Combination therapy extends survival in advanced skin cancer, trial finds
In patients with an advanced type of skin cancer called cutaneous squamous cell carcinoma (cSCC), those who received the combination of the immunotherapy drug avelumab and targeted agent cetuximab had almost four times longer median progression-free survival compared to patients who received avelumab alone, according to the results of a phase 2 trial presented today at the American Society of Clinical Oncology (ASCO) meeting and concurrently published in the Journal of Clinical Oncology.
"It is both an honor and humbling to develop clinical trials that can be potential options for our patients," said lead author and study chair for the trial, Dan Zandberg, M.D., associate professor of medicine at the University of Pittsburgh and medical oncology co-leader of the head and neck cancer program at UPMC Hillman Cancer Center. "My hope is that the insights we made with this trial will lead to additional studies that can ultimately bring a new immunotherapy-based combination into standard of care for patients with advanced cSCC."
cSCC is a common type of skin cancer with about 1.8 million cases diagnosed in the U.S. each year. About 95% of cSCCs are detected early and can be treated with minor surgery. But in rare cases, patients will go on to develop advanced cSCC, which includes locally advanced tumors that cannot be surgically removed and metastatic disease. At this point, the prognosis is poor and treatment is focused on extending survival, not cure.
Zandberg developed the Alliance A091802 (NCT03944941) phase 2 trial in collaboration with the Alliance for Clinical Trials in Oncology through the National Cancer Institute's (NCI) National Clinical Trials Network.
This trial, which was open nationwide, included 57 patients with advanced cSCC. UPMC Hillman was the leading site for patient recruitment, with some of those patients recruited and treated at its network of more than 70 community cancer centers.
Twenty-nine patients received avelumab and cetuximab and 28 received avelumab alone. Because the trial had a crossover design, nine patients in the avelumab group whose cancer progressed switched to the combination group.
Avelumab is an immune checkpoint inhibitor drug that targets a protein found on cancer cells called PD-L1. When PD-L1 binds to a receptor on T cells called PD-1, it acts like a brake, slowing down the cancer-killing activity of T cells. Avelumab and other anti-PD-1/PD-L1 therapies release those brakes.
Cetuximab is a monoclonal antibody that targets EGFR (epidermal growth factor receptor), a protein that plays a critical role in tumor cell growth, proliferation and survival and which is often found in high levels on cSCC cells. It activates natural killer cells, which help fight tumors, and can also activate dendritic cells, which can then stimulate T cells. Previous research done at UPMC Hillman by Robert Ferris, M.D., Ph.D. and his lab helped reveal cetuximab's effect on the immune system.
"The rationale for the combination is that avelumab and other anti-PD-1/PD-L1 therapies have been shown to take the foot off the brake of the immune system, while cetuximab is pressing on the gas pedal—trying to work together to make the immune system go faster and attack the tumor," said Zandberg. "What's exciting is that in this trial the efficacy of the combination suggests that the two drugs were synergistic, rather than just additive."
The study showed that the primary endpoint of progression-free survival was significantly higher in patients who received avelumab plus cetuximab with a median of 11 months compared to just 3 months in patients who received avelumab alone.
Even though avelumab and cetuximab led to an almost quadrupling of median progression-free survival compared to avelumab alone, the trial does not support this combination as a standard treatment for patients. That's because since the trial was launched, two other anti-PD-1/PD-L1 therapies—cemiplimab and pembrolizumab—have been approved and had higher efficacy than avelumab in trials in patients with cSCC.
However, the trial represents the first completed prospective randomized comparison of cetuximab plus blockade of the PD-1/PD-L1 pathway versus blockade of that pathway alone in cSCC or head and neck cancer, where this combination has also shown promise. The trial provides valuable information for future trials.
"These findings highlight the potential benefits of combining cetuximab with an anti-PD-1/PD-L1 therapy and points to the importance of additional clinical trials combining either standard of care pembrolizumab or cemiplimab with cetuximab as a potential way to improve patient outcomes in advanced cSCC," said Zandberg.
Notably, patients in the crossover arm had a similar progression-free survival to those who received the combination from the start. Currently, if a patient fails immunotherapy with pembrolizumab or cemiplimab, they switch to cetuximab or chemotherapy. But this trial suggests that continuing immunotherapy and adding cetuximab could be more beneficial.
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