Pembrolizumab and cabozantinib in recurrent metastatic head and neck squamous cell carcinoma: a phase 2 trial

Abstract

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 .

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).

Fig. 1 |. CONSORT diagram.

Study CONSORT diagram.

Fig. 2 |. Response assessments.

a, Waterfall diagram describing the percentage change in tumor size for 33 evaluable patients. (Patients with missing response or percentage tumor size change were excluded.) The red star represent patients with a high median TMB ≥ 6.71; responses noted by HPV or p16 status and programmed cell death 1 ligand 1 (PD-L1)-CPS < 20 or ≥ 20. b, Spider plot curve for 33 patients evaluable for response with highlighted tumor HPV or p16 status. (The ORR was calculated with 95% CI using a one-sided binomial distribution; the biomarker correlation with the ORR was estimated by chi-squared test or logistic regression model.).

Fig. 3 |. Survival assessments.

a, PFS for the 36 treated patients. The median PFS was 14.6 months (95% CI = 8.2–19.6); the 1-year PFS was 54% (95% CI = 31.5%–72%). b, OS of the 36 treated patients. The median OS was 22.3 months (95% CI = 11.7– 32.9) and the 1-year OS was 68.4% (95% CI = 45.1%–83.5%). c, Swimmer plot for patients who responded to therapy. Each bar represents one patient. Patients with arrows represent continued response. A durable responder is a patient with confirmed response for at least 6 months.

Fig. 4 |. Correlative assessments.

a, Univariate Cox proportional-hazards association with OS by patient and clinical characteristics at baseline. Data are presented as the HR and 95% CI by potential confounders. HR < 1 represents a lower hazard; HR > 1 represents a higher hazard. OP, oropharynx carcinoma. b, OS of 36 patients treated with PD-L1-CPS. CPS < 20, median OS of 14.6 months (95% CI = 8.2–NE); 1-year OS of 54.9% (95% CI = 24.5%–31.4%). CPS ≥ 20, median OS of 32.9 months (95% CI = 6.9–32.9); 1-year OS of 83.6% (95% CI = 48.0%–95.7%). Association of OS with CPS was assessed using the Kaplan–Meier method (log-rank test); the significance level was set at P < 0.05 (two-tailed). c, Preexisting CD8⁺ T cell tumor infiltration (25 patients) with representative IHC. Data are presented as mean values ± s.d. The length of the error bars is the s.d. Mean number of CD8⁺ positive cells per field in the PD + SD and PR groups is 52.57 and 137.8, respectively. An unpaired two-tailed t-test was used. WCI, Winship Cancer Institute.