Pazopanib/Cetuximab Combo Promising in Recurrent, Metastatic Head and Neck Squamous Cell Carcinoma

July 23, 2018

A Washington University School of Medicine team’s findings might inform future research into inhibitors of angiogenesis and PD-1 in head and neck cancer.

Combining the angiogenesis inhibitor pazopanib with EGFR inhibitor cetuximab was feasible in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), according to the findings of an early-phase study by investigators from Washington University School of Medicine, St. Louis, Mo., that was published in Lancet Oncology.

“The results of this trial support further studies to assess angiogenesis inhibitors in combination with targeted drugs in HNSCC,” wrote Douglas Adkins, MD, of Alvin J Siteman Cancer Center, Washington University School of Medicine, and colleagues. “Other reports have linked angiogenesis to resistance to immunotherapy, and the results of this trial might inform development of studies of combination of angiogenesis and PD-1 [programmed death 1] inhibitors in HNSCC.”

According to the study, angiogenesis is a “hallmark” of HNSCC and thought to be a mechanism of resistance to EGFR inhibition. Therefore, Adkins and colleagues sought to investigate that activity of combined angiogenesis and EGFR inhibition in patients with recurrent or metastatic head and neck squamous cell carcinoma.

The initial study was a dose-escalation phase Ib trial that used a 3 + 3 design. The trial included 22 patients with confirmed recurrent or metastatic head and neck squamous cell carcinoma. During this phase, pazopanib was given in 8-week cycles with the dose escalated from 200 mg per day to 800 mg per day, plus cetuximab once per week. The primary endpoint was maximum tolerated dose or recommended phase II dose.

During dose escalation, no maximum tolerated dose was reached. There was one dose-limiting toxicity that occurred with pazopanib at 400 mg (neutropenia with infection), 600 mg (proteinuria), and 800 mg (fatigue). Based on these results, the researchers established 800 mg per day as the phase II dose.

During the expansion cohort phase, an additional 9 patients were enrolled and treated at the phase II dose.

Overall, the most commonly occurring grade 3 or 4 adverse events were hypertension (32%), lymphocyte count decrease (23%), and dysphagia (23%). No treatment-related deaths occurred.

There was encouraging preliminary antitumor activity, the researchers wrote. About one-third (35%) of patients achieved an overall response; 6% of these patients had a complete response and 29% had a partial response. More than half (55%) of patients who had platinum-naive and cetuximab-naive disease experienced tumor response. Additionally, 25% of patients with cetuximab-resistant disease and 28% of patients with platinum-resistant disease also had a tumor response.

“Although cross-trial comparison might be done with caution, in previous studies the overall tumor response with cetuximab monotherapy in patients with platinum-resistant HNSCC was 13%, and median time to progression was 70 days,” the researchers wrote.

A post-hoc analysis of survival showed a median time to progression of 5.3 months and a median overall survival of 9.5 months.

The researchers acknowledged several limitations to the study, including its small size and fairly heterogenous patient population, which they said “did not allow for detection of rare adverse events or adverse events to certain populations.”