Howard L. Kaufman, MD
The PD-L1 inhibitor avelumab demonstrated durable responses and promising early survival data for patients with pretreated metastatic Merkel cell carcinoma, according to phase II findings from the JAVELIN Merkel 200 trial presented at the 2016 ASCO Annual Meeting.
In the open-label trial, the objective response rate (ORR) with avelumab was 31.8%, which included a 9.1% complete response rate. Median progression-free survival (PFS) with avelumab was 2.7 months (95% CI, 1.4-6.9). The median overall survival (OS) was 11.3 months (95% CI, 7.5-14.0) and the 6-month OS rate was 69%.
Based on these data, Merck KGaA and Pfizer, the companies codeveloping the PD-L1 inhibitor, plan to submit an application to the FDA for regulatory approval. Prior to the release of the data, avelumab had received a breakthrough therapy designation for avelumab as a potential treatment for patients with Merkel cell carcinoma.
"Clinical results support the use of avelumab as a new therapeutic option for advaned or metastatic Merkel cell carcinoma patients," said lead investigator Howard L. Kaufman, MD, Rutgers Cancer Institute. "This has the potential to change clinical practice in an aggressive malignancy without a current standard-of-care."
In the trial, 88 previously treated patients at a median age of 72.5 years received avelumab at 10 mg/kg every 2 weeks. Patients had received at least one prior therapy (59.1%), with 11.4% having ≥3 prior system treatments. Most patients in the study were male (73.9%) and the ECOG performance status was 0 (55.7%) and 1 (44.3%).
The most common site of primary tumor was the skin (76.1%) and all patients had metastatic involvement at the time of study entry. Visceral disease was present for 53.4% of patients. Overall, 65.9% of patients were PD-L1-positive and 52.3% were positive for the Merkel cell polyomavirus (MCPyV). Eight percent of patients were negative for both PD-L1 and MCPyV and 40.9% were positive for both markers.
In addition to responses, 10.2% of patients had stable disease and 20.5% were not evaluable for response. At the March 2016 data cutoff, the median duration of response was not yet reached (95% CI, 8.3-not estimable). Ninety-two percent of patients responded for ≥6 months (95% CI, 70-98) and the 6-month durable response rate was 29.1%.
“To see a tumor response in almost a third of patients in this trial, and for the majority to keep responding after six months, represents a potential breakthrough for this challenging disease,” Kaufman said in a press release. “Currently, the only treatment option available for advanced stages of this aggressive type of skin cancer is chemotherapy, where the response rates are not adequate or durable.”
The ORR in patients with visceral metastases was 34%. Those with low disease burden at baseline experienced a greater response with avelumab. In patients in the lowest quartile for disease burden, the ORR was 42.9%. Those treated with just 1 prior therapy had an ORR of 40.4% versus 19.4% in those treated with ≥2 prior therapies.
The ORR was 34.5% in the PD-L1-positive arm and 18.8% in the PD-L1-negative group. The response rate in those who were not evaluable for PD-L1 status was 35.7%. In patients who were MCPyV-positive, the ORR was 26.1%. In the negative arm, ORR was 35.5% and in those not evaluable for the virus the ORR was 45.5%. Patients who were positive for both markers had an ORR of 30.6% and those negative for both markers had an ORR of 28.6%.
"Avelumab showed durable antitumor activity in patients with chemotherapy-refractory metastatic Merkel cell carcinoma. The response was rapid and sustained," said Kaufman. "Efficacy was seen in patients with PD-L1-postive and -negative tumors and those with MCPyV-positive and -negative tumors."
Treatment-related adverse events (AEs) of any grade were experienced by 70.5% of patients in the study. The most common AEs, which were mostly grade 1/2, were fatigue (23.9%), infusion-related reaction (17%), diarrhea (9.1%), nausea (9.1%), asthenia (8%), rash (6.8%), decreased appetite (5.7%), and maculopapular rash (5.7%).
Grade 3 AEs were experienced by 4.5% of patients and were mostly laboratory abnormalities, such as lymphopenia, blood CPK increase, transaminase increase, and blood cholesterol increase. There were no grade 4 AEs or deaths related to avelumab. Two patients discontinued treatment due to AEs.
"Avelumab was well-tolerated in this second-line or greater Markel cell carcinoma population," said Kaufman. "Most treatment-related AEs were low-grade and there were no grade 4 treatment-related AEs or fatal outcomes."
In addition to Merkel cell carcinoma, avelumab is also being explored across a variety of other types of cancer that have shown susceptibility to PD-L1 inhibition. Altogether, the clinical development program for avelumab now contains more than 2200 patients.
Kaufman H, Russell JS, Hamid O, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic Merkel cell carcinoma previously treated with chemotherapy: Results of the phase 2 JAVELIN Merkel 200 trial. J Clin Oncol. 2016;34 (suppl; abstr 9508).
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