Best Practices in Immunotherapy – June/July 2017 Vol 8

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2017 ASCO-SITC Clinical Immuno-Oncology Symposium

Avelumab Demonstrates Efficacy Across All Subgroups in Metastatic Merkel Cell Carcinoma

Avelumab Demonstrates Efficacy Across All Subgroups in Metastatic Merkel Cell CarcinomaFor patients with metastatic Merkel cell carcinoma, a rare and aggressive form of skin cancer associated with poor survival, avelumab may soon offer a new therapeutic option.

According to subgroup analysis of efficacy presented at the 2017 ASCO- SITC Clinical Immuno-Oncology Symposium, avelumab monotherapy showed durable antitumor activity across all evaluable subgroups of patients with chemotherapy-refractory metastatic Merkel cell carcinoma.

No predictive biomarker with clear clinical utility was identified, but there was a trend of higher response in patients with PD-L1–positive versus PD-L1–negative tumors, the researchers reported.

“Although the disease is considered to be chemosensitive, responses to chemotherapy in stage IV metastatic Merkel cell carcinoma are rarely durable, and an associated overall survival benefit has not been shown,” said Howard L. Kaufman, MD, FACS, a surgical oncologist at Rutgers Cancer Institute of New Jersey.

“Patients who fail chemotherapy are particularly challenging to treat, as there really is no effective treatment,” Dr Kaufman added. “In this population, median progression-free survival is generally less than 3 months, and essentially no patients are alive after 1 year of therapy.”

Avelumab is a fully human immunoglobulin G1 monoclonal antibody directed against the human immunosuppressive ligand PD-L1 protein. It inhibits the interaction with PD-1 on T cells, allowing the T cells to stay active, and it does not interfere with the PD-1/PD-L1 pathway.

Along with preclinical evidence of activity, avelumab has demonstrated antitumor activity in lung, bladder, gastric, ovarian, and renal cancers and other malignancies. Avelumab received breakthrough therapy, fast track, and orphan drug designations by the FDA for treatment of Merkel cell carcinoma, Dr Kaufman noted.

JAVELIN Merkel 200 Trial

For this phase 2, prospective, open-label, international, multicenter study, patients with stage IV metastatic Merkel cell carcinoma and prior disease progression on chemotherapy received an intravenous infusion of avelumab 10 mg/kg every 2 weeks. Patients stayed on therapy until confirmed progression of disease, unacceptable toxicity, or other criteria were met.

The primary end point of the study was best overall response by RECIST v1.1 and was reviewed by an independent review committee. Additional end points included duration of response, progression-free and overall survival, and safety and tolerability. Investigators also measured PD-L1 expression and Merkel cell polyoma­virus status, but this was not required for study entry.

As Dr Kaufman reported, initial results from the trial were published in Lancet Oncology and presented at ASCO 2016. The goal of this particular study was a post hoc analysis of efficacy in subgroups based on baseline patient and disease characteristics.

“We wanted to see if we could identify potential predictive biomarkers that would help us to better select patients who might benefit from avelumab treatment,” he explained.

Durable Efficacy Observed Across All Subgroups

Dr Kaufman and colleagues treated 88 patients (median age, 72.5 years) with avelumab and followed them for at least 6 months. Whereas 59.1% of patients had 1 prior line of therapy, 29.5% had 2 and 11.4% had 3 or more lines of prior therapy. Overall, there was a 31.8% objective response rate, and an additional 10% of patients had stable disease.

“The median duration of response has not been reached, as 92% of patients were still in response at 6 months,” said Dr Kaufman, who noted that median progression-free survival was 2.7 months.

“Although progression-free survival analysis is comparable to other second-line therapies, the difference is the tail of the curve,” he added. “A significant percentage of patients on avelumab are still alive well beyond the 12-month cutoff point.”

Avelumab was also well tolerated by patients. The most common side effects were fatigue and infusion reactions, and the vast majority of treatment-related adverse events were low grade. There were no grade 4 or 5 events in this trial.

Although subset analysis showed no statistically significant difference in a number of patient and tumor characteristics, a few trends were observed. “Patients who had only 1 prior line of therapy had a response rate of 40% compared to only 19% in those patients with 2 or more lines of therapy,” said Dr Kaufman. “In addition, patients with lower disease burden had a 41% response rate compared to 26% for those with larger, bulkier tumors.”

Researchers observed a slight trend favoring patients who had PD-L1 expression in their tumors, said Dr Kaufman, who noted a 52% response rate for PD-L1–positive tumors compared with 23% for PD-L1–negative tumors. The median progression-free survival for patients with PD-L1–positive tumors has not been reached but was 1.6 months for patients with PD-L1–negative tumors. According to Dr Kaufman, no trends could be discerned based on polyomavirus status.

This ongoing multicenter trial is currently enrolling treatment-naive patients with metastatic Merkel cell carcinoma to receive first-line avelumab treatment.

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