Head and neck squamous cell carcinoma (HNSCC) is one of the major causes of cancer-associated morbidity and mortality globally. Recurrent/metastatic HNSCC (RMHNSCC) refers to HNSCC that has recurred after initial treatment. Patients with RMHNSCC are known to have poor prognoses. Depending on the location of the cancer and level of metastases, the 5-year survival rate for metastatic HNSCC ranges from 4 percent to 35 percent. The median survival of patients with RMHNSCC receiving platinum-based chemotherapy is 7.4 months. Treatment options for RMHNSCC are inadequate, leaving a critical unmet need for this patient population.
A Phase II trial investigating the combination regimen of pembrolizumab and cabozantinib produced reassuring results for patients with RMHNSCC. Pembrolizumab is a PD-1 inhibitor that is now standard of care as first-line treatment of head and neck cancer. Cabozantinib is a multiple-receptor tyrosine kinase inhibitor (TKI) shown to reduce tumor growth, metastasis, and angiogenesis and has immuno-modulatory properties (J Clin Oncol 2022; doi: 10.1200/JCO.2022.40.16_suppl.6008).
Study Details
The primary objectives of the open-label, multicenter, single-arm, Phase II trial (NCT03468218) were evaluating the efficacy and safety of pembrolizumab + cabozantinib and assessing the overall response rate (ORR) achieved with the regimen. The trial enrolled patients who had inoperable RMHNSCC with a tumor PD-L1 CPS >1, RECIST 1.1 measurable disease, up to one prior radiation treatment to the head/neck, a life expectancy of >3 months, and an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1.
In total, 36 eligible and evaluable patients were treated with the combination therapy. Of the 36 evaluable patients, 61 percent had cancer in the oropharynx, 16 percent in the nasopharynx, 11 percent in the larynx, 6 percent in the hypopharynx, and 6 percent in the oral cavity. Eighty-nine percent of patients had received prior radiation therapy and all had received prior chemotherapy. The median age was 62 years (range, 54-67); 83 percent of patients were male.
Regarding ECOG performance status, 50 percent of patients had a status of 0 and the remainder had a status of 1. Furthermore, 47 percent of patients had HPV-positive disease, 33 percent had negative status, and 20 percent had unknown status. The study participants were administered intravenous pembrolizumab at 200 mg every 3 weeks and oral cabozantinib at 40 mg daily. Tumor assessments were performed every 9 weeks in accordance with RECIST v1.1 criteria.
The trial met its primary endpoint of ORR per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 45.2 percent with an overall clinical benefit of 90.4 percent observed. At a median follow-up of 12.7 months, the 1-year progression-free survival (PFS) was 52.8 percent (95% CI: 28.8-70.7%; median 14.6 months) with the combination and the 1-year overall survival (OS) was 67.7 percent (95% CI: 42.9-83.6%; median 22.3 months).
Regarding safety, the most common 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 or higher treatment-related AEs comprised of dysphagia (8.3%), hypertension (8.3%), increased aspartate or alanine aminotransferase (8.3%), back pain (5.6%), hypotension (5.6%), oral mucositis (5.6%), anemia (2.8%), and anorexia (2.8%). Cabozantinib presented some tolerability issues and 17 of the 36 patients required dose reductions. AEs leading to discontinuation occurred in 25.0 percent of patients.
Oncology Times connected with senior study author, Nabil F. Saba, MD, FACP, for additional insights on the trial potential implications of the findings on treatment approaches for this patient population. Saba is Professor and Vice Chair of Quality and Safety in the Department of Hematology and Medical Oncology and Adjunct Professor in the Department of Otolaryngology at Emory University School of Medicine; the Lynne and Howard Halpern Chair of Head and Neck Cancer Research; and Co-Director of Head and Neck Cancers in the Multi-Disciplinary Program at Winship Cancer Institute.
Oncology Times: What are the treatment goals for patients with RMHNSCC and some of the treatment challenges?
Saba: "Treatment of patients with recurrent metastatic HNSCC is challenging. Extending survival is usually a primary goal; however, preserving quality of life and functioning is an important goal."
Oncology Times: What was the rationale for combining anti-angiogenics with immune checkpoint inhibitors for this patient population?
Saba: "Anti-angiogenics are known to modulate the immune microenvironment and this has been shown in different tumors. Even though using these agents is not new in HNSCC, the combination with immune checkpoint inhibitors is rather a novel approach in this disease and is receiving quite a bit of attention. It is important to note that not all tyrosine kinase inhibitors are equivalent in their VEGFR inhibition or their overall immune or other targets."
Oncology Times: Looking at the study data, was there anything you found particularly interesting/surprising? What are the potential clinical implications of this combination therapy for patients with RMHNSCC?
Saba: "What was most surprising is the tolerability of the combination coupled with the very encouraging clinical activity namely in controlling the disease for a large number of patients in the study. Even though we did observe side effects related mostly to cabozantinib, these were relatively manageable and most patients were able to resume therapy with the lower dose. We also did not observe a worsening outcome for patients receiving the lower cabozantinib dose. I would also say that our PFS data appears to be very encouraging as it seems to be a clear departure from our observations with single agent PD-1 inhibitors and even chemo-immunotherapy."
Oncology Times: What other clinical trials/developing therapies in metastatic HNSCC are you intrigued by?
Saba: "Certainly immune-on-immune combinations will be very interesting to observe, namely TIGIT and LAG3 targeting. What is attractive in the TKI combinations such as cabozantinib is the non-overlapping toxicities and perhaps that lack of a need for a specific biomarker that would dictate the use (or lack of) these agents, unlike other combination approaches with anti-PD1."
Dibash Kumar Das is a contributing writer.