Cutaneous Malignancies: Does Immunotherapy Have a Role?
Researchers are working to unravel and understand the mechanisms of skin cancer development and progression to define and test treatments to improve care and increase cure rates. In a session on novel therapies for cutaneous malignancies, work related to cutaneous squamous cell carcinoma (cuSCC) and Merkel cell cancer (MCC) were reviewed.
Skin cancer is among the most highly mutated of all human cancers, with 30,000 to 40,000 mutations per tumor, in contrast with 100-200 mutations in the average leukemia. Ultraviolet (UV) damage is a major driver of the mutations in skin cancer, according to Kenneth Y. Tsai, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, Texas. cuSCC is most closely related to head and neck squamous cell cancer (HNSCC), arising in the oral pharynx, larynx, lung SCC, esophageal SCC, and specific subtypes of breast cancer, based on genetic transcriptional profiling in human and UV-driven mouse models.
Dr. Tsai said that he considers cuSCC an orphan disease. No signaling pathway has been identified as a major driver in cuSCC, because there has not been any consistent approach to molecular phenotyping of tumors before, during, and after treatment. The biology of epidermal growth factor receptor (EGFR) in cuSCC remains unclear, stated Dr. Tsai. Most of the literature in cuSCC describes treatment with multiple active agents, particularly platinum-based agents, but these have been small case reports and series.
Monoclonal antibodies, such as cetuximab and panitumumab, and small molecule kinase activity inhibitors, such as erlotinib and lapatinib, are two broad classes of drugs used for EGFR antagonism. Some small studies have provided some insights into the therapeutic potential of EGFR blockade, but, according to Dr. Tsai, the small numbers of patients limit the enthusiasm regarding the results. Further, the lack of a target or test for mutations in cuSCC means there is no information about who will or will not respond to a treatment.
A small study of 36 patients with cuSCC with at least moderate EGFR-expression treated with cetuximab (initial dose of 400 mg/m2 followed by weekly doses of 250 mg/m2 for at least 6 weeks) as first-line therapy reported a 69% disease control rate at 6 weeks, by Response Evaluation Criteria in Solid Tumors criteria [Maubec E et al. J Clin Oncol 2011]. At 48 weeks, 2 patients had a complete response; 8 patients had a partial response that lasted 6.4 months. In a study with the EGFR tyrosine kinase inhibitor gefitinib as neoadjuvant therapy in 23 patients with aggressive HNSCC, 18.2% had a complete response and 27.3% had a partial response [Lewis CM et al. Clin Cancer Res 2012]. A number of phase 2 studies are underway with high anticipation for the results, although the number of patients enrolled remains small.
Immunotherapy has proven successful in the treatment of melanoma and is now being studied for cuSCC. Both HNSCC and cuSCC have high levels of expression of programmed death-ligand 1 (PD-L1), suggesting this as a potential target in cuSCC.
Dr. Tsai also highlighted one study in their laboratory which has suggested that MEK inhibitors could be a potential treatment for cuSCC, although it is likely that they would used in conjunction with other therapeutic agents. In this work, trametinib and combimetinib, two MEK inhibitors, were tested in a panel of cell lines derived from patients and all of the cells showed a response to treatment.
According to Paul Nghiem, MD, PhD, Fred Hutchinson Cancer Research Center, University of Washington Medicine, Seattle Washington, USA, MCC is two- to threefold more lethal than melanoma, with about a 40% mortality compared to 15% with melanoma. The reported incidence of MCC is increasing, having quadrupled since 1966, with some 2000 new cases annually in the United States.
Although >95% of patients with MCC respond to initial therapy with surgery and radiation therapy, nearly one-half of patients have disease recurrence. For metastatic MCC, the standard of care is cytotoxic chemotherapy. However, the median progression-free survival is only 94 days, and chemotherapy is immunosuppressive and promotes resistance.
A new polyomavirus (PyV) has been identified as being associated with MCC, and genetic mutations in virus-positive and virus-negative MCC, including those driven by UV, are being investigated to identify treatment targets.
Another active avenue of research is PDL-1 blockade and trials are underway. In a recent study by Nghiem and colleagues, pembrolizumab, a PD-1 blocker, was tested as the first systemic treatment for advanced MCC. The multicenter, single-arm, open-label, phase 2 study of 14 patients showed that 2 patients had a complete response and 8 had a partial response, according to RECIST criteria, at the interim analysis reported in September 2015, while 4 patients had progressive disease. Notably, these results were achieved at 90 days, which is the time point when about one-half of patients treated with chemotherapy usually have disease progression.
The 71% response rate in the 14 patients has been more durable than the response rate in patients treated with standard chemotherapy, and Dr. Nghiem characterized it as an extremely high response rate for a solid tumor. Biomarker studies are underway to understand who is and is not responding and understand the role of virus-negative and virus-positive MCC. The study with pembrolizumab has been expanded to 50 patients. Other studies using immunotherapeutics for the treatment of MCC are currently being conducted and it is hoped the results will improve patient outcomes.