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Immune Checkpoint Inhibitors
Immune Checkpoint Inhibitors: A New Hope for Patients With Merkel Cell Carcinoma

Released: November 30, 2016

Expiration: November 29, 2017

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I recently was able to share exciting news with my 86-year-old patient with metastatic Merkel cell carcinoma (MCC). “You’ve had a complete response for 6 months, and you can now discontinue therapy and remain on study under close observation.” After progression on frontline chemotherapy, this patient had enrolled in a phase II study investigating avelumab, a novel anti–PD-L1 antibody. She has had a remarkable response and has tolerated therapy well with no adverse events.

MCC: A Desperate Need for New Therapies
MCC is a rare and aggressive cutaneous neuroendocrine carcinoma first described by Cyril Toker in 1972. There are approximately 1300 cases of MCC diagnosed in the United States each year, and the incidence is rising. MCC is more common in older, white men. Risk factors include ultraviolet radiation exposure as well as immunosuppression such as transplantation and HIV infection/AIDS. A polyomavirus is believed to play a role in its pathogenesis and is identified in approximately 80% of patients diagnosed with MCC. MCC is considered to be chemosensitive, with response rates to first-line chemotherapy ranging from 50% to 60%. Unfortunately, the median duration of response is approximately 9 months. Furthermore, chemotherapy has yet to demonstrate an improvement in OS for these patients.

MCC: An Immunogenic Tumor
The association of MCC with immunosuppression and the presence of the polyomavirus implicate the role of the immune system in the pathogenesis and progression of the disease. Specifically, MCC incidence is markedly higher in immunocompromised populations. There are multiple reports of spontaneous tumor resolution and anecdotal responses to immune modulators, and tumor-infiltrating lymphocytes (TIL) have been associated with improved clinical outcomes. Most recently, tumor cell and TIL PD-L1 expression were observed in 49% and 55% of patients, respectively. In tumor specimens that expressed PD-L1, 97% were associated with immune infiltrates.

Frontline Pembrolizumab Achieves High Responses in Treatment-Naive Metastatic MCC
In a phase II study evaluating pembrolizumab in 26 patients with untreated metastatic MCC, the ORR was 56% (4 CR; 10 PR). With a median follow-up of 33 weeks, relapses occurred in 2 of 14 patients who had an initial response. The PFS at 6 months was 67%. Of 26 patients, 17 (65%) had virus-positive tumors, and 14 (56%) had > 1% expression of PD-L1 in the tumor. There was no reported correlation between clinical efficacy and either viral status or PD-L1 expression by IHC. Grade 3/4 treatment-related adverse events were reported in 15% of patients. As a result of this study, pembrolizumab has been added to the NCCN guidelines as a potential systemic treatment option for patients with metastatic MCC.

Avelumab Shows Promise in Chemotherapy-Refractory MCC
In a larger multicenter, open-label phase II study enrolling 35 patients with stage IV chemotherapy-refractory MCC, avelumab demonstrated an ORR of 32% (8 CR; 20 PR). Patients received avelumab 10 mg/kg IV once every 2 weeks. The median duration of response had not yet been reached. The PFS at 6 months was 40% (95% CI: 58% to 78%) with a median OS of 11.3 months. Grade 3/4 treatment-related adverse events were reported in 5% of patients.

Current Approach for Our Patients With Metastatic MCC
These data are practice changing. Patients with metastatic MCC should be considered for treatment with anti–PD-1 therapy provided they have no contraindications to this approach. If an appropriate clinical trial is available, that would be the preferred approach as it allows the field to continue to evolve and optimize our approach. Moving forward, it will be essential to identify biomarkers predictive of benefit from these agents. In addition, one must appreciate that at least 50% of patients do not benefit from single-agent anti–PD-L1 antibodies. Therefore, combination strategies may be necessary to extend this benefit to more patients, understanding the potential for increased risk of immune-mediated adverse events. Nonetheless, it is safe to assume that immune checkpoint inhibitors will soon become the new standard of care for this rare, orphan cancer.

Managing Immune-Related Adverse Events
For practical guidance on managing the unique immune-mediated toxicities associated with immune checkpoint inhibition, try CCO’s new interactive algorithm tool, “The Clinician’s Guide to Managing Immune-Related Adverse Events.” This tool provides evidence-based, expert-recommended management strategies for immune-related adverse events based on the type and severity of the event.

Your Thoughts?
Have you used immune checkpoint inhibitors for your patients with metastatic MCC? If so, which agents have you used and what was the outcome? Please leave your feedback below.

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