In a single-arm, phase II trial, the programmed death receptor 1 (PD-1) inhibitor, nivolumab, was associated with an overall response rate (ORR) of 24% in patients with treatment-refractory metastatic squamous cell carcinoma of the anal canal (SCCA). SCCA is a rare malignancy typically associated with human papillomavirus (HPV) infection that has no effective treatment options following progression on cisplatin-based chemotherapy. Because HPV causes up-regulation of immune checkpoint proteins such as PD-1, immune checkpoint blockade represents a potentially attractive treatment option.
At a median follow-up of 10.1 months, 9 of 37 (24%) patients treated with nivolumab 3 mg/kg every two weeks had responded, including 2 complete responses (CR) and 7 partial responses (PR). The median duration of response was 5.8 months, but at data cut-off responses were ongoing in 67% of responders. The median progression-free survival (PFS) was 4.1 months and the median overall survival was 11.5 months.
The most common adverse events (AEs) of any grade included anemia, fatigue, and rash. Grade 3 AEs occurred in 5 patients and included anemia, fatigue, rash, and hypothyroidism. There were no serious AEs and no discontinuations due to AEs, though one patient required a treatment break due to grade 2 pneumonitis.
The small sample size and lack of plasma and tissue samples for all patients prevented a thorough analysis of response markers. Among 13 patients with paired tumor biopsies, higher baseline levels of CD8 T cells and higher concentrations of PD-1 and PD-L1 expression (≥40%) in the tumor microenvironment were associated with response.
The authors concluded that these results support further evaluation of nivolumab in this population, with an emphasis on the need to identify biomarkers predictive of response. A second PD-1 inhibitor, pembrolizumab, was also evaluated in patients with SCCA as part of the phase Ib KEYNOTE-028 trial in patients with PD-L1 expressing solid tumors. Of 24 patients with SCCA treated with pembrolizumab, four (17%) patients achieved a confirmed PR.
In an accompanying commentary, Stefano Cascinu, MD (University of Modena, Modena, Italy), discussed the importance of these results in providing a potential treatment option for an otherwise untreatable, incurable disease. He commented that this study opens several new areas for investigation with immunotherapy, including identifying patients more likely to respond to nivolumab treatment and the potential to bring PD-1 inhibitors to earlier lines of therapy to improve long-term outcomes. However, Dr Cascinu cautioned that the utility of immunotherapy, particularly combinations of multiple agents, may be limited by the inflammation associated with HPV infection.