Division of Medical Oncology
Department of Medicine
University of Washington
Seattle Cancer Care Alliance
Fred Hutchinson Cancer Research Center
Shailender Bhatia, MD, has disclosed he has received consulting fees from Genentech and participated without compensation in an advisory board for EMD Serono.
In December 2014, I saw a 56-year-old woman in my clinic for rapidly growing liver metastases from Merkel cell carcinoma (MCC). She had been diagnosed with a primary MCC lesion on her left chest in July 2014, and the staging FDG PET scan had shown at least 5 masses scattered throughout both liver lobes, which a biopsy confirmed to be metastatic MCC. Although her skin and some liver lesions regressed after cytotoxic chemotherapy, 2 of the liver lesions had grown. In addition, she was suffering from severe fatigue, nausea, vomiting, and alopecia from the chemotherapy.
After we discussed various options, she decided to enroll on a clinical trial investigating avelumab—an investigational anti–PD-L1 antibody—in patients with metastatic MCC who had progressed on chemotherapy. Just before she started treatment with avelumab in December 2014, her restaging scan showed rapid growth of the liver lesions. She also reported increasing pain in the right upper quadrant of her abdomen and had new, mild liver transaminase elevation as well.
She received her first avelumab dose in January 2015. Her scan 6 weeks later revealed an impressive PR per RECIST 1.1, with approximately 45% regression in target lesions. Now, 2 years later, she is still receiving avelumab with no sign of progression and a near CR, comprising approximately 80% regression. I am glad to say that she is tolerating therapy exceedingly well and is enjoying an excellent quality of life.
Metastatic MCC: A Challenging Disease
Between its poor outcomes including short OS, metastatic MCC is a challenging disease. It is generally sensitive to chemotherapy—the common combination of a platinum agent plus etoposide is initially associated with tumor regression and an ORR slightly more than 50%. Unfortunately, this response is seldom durable and the median PFS is a modest 3 months, similar to my patient’s experience. Hence, we desperately need novel therapies to improve outcomes for patients with metastatic MCC.
MCC and Immunotherapy Trials
The patient’s immune response to MCC is critical to survival, as well as MCC pathogenesis—the importance of host immunity was greatly bolstered by the 2008 discovery of Merkel cell polyomavirus (MCPyV). Fueled by our growing understanding of immune evasion mechanisms, several immunotherapy clinical trials were recently launched for patients with advanced MCC. I consider the results of these ongoing trials to be unprecedented for this disease: PD-1/PD-L1 blockade provides a high ORR and, of most importance, durable responses.
Results from an ongoing phase II trial of avelumab in 88 chemotherapy-treated patients with stage IV MCC showed this drug to be active against MCC, with responses in a sizable proportion (32%) of patients. It is important to mention that the patients were not selected based on PD-L1 expression or MCPyV status. Encouragingly, there were only 5 serious treatment-related adverse events: enterocolitis, infusion-related reaction, increased aminotransferases, chondrocalcinosis, synovitis, and interstitial nephritis. At the time of analysis, responses were ongoing in 23 (82%) of 28 patients.
In the chemotherapy-naive setting, a separate phase II trial is examining pembrolizumab—an anti–PD-1 antibody approved for treatment of melanoma and other solid tumors—in 26 treatment-naive patients with advanced MCC. The ORR was 56%, and after a median follow-up of 33 weeks, only 2 (14%) of the 14 responding patients had relapsed. The ORR was 62% among patients with MCPyV-positive tumors (10 of 16 patients) and 44% among those with MCPyV-negative tumors (4 of 9 patients), although there was no statistically significant difference by virus status. The higher ORR with pembrolizumab compared with avelumab may be due to the treatment-naive population. The avelumab trial has been expanded to include a cohort of chemotherapy-naive patients. Drug-related grade 3/4 adverse events occurred in 15% of the patients treated with pembrolizumab.
Immunotherapy in Patients With Bulky Disease
One of the reasons I am impressed by the response in my patient is that this response occurred in the setting of bulky, symptomatic, rapidly growing metastases. These features reflect the aggressive nature of her disease and called for a fast-acting treatment. Immunotherapy is generally considered to have a more delayed response compared with traditional anticancer treatments and is thought to be better suited for slow-growing and relatively small tumors.
By contrast, this patient responded quickly to avelumab (within 6 weeks), and we were able to achieve control over her aggressive disease. Also, her tumors were MCPyV negative. In the trials reported above, viral status has not significantly correlated with efficacy. Moreover, responses from checkpoint inhibitors have occurred in both chemotherapy-naive patients and chemotherapy-experienced patients. I would argue that the observations of durable, rapid-onset responses in a large proportion of immunotherapy-treated patients support using these agents in the frontline setting in immune-competent patients. Chemotherapy can have deleterious effects on the host immune system that may potentially affect the efficacy of subsequent immunotherapy.
To summarize, the unparalleled efficacy and favorable safety profile of immune checkpoint inhibitors—specifically, avelumab and pembrolizumab—in advanced MCC suggests that these drugs should be the new standard of care for this rare, aggressive cancer, regardless of the viral status.
Have you used avelumab or pembrolizumab for your chemotherapy-naive patients with advanced or metastatic MCC? If so, did the patient have a durable response? Please leave your feedback below.