New Standard of Care Emerging for Merkel Cell Carcinoma

Alexander M. Castellino, PhD

September 30, 2016

"For the first time, there is some optimism on the horizon for treating patients with Merkel cell carcinoma," say editorialists commenting on new results with programmed death ligand 1 (PD-L1) inhibitors in this patient population.

The editorialists, Axel Hauschild, MD, of the University Hospital Schleswig-Holstein, Kiel, Germany, and Dirk Schadendorf, MD, of the University Hospital Essen, Germany, were writing in a commentary that accompanies the publication of a study of the investigational agent avelumab (Pfizer), but they also referred to study of another PD-inhibitor, pemrolizumab (Keytruda, Merck) which showed "remarkable responses" in this patient population, as previously reported by Medscape Medical News.

"Taken together, these reports strongly suggest that checkpoint blockade is the best option to treat patients with advanced Merkel cell carcinoma, establishing a new standard of care, especially in view of the excellent tolerability of pembrolizumab and avelumab and the substantial comorbidities in this elderly patient cohort," Dr Hauschild and Dr Schadendorf write in their editorial.

"Results of these two independent phase 2 trials have increased clinical expectations by their high proportion of responses and long response duration and are increasing hopes of achieving a long-term clinical benefit in a larger subset of patients," they add.

"In this near fatal disease in its advanced stage, drugs targeting PD-L1 and PD-1 are inducing rapid and durable responses," commented surgical oncologist Howard L. Kaufman, MD, associate director for clinical science at Rutgers Cancer Institute of New Jersey, in New Brunswick, who led the avelumab study.

The avelumab study, known as JAVELIN Merkel 2000, was published online September 1 in Lancet Oncology. It included 88 patients with chemotherapy-refractory Merkel cell carcinoma and showed that avelumab achieved an overall response rate of 32%.

"To our knowledge, this study is the largest trial of metastatic Merkel cell carcinoma ever reported," write the study investigators. They explain that large, randomized studies in this patient population are difficult because Merkel cell carcinoma — an aggressive form of skin cancer — is a rare disease that has a rapid natural history and generally occurs in patients with substantial comorbidities.

"Achieving rapid, durable responses are difficult in this population of patients who have already progressed on chemotherapy," corresponding author Dr Kaufman told Medscape Medical News.

"It is a significant advancement for avelumab to show an impact in this setting," he added.

The editorialist agree. "These results in patients heavily pretreated with chemotherapy indicate that avelumab has a high potential to change clinical practice in this aggressive cutaneous malignancy," Dr Hauschild and Dr Schadendorf write.

Targeting the PD-1/PD-L1 Axis in Merkel Cell Carcinoma

In approximately 80% of patients with Merkel cell carcinoma, the disease is associated with the Merkel cell polyomavirus; in the remainder, it is associated with ultraviolet exposure.

The study investigators explain that mutational landscape analyses suggest that Merkel cell carcinoma associated with polyomavirus-positive and polyomavirus-negative signatures may represent viral-dependent and ultraviolet-induced subtypes.

Avelumab showed activity in both subtypes of the disease. Of the 88 patients who took part in the trial, 52% were confirmed positive for the polyoma virus, and 35% were confirmed negative.

Approximately 60% of patients had received one previous systemic therapy; 30% had received two prior therapies; and 11% had received three or more lines of therapy. PD-L1 expression was reported in 66% of patients.

Patients received avelumab 10 mg/kg as an hourly infusion every 2 weeks until disease progression or unacceptable toxicity or occurrence of any other factor that necessitated treatment withdrawal.

Radiologic tumor assessments for responses using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were undertaken every 6 weeks using CT or MRI.

Median follow-up time was 10.4 months. Patients received a median of seven doses of avelumab. The median duration of treatment was 17 weeks.

Confirmed objective responses were achieved in 28 patients (31.8%; 95.9% confidence interval, 21.9 – 43.1), and the study met its primary endpoint.

At the first post-baseline tumor assessment, responses were reported in 22 (79%) of the 28 patients at the time of analysis. Responses were ongoing in 23 (82%) patients, and 92% of patients were reported to have had responses that lasted for at least 6 months.

"Responses to avelumab were observed irrespective of PD-L1 expression or Merkel cell polyoma status, suggesting that avelumab might achieve a therapeutic benefit in patients whose disease response and cause are driven by different underlying mechanisms," the study investigators write.

Median duration of response was not reached but ranged from 2.8 months to 17.5+ months.

Although median progression-free survival was 2.7 months, 40% of patients were progression free at 6 months, with the progression-free Kaplan-Meier curve reaching a plateau. At 6 months, 69% of patients were alive, and median overall survival was 11.3 months, as determined on the basis of the 43 of 88 patients who experienced an event.

Dr Kaufman indicated that progression-free survival is not always a predictor of survival. "It is a little too early to know," he said, pointing out that late responses have been observed. "Some patients respond even after 1 year," he added.

In Merkel cell carcinoma, the imaging of lymph nodes, which are common metastatic sites, is tricky, he explained. From imaging, it is difficult to determine whether there is residual disease or whether the findings represent an immune response, he indicated. "That is why longer follow-up of these patients is important," he said.

Treatment-related adverse events were reported in 62 (70%) of 88 patients, with fatigue (24%) and infusion-related reaction (17%) having the highest incidence. Six (7%) of 88 patients had one or more immune-mediated adverse events.

Pembrolizumab in the First-Line Treatment of Merkel Cell Carcinoma

The positive results of avelumab in the treatment-refractory setting is supported with data from other studies, notably, a phase 2 study that showed remarkable responses with pembrolizumab in patients with advanced Merkel cell carcinoma, Dr Hauschild and Dr Schadendorf note in their editorial.

The data on pembrolizumab, were presented at the American Association of Cancer Research 2016 Annual Meeting and were simultaneously published online in the New England Journal of Medicine.

In 26 treatment-naive patients who were treated with pembrolizumab 2 mg/kg every 3 weeks, an objective response rate of 56% was reported. Four patients achieved complete responses, and 10 showed partial responses.

The editorialists comment that the difference between the 56% response rate with pembrolizumab and the 32% rate with avelumab may be explained by the differences in patient populations: the patients who received pembrolizumab were treatment-naive, whereas the patients who received avelumab were chemotherapy refractory.

Dr Kaufman was cautiously optimistic that both drugs will finally receive US Food and Drug Administration approval in their respective settings ― pembrolizumab for first-line treatment, and avelumab for treatment-refractory Merkel cell carcinoma.

He also indicated that his current practice is to enroll patients in a clinical trial. The pembrolizumab study has now expanded to a larger sample size and will accrue up to 50 patients, he pointed out. For patients who do not qualify for enrollment in a clinical trial, pembrolizumab is given off label, he added. "Insurance companies are impressed with the data, and getting coverage has not been a hurdle," he said.

"In view of these fascinating clinical results, running definitive phase 3 trials with chemotherapy as a comparator will be almost impossible for ethical reasons and because Merkel cell carcinoma is an orphan disease," write Dr Hauschild and Dr Schadendorf.

They also indicate that evidence from case reports suggests that the PD-1/PD-L1 antibodies may be useful for other nonmelanoma skin cancers, such as basal cell carcinomas and cutaneous squamous cell carcinomas.

The avelumab study was sponsored by Merck KGaA and is part of an alliance between Merck KGaA and Pfizer. Dr Kaufman serves on advisory boards for Merck and Merck KGaA. Several coauthors have received personal fees, nonfinancial support, grants, and/or institutional funding from industry. Dr Hauschild and Dr Schadendorf are both consultants to Merck.

Lancet Oncol. Published online September 1, 2016. Abstract, Editorial

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