Douglas Adkins, MD
The combination of pazopanib (Votrient) and cetuximab (Erbitux) showed a disease control rate of 77% in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), including patients with cetuximab- or platinum-resistant disease, according to a phase I study presented at the 2016 Multidisciplinary Head and Neck Cancer Symposium.
In the trial, which was the first to evaluate pazopanib in HNSCC, the response rate was 32% and the stable disease rate was 45%. Target lesion size decreased in 59% of patients, and 32% experienced a tumor lesion decrease of 40% or more.
“Time to progression was also significantly longer than what one would have expected in these patients if they had been given the traditional chemotherapy approach,” said presenter and first author Douglas Adkins, MD, Washington University School of Medicine, St Louis, Missouri.
Prior studies have shown that angiogenesis could be an important pathway of resistance to EGFR inhibitors, which established the rationale to investigate pazopanib, which targets angiogenesis through multiple targets that include VEGFR. The study used a suspension formulation of pazopanib, since patients may have problems swallowing or gastrostomy tube dependency. The suspension formulation was not found to have altered pharmacokinetics relative to the tablet form.
The ongoing phase I study enrolled 22 patients, whose mean age was 58 years (range, 43-72). The majority of patients were male (77%). ECOG performance status was 0 for 13 of the patients and 1 for 9. Sixteen patients had a history of smoking and 6 did not.
The primary tumor sites were oropharynx (n = 6; 5 positive for p16), oral cavity (n = 8), hypopharynx (n = 4), larynx (n = 3), and nasopharynx (n = 1). The sites of recurrence were local/regional for 2 patients, distant in 11, and both for 9. Due to progression on prior therapy, 12 patients were cetuximab-resistant, 14 were platinum-resistant, and 10 were resistant to both.
The primary endpoint of the study was to establish a maximum tolerable dose (MTD) of pazopanib suspension in combination with fixed dose cetuximab (400 mg/m2
cycle 1 induction followed by weekly doses at 250 mg/m2
). Secondary endpoints assessed response by RECIST 1.1 criteria after each 8-week cycle and safety.
Among patients with cetuximab-resistant HNSCC, the partial response rate was 25%, and the median time-to-progression was 152 days (range, 48-282). Among patients with platinum-resistant HNSCC, the complete response rate was 7% and the partial response rate was 21%. The median time-to-progression was 140 days (range, 13-282).
In addition to RECIST responses, cavitation was observed within the tumors on scans after the first 8 weeks of treatment. “Cavitation in the lesion is a response that I’ve rarely seen with chemotherapy with this disease, but it seems to be a class effect of VEGF inhibitors,” noted Adkins.
The largest dose of pazopanib administered in the study was 800 mg/day, which was established as the MTD; however, dose-limiting toxicities were not seen at this dose. At 400 mg/day of pazopanib, 1 of 6 patients experienced grade 3 neutropenia with infection. At 600 mg/day of pazopanib, 1 of 7 patients experienced grade 3 proteinuria. At 800 mg/day of pazopanib, 1 of 6 patients experienced fatigue.
The adverse events associated with the two therapies were not overlapping. Most adverse events attributed to pazopanib were grade 1 or 2. Fatigue and hypertension were the most common adverse events. One fistula occurred.
An ongoing expansion cohort that aims to enroll 9 patients is following this study. They will receive a fixed dose of pazopanib suspension, based on its MTD, and a standard weekly dose of cetuximab.
Adkins D, Ley J, Wildes T, et al. A phase 1 trial of pazopanib added to cetuximab in patients with incurable head and neck squamous cell carcinoma (HNSCC). Presented at: 2016 Multidisciplinary Head and Neck Cancer Symposium; February 18-20, 2016; Scottsdale, AZ. Abstract 9.
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