Pembrolizumab and cabozantinib in recurrent metastatic head and neck squamous cell carcinoma: a phase 2 trial
Nabil F Saba, Conor E Steuer, Asari Ekpenyong, Ashley McCook-Veal, Kelly Magliocca, Mihir Patel, Nicole C Schmitt, William Stokes, James E Bates, Soumon Rudra, Jill Remick, Mark McDonald, Marin Abousaud, Aik Choon Tan, Muhammad Zaki Hidayatullah Fadlullah, Ritu Chaudhary, Jameel Muzaffar, Kedar Kirtane, Yuan Liu, Georgia Z Chen, Dong M Shin, Yong Teng, Christine H Chung, Nabil F Saba, Conor E Steuer, Asari Ekpenyong, Ashley McCook-Veal, Kelly Magliocca, Mihir Patel, Nicole C Schmitt, William Stokes, James E Bates, Soumon Rudra, Jill Remick, Mark McDonald, Marin Abousaud, Aik Choon Tan, Muhammad Zaki Hidayatullah Fadlullah, Ritu Chaudhary, Jameel Muzaffar, Kedar Kirtane, Yuan Liu, Georgia Z Chen, Dong M Shin, Yong Teng, Christine H Chung
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 .
Conflict of interest statement
Competing interests
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.
© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.
Figures
References
- Mody MD, Rocco JW, Yom SS, Haddad RI & Saba NF Head and neck cancer. Lancet 398, 2289–2299 (2021).
- Vermorken JB et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N. Engl. J. Med. 359, 1116–1127 (2008).
- Eberhardt CS et al. Functional HPV-specific PD-1+ stem-like CD8 T cells in head and neck cancer. Nature 597, 279–284 (2021).
- Wieland A et al. Defining HPV-specific B cell responses in patients with head and neck cancer. Nature 597, 274–278 (2021).
- Ferris RL et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 375, 1856–1867 (2016).
- Burtness B et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394, 1915–1928 (2019).
- Saba NF et al. Nivolumab versus investigator’s choice in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: efficacy and safety in CheckMate 141 by age. Oral Oncol. 96, 7–14 (2019).
- Harrington KJ et al. Nivolumab versus standard, single-agent therapy of investigator’s choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol. 18, 1104–1115 (2017).
- Saba NF et al. Targeting angiogenesis in squamous cell carcinoma of the head and neck: opportunities in the immunotherapy era. Cancers 14, 1202 (2022).
- Li Y-L, Zhao H, & Ren X-B Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward? Cancer Biol. Med. 13, 206–214 (2016).
- Peeters MJW, Rahbech A, & Thor Straten P TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting. Cancer Immunol. Immunother. 69, 237–244 (2020).
- George DJ et al. Cabozantinib versus sunitinib for untreated patients with advanced renal cell carcinoma of intermediate or poor risk: subgroup analysis of the alliance A031203 CABOSUN trial. Oncologist 24, 1497–1501 (2019).
- Abou-Alfa GK, Borgman-Hagey AE & Kelley RK Cabozantinib in hepatocellular carcinoma. N. Engl. J. Med. 379, 1384–1385 (2018).
- Stukalin I et al. Real-world outcomes of nivolumab and cabozantinib in metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Curr. Oncol. 26, e175–e179 (2019).
- Brose MS et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 22, 1126–1138 (2021).
- Chen J-Y et al. Cancer-derived VEGF-C increases chemokine production in lymphatic endothelial cells to promote CXCR2-dependent cancer invasion and MDSC recruitment. Cancers 11, 1120 (2019).
- Linger RM, Keating AK, Earp HS & Graham DK TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv. Cancer Res. 100, 35–83 (2008).
- Grüllich C Cabozantinib: multi-kinase inhibitor of MET, AXL, RET, and VEGFR2. Recent Results Cancer Res. 211, 67–75 (2018).
- Desai A & Small EJ Treatment of advanced renal cell carcinoma patients with cabozantinib, an oral multityrosine kinase inhibitor of MET, AXL and VEGF receptors. Future Oncol. 15, 2337–2348 (2019).
- Wu H et al. Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury. J. Neuroinflammation 18, 2 (2021).
- Bergerot P, Lamb P, Wang E & Pal SK Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence. Mol. Cancer Ther. 18, 2185–2193 (2019).
- Chalmers ZR et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 9, 34 (2017).
- Choueiri TK et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 384, 829–841 (2021).
- Jiang A-M et al. Tumor mutation burden, immune cell infiltration, and construction of immune-related genes prognostic model in head and neck cancer. Int. J. Med. Sci. 18, 226–238 (2021).
- Li J et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity 49, 178–193 (2018).
- Liu Z et al. TIGIT and PD-1 expression atlas predicts response to adjuvant chemotherapy and PD-L1 blockade in muscle-invasive bladder cancer. Br. J. Cancer 126, 1310–1317 (2022).
- Du H et al. The co-expression characteristics of LAG3 and PD-1 on the T cells of patients with breast cancer reveal a new therapeutic strategy. Int. Immunopharmacol. 78, 106113 (2020).
- van Boxtel W et al. Excessive toxicity of cabozantinib in a phase II study in patients with recurrent and/or metastatic salivary gland cancer. Eur. J. Cancer 161, 128–137 (2022).
- Emancipator K et al. Comparing programmed death ligand 1 scores for predicting pembrolizumab efficacy in head and neck cancer. Mod. Pathol. 34, 532–541 (2021).
- Xiong Y et al. Nck-associated protein 1 associates with HSP90 to drive metastasis in human non-small-cell lung cancer. J. Exp. Clin. Cancer Res. 38, 122 (2019).
- Zhao X et al. FGFR4 provides the conduit to facilitate FGF19 signaling in breast cancer progression. Mol. Carcinog. 57, 1616–1625 (2018).
- Chen X et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32, 1220–1222 (2016).
- Kim S et al. Strelka2: fast and accurate calling of germline and somatic variants. Nat. Methods 15, 591–594 (2018).
- Knaus BJ & Grünwald NJ vcfr: a package to manipulate and visualize variant call format data in R. Mol. Ecol. Resour. 17, 44–53 (2017).
- Bauml J et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J. Clin. Oncol. 35, 1542–1549 (2017).
- Zhou H, Lee JJ & Yuan Y BOP2: Bayesian optimal design for phase II clinical trials with simple and complex endpoints. Stat. Med. 36, 3302–3314 (2017).
- Liu N, Zhou Y & Lee JJ IPDfromKM: reconstruct individual patient data from published Kaplan–Meier survival curves. BMC Med. Res. Methodol. 21, 111 (2021).
- Schober P & Vetter TR Chi-square tests in medical research. Anesth. Analg. 129, 1193 (2019).
- Hu K & Tong W Which to select when evaluating risk factors for permanent stoma, COX regression model or logistic regression model? Ann. Transl. Med. 9, 1634 (2021).
Source: PubMed