Results from a phase 2, investigator-sponsored trial of cabozantinib (Cabometyx®; Exelixis) in combination with pembrolizumab (Keytruda®; Merck & Co.), in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) shows an objective response rate of 54% and an overall clinical benefit rate of 91%.[1]

This is the outcome of the – trial. The data will be presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 3 – 7, 2022, in Chicago, Il.

Head and neck squamous cell carcinoma (HNSCC) comprises head and neck cancers that begin in the squamous cells that line the mucosal surfaces of the head and neck.[2] Accounting for about 90% of all head and neck cancers, HNSCC is classified by its location: it can occur in the oral cavity, oropharynx, nasal cavity and paranasal sinuses, nasopharynx, larynx or hypopharynx.[2][3]

Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16.[4]

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About 50,000 new cases of HNSCC are diagnosed in the U.S. every year.[1] HNSCC is more common among men and people over the age of 50.[5] Depending on the site of the cancer and level of metastases, the five-year survival rate for metastatic HNSCC ranges from 4-35%.[6]

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Nabil F. Saba, M.D., Professor and Vice Chair, Hematology and Medical Oncology, The Lynne and Howard Halpern Chair in Head and Neck Cancer Research, Co-Director of Head and Neck Cancer Multidisciplinary Program, Winship Cancer Institute, Emory University Photo courtesy: © 2018 – 2022 Winship Cancer Institute. Used with permission.

Study results
The trial met its primary endpoint of objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 54%. The overall clinical benefit rate was 91%. At a median follow-up of 10.6 months, the one-year progression-free survival rate was 54.0% (95% confidence interval [CI]: 31.5- 72.0%), and median progression-free survival was 14.6 months. The one-year overall survival (OS) rate was 68.4% (95% CI: 45.1-83.5%; median OS: 22.3 months).

For the 17 patients with a PD-L1 combined positive score (CPS) under 20, the one-year OS rate was 54.9% (95% CI: 24.5-77.5%; median OS: 14.6 months). For the 17 patients with a CPS score of 20 or more, the one-year OS rate was 83.6% (95% CI: 48.0-95.7%; median OS: 32.9 months).

“Metastatic head and neck cancer is a challenging disease to treat, particularly following disease progression after definitive therapy, meaning patients need additional options beyond radiation and chemotherapy,” noted Nabil F. Saba, M.D., Professor and Vice Chair, Hematology and Medical Oncology, The Lynne and Howard Halpern Chair in Head and Neck Cancer Research, Co-Director of Head and Neck Cancer Multidisciplinary Program, Winship Cancer Institute, Emory University.

“These results showing promising clinical activity of cabozantinib in combination with pembrolizumab are encouraging to these patients who face poor outcomes,” added Saba, who iwas the primary investigator of this investigator-sponsored trial.

Treatment options
In this phase 2 trial, eligible patients had recurrent or metastatic HNSCC that was deemed inoperable, with measurable disease per RECIST version 1.1, a life expectancy of at least 3 months and an Eastern Cooperative Group Performance Status of 0 or 1. Of the 36 evaluable patients, 61% had cancer in the oropharynx, 16% in the nasopharynx, 11% in the larynx, 6% in the hypopharynx and 6% in the oral cavity. Eighty-nine percent of patients had received prior radiation therapy and all had received prior chemotherapy.

The most frequent adverse events (AEs) were fatigue (44.4%), diarrhea (33.3%), hypothyroidism (33.3%), constipation (30.6%), dry mouth (27.8%), anorexia (25.0%), headache (25.0%), hypertension (25.0%), hyponatremia (25.0%) and oral mucositis (25.0%). Grade 3/4 treatment-related AEs were aspartate aminotransferase (AST) increase (8.3%), hyponatremia (8.3%), gamma-glutamyl transferase increase (5.6%), lipase increase (5.6%), oral mucositis (5.6%), alanine transaminase/AST increase (2.8%), bilirubin increase (2.8%) and hypertension (2.8%). Dose reductions occurred in 47.2% of patients, and AEs leading to discontinuation occurred in 25.0% of patients.

“Treatment options for patients with metastatic head and neck squamous cell carcinoma are limited, leaving a critical unmet need for this community,” said Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis.

“These data support the further development of a combination regimen of cabozantinib and an immune checkpoint inhibitor in patients with metastatic head and neck carcinoma and we are pleased to share these data at ASCO. Through our research, including our investigator-sponsored trials program, we continue to advance toward our goal of bringing new treatment options to people with difficult-to-treat cancers,” Goodman concluded.

Approval
In the U.S. cabozantinib is approved for the treatment of patients with advanced renal cell carcinoma (RCC), for hepatocellular carcinoma (HCC) who have been previously treated with sorafenib (Nexavar®; Bayer); and for patients with advanced RCC as a first-line treatment in combination with nivolumab (Opdivo®; Bristol-Myers Squibb) as well as for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible.

The drug is not indicated as a treatment for recurrent or metastatic HNSCC.

Clinical trial
Pembrolizumab & Cabozantinib in Patients With Head and Neck Squamous Cell Cancer – NCT03468218

Highlights of prescribing information
Cabozantinib (Cabometyx®; Exelixis)[Prescribing information]
Pembrolizumab (Keytruda®; Merck & Co.)[Prescribing Information]
Sorafenib (Nexavar®; Bayer) [Precscribing Information]
Nivolumab (Opdivo®; Bristol-Myers Squibb)[Prescribing Information]

Reference
[1] Saba NF, Ekpenyong A, McCook-Veal A, Patel M, Schmitt NC, Stokes WA, Bates JA, et al. A phase II trial of pembrolizumab and cabozantinib in patients (pts) with recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). J Clin Oncol 40, 2022 (suppl 16; abstr 6008) | DOI 10.1200/JCO.2022.40.16_suppl.6008
[2] Head and neck squamous cell carcinoma. National Library of Medicine/MedlinePlus. Online. Last accessed on June 3, 2022.
[3] Squamous cell carcinoma of the head and neck. Penn Medicine. Online. Accessed May 2022.
[4] Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020 Nov 26;6(1):92. doi: 10.1038/s41572-020-00224-3. PMID: 33243986; PMCID: PMC7944998.
[5] Head and neck cancers. National Cancer Institute. Online. Last accessed on June 4, 2022
[6] Beckham, TH, Leeman, JE, Xie, P, et al. Long-term survival in patients with metastatic head and neck squamous cell carcinoma treated with metastasis-directed therapy. Br J Cancer. November 2019;121(11):897-903.

Featured image: Attendees during the day at the American Society of Clinical Oncology (ASCO). Courtesy: 2017 – 2022 ASCO/Scott Morgan. Used with permission.

 

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