Research grant (no. 21K04 to C.H.C. and A.C.T.). The biomarker study was partially supported by a Winship Invest$ Team Science Award (to Y.T. and N.F.S.), I3 Nexus award from Emory School of Medicine (to Y.T. and N.F.S.) and the National Institute of Dental and Craniofacial Research grant no. R01DE028351 (to Y.T.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors thank A. Hammond for her editorial feedback.
N.F.S. reports advisory roles for Merck, AZ, Eisai, Exelixis, Vaccinex, BNT and CUE. J.E.B. reports advisory roles for Galera Therapeutics and Castle Biosciences. N.C.S. reports research funding from Astex. C.H.C. reports advisory board participation for Merck, Exelixis, Fulgent, Genmab and Brooklyn ImmunoTherapeutics. The other authors declare no competing interests.
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Extended Data Fig. 1 Survival outcomes by T and N stage.
Overall survival by T (a) and N (b) stage (p=0.891, p=0.550 respectively), and progression-free survival by T (c) and N (d) stage (p=0.599, p=0.732 respectively).
Extended Data Fig. 2 Survival outcomes by response and smoking history.
PFS (a) and OS (b) in responders versus non-responders (p=0.028 and p=0.3347 respectively). (c) OS by smoking history (former or current smokers versus never smokers) (p=0.442).
Extended Data Fig. 3 Tumor mutational burdens for HNSCC patients.
Distribution of the TMB (Mut/MB) computed for the 16 HNSCC patients with sufficient tumor sample. The red line indicates the median of TMB for these patients, which is 6.71/MB.
Extended Data Fig. 4 Survival outcomes by tumor mutation burden.
(a) Overall survival and (b) Progression-free survival by tumor mutation burden (TMB).
Clinical trial protocol.
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Saba, N.F., Steuer, C.E., Ekpenyong, A. et al. Pembrolizumab and cabozantinib in recurrent metastatic head and neck squamous cell carcinoma: a phase 2 trial. Nat Med 29, 880–887 (2023). https://doi.org/10.1038/s41591-023-02275-x