New Combination Therapy Significantly Improves Survival Rates in Advanced Skin Cancer Patients

Recent research has unveiled promising results in the treatment of advanced cutaneous squamous cell carcinoma (cSCC), a prevalent form of skin cancer. A phase 2 clinical trial demonstrated that patients receiving a combination of the immunotherapy agent avelumab and the targeted therapy cetuximab experienced nearly four times longer median progression-free survival compared to those treated with avelumab alone. These findings were presented at the American Society of Clinical Oncology (ASCO) annual meeting and published in the Journal of Clinical Oncology.

Lead researcher Dan Zandberg, an associate professor of medicine at the University of Pittsburgh, expressed optimism about the trial's implications for future treatment options. He emphasized the need for further studies to potentially integrate this immunotherapy-based combination into standard care for patients facing advanced cSCC.

cSCC is diagnosed in approximately 1.8 million individuals annually in the United States. While about 95% of cases are typically detected early and treated successfully through minor surgical procedures, a small percentage progress to advanced stages, characterized by tumors that cannot be surgically removed or have metastasized. In such instances, the focus of treatment shifts towards prolonging survival rather than achieving a cure.

The study, known as the Alliance A091802 trial, included 57 participants nationwide, with the University of Pittsburgh's UPMC Hillman Cancer Center serving as the primary recruitment site. Participants were divided into two groups: 29 received the combination of avelumab and cetuximab, while 28 were treated with avelumab alone. Notably, the trial featured a crossover design, allowing nine patients from the avelumab-only group to switch to the combination treatment upon disease progression.

Avelumab functions as an immune checkpoint inhibitor, targeting the PD-L1 protein present on cancer cells. This interaction typically inhibits the immune response against cancer; however, avelumab helps to release this brake, enhancing the activity of T cells against tumors. Conversely, cetuximab is a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), a protein crucial for tumor growth and survival. Cetuximab not only activates natural killer cells to combat tumors but also stimulates dendritic cells, which in turn activate T cells. Previous investigations at UPMC Hillman have explored the immune-modulating effects of cetuximab.

The rationale for combining these therapies lies in their complementary mechanisms: while avelumab releases the brakes on the immune system, cetuximab accelerates its activity against tumors. The trial's results indicated a significant improvement in progression-free survival for the combination group, with a median duration of 11 months compared to just 3 months for those receiving avelumab alone.

Despite the impressive results, it is important to note that the trial does not endorse this combination as a standard treatment option. Since the trial's initiation, two other anti-PD-1/PD-L1 therapies--cemiplimab and pembrolizumab--have been approved, demonstrating superior efficacy in treating cSCC.

However, this trial marks a significant milestone, being the first prospective randomized comparison of cetuximab combined with PD-1/PD-L1 blockade versus PD-1/PD-L1 blockade alone in cSCC and head and neck cancers. The findings from this research can guide future clinical trials exploring the benefits of combining cetuximab with either cemiplimab or pembrolizumab to enhance patient outcomes.

Interestingly, patients who crossed over to the combination treatment exhibited progression-free survival rates comparable to those who received the combination from the outset. Current protocols typically recommend transitioning patients who do not respond to immunotherapy with pembrolizumab or cemiplimab to cetuximab or chemotherapy; however, this trial suggests that maintaining immunotherapy while adding cetuximab may yield better results.