Merkel cell carcinoma is a skin cancer where the Merkel cells grow out of control. In this excerpt of the transcript from their continuing medical education/nursing continuing professional development (CME/NCPD)–approved activity, Update on Immunotherapeutic Strategies for Advanced Merkel Cell Carcinoma, Shailender Bhatia, MD, Associate Professor at the University of Washington School of Medicine, and Ciara Kelly, MBBCh, BAO, Assistant Attending Physician at Memorial Sloan Kettering Cancer Center, discuss the rarity of Merkel cell carcinoma and the immunotherapeutic options for treatment.
Ciara Kelly, MBBCh, BAO: Merkel cell carcinoma is quite a rare cancer. It's an aggressive form of skin cancer and has a high disease mortality rate in the order of 33%-46%, which is three-fold higher than that which we see with melanoma. In the advanced setting, stage IV disease, the five-year survival rate is less than 20%. Another reason why it's important to be aware of this disease is that its incidence is rising. This has been shown to be associated with our aging population. This is a disease that occurs most commonly in older patients. Our population is now aging, and with that, we're seeing a higher incidence of Merkel cell carcinoma. It's reported that by the year 2025, we will see approximately 3,300 Merkel cell carcinoma cases in the US.
Despite its rarity, it is an excellent model for cancer immunotherapy. Merkel cell carcinoma is an immunogenic cancer. The reason we say that is because it relates to its underlying pathogenesis, in that the majority of Merkel cell carcinomas that we see are associated with a virus called the Merkel cell polyomavirus. The other proportion of patients that we see with Merkel cell without the virus association have a high tumor mutational burden associated with chronic ultraviolet (UV) exposure. We now know, having researched further with respect to treatment options for these patients, particularly those with advanced disease, that immunotherapy with immune checkpoint inhibition works very well for these patients, with response rates in the order of 50%, which is one of the highest we see in patients with solid tumors that are responsive to immune checkpoint inhibition. Therefore, this disease provides a really great opportunity for further correlative studies looking at tumor-specific T cells and trying to identify biomarkers predictive for response to this form of therapy, which may, in fact, be applicable to other tumor types.
Shailender Bhatia, MD: As medical oncologists, we mostly focus on melanoma in our practices, because those are the patients who we tend to see. Sometimes it's easy to forget that the skin is the largest organ in the body. Skin cancers are the most common cancers that occur. The vast majority of skin cancers are basal cell and squamous cell carcinomas, which are dealt with by the dermatologist. But then we have these aggressive nonmelanoma skin cancers like Merkel cell carcinoma and a substantial proportion of cutaneous squamous cells. Dr. Kelly, as you mentioned, all skin cancers, because of their UV-associated tumor mutational burden, are proving to be very immunogenic. We are seeing an increasing role of immunotherapy in pretty much all of these nonmelanoma skin cancers.
Dr. Kelly: With respect to the pathogenesis of this disease, 80% of the cases that we see in the US are associated with a virus called the Merkel cell polyomavirus, which was identified back in 2008. The Merkel cell polyomavirus is quite a prevalent infection. It occurs in childhood, often in the absence of symptoms or signs. Yet despite this, Merkel cell carcinoma is quite rare. How does the virus itself cause such a rare cancer? What we've seen is that the viral DNA integrates itself into the genome of Merkel cell cancer cells. It then interacts with the immune system and has the ability to allow the cancer cells to invade the immune system's defense. It should be recognized as foreign and eradicated, but it has developed complex ways to evade how the immune system would normally respond.
We also see that in Merkel cell carcinoma, the immune system appears to be dysfunctional. We see downregulation of the antigen presentation and we see one pathway on the tumor cells. This is again alluding to how the virus evades the normal effects of the immune system. We also know that intratumoral T cells are very rare in Merkel cell carcinoma. We only see them in approximately 20% of cases. They are associated with better outcomes, but it's quite rare to see this in Merkel cell carcinoma. The tumor-infiltrating lymphocytes that we do see often have an exhausted immune phenotype. All of this lends itself to why we should look at immunotherapy in this disease, which we are already doing, and potentially why we're seeing good responses with immune checkpoint inhibition. We see high levels of programmed death ligand 1 (PD-L1) expression within the Merkel cell. That lends itself to targeting with immune checkpoint inhibition in Merkel cell carcinoma.
Although Merkel cell carcinoma is quite a rare form of cancer, there have been a number of clinical trials exploring immune checkpoint inhibition with monotherapy. Initially in the second-line setting with avelumab, where we saw, in the setting of advanced Merkel cell carcinoma—patients with generally stage IV disease, where they had progressed on prior chemotherapy, be that one line or two or more lines—we saw an objective response rate of 32% in that setting. That led to further investigation of immune checkpoint inhibition in frontline therapy. We have pembrolizumab, where we saw an objective response rate of 56%, and avelumab in the frontline setting, with an initial objective response rate of 62%. Initially, in years gone by, we relied upon chemotherapy to manage patients with advanced Merkel cell carcinoma, where we did see high response rates, but it was not a durable form of treatment. Fortunately, now we have a new treatment with immune checkpoint inhibition, which has now become the standard-of-care frontline therapy for patients with advanced Merkel cell carcinoma. I think that immune checkpoint inhibition has really revolutionized the management of this disease. One of the highest response rates to immune checkpoint inhibition in all solid tumors is seen and witnessed in Merkel cell carcinoma.
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About Dr. Bhatia and Dr. Kelly
Shailender Bhatia, MD, is Director of the Medical and Renal Cancer Team at the Seattle Cancer Care Alliance and an Associate Professor at the University of Washington School of Medicine and Fred Hutchinson Cancer Research Center. His research efforts include clinical trials that aim at improving outcomes in melanoma and Merkel cell carcinoma. He is the principal investigator for several clinical trials that focus on improving the immune response against Merkel cell carcinoma.
Ciara Kelly, MBBCh, BAO, is a medical oncologist at Memorial Sloan Kettering Cancer Center, specializing in Merkel cell carcinoma and bone and soft tissue sarcomas. Her research focuses on developing new and more personalized therapies to treat sarcomas. She is also actively involved in developing and designing clinical trials that look at novel agents that target molecular changes within tumors. Her research work includes studying innovative combination immunotherapy options that would harness patients' immune defenses against their cancers.
Edits have been made to this excerpt for the sake of clarity and brevity. Any views expressed above are the speakers' own and do not necessarily reflect those of i3 Health. Gain additional expert perspectives from Dr. Bhatia and Dr. Kelly by completing the full complimentary CME/NCPD activity.