The US Food and Drug Administration (FDA) has granted accelerated approval to the checkpoint inhibitor Bavencio (avelumab) for the treatment of patients with metastatic Merkel cell carcinoma (MCC), including those who have not received prior chemotherapy.
Avelumab is the first FDA-approved treatment for metastatic MCC and the first disease that the drug has ever been approved to treat.
A rare and aggressive form of skin cancer, MCC, is 35 times less common than melanoma, but on average, it is about three times more likely to be deadly. Until now, there were no systemic therapies approved by the FDA for this cancer, and no approved therapies once the cancer had spread.
Tom Judd, who lives near Portland, Oregon, knows what it is like to be diagnosed with a deadly cancer for which there is no approved drug. After being diagnosed with MCC in 2013, his cancer jumped from a small pimple on his nose throughout his body, growing until it interfered dangerously with organ function.
By early 2015, the disease had nearly killed him, despite surgery, radiation and chemotherapy. Then he enrolled in a clinical trial and received his first of many infusions of the new immunotherapy drug – avelumab. Within six weeks of that first infusion, more than one-third of the cancer throughout his body was gone, and today, more than 90 percent of his tumor mass has disappeared.
Because of the data from this clinical trial, avelumab (brand name Bavencio) has become the first systemic therapy approved by the FDA for MCC, and the first treatment of any kind approved for metastatic MCC.
Dr Paul Nghiem, affiliate investigator of the clinical research division at the Fred Hutchison Cancer Research Centre, and the George F Odland Endowed chair in dermatology at the University of Washington School of Medicine, is a senior investigator on the clinical trial that led to the FDA approval. He is a leading expert on MCC and a pioneer of immunotherapy for the disease.
The approval as a first- and second-line therapy “is a really big deal,” said Nghiem. His team foundational work on the role of immune cells in MCC paved the way for immunotherapy trials in the disease, including one he leads of another immunotherapy drug with a similar mechanism of action (Merck’s Keytruda), whose results were published last year and changed the field overnight.
Summary
Background: Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy.
Methods: In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647.
Findings: Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6–13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9–43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each).
Interpretation: Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma.
Authors
Howard L Kaufman, Jeffery Russell, Omid Hamid, Shailender Bhatia, Patrick Terheyden, Sandra P D'Angelo, Kent C Shih, Céleste Lebbé, Gerald P Linette, Michele Milella, Isaac Brownell, Karl D Lewis, Jochen H Lorch, Kevin Chin, Lisa Mahnke, Anja von Heydebreck, Jean-Marie Cuillerot, Paul Nghiem
[link url="https://www.sciencedaily.com/releases/2017/03/170324192324.htm"]Fred Hutchison Cancer Research Centre material[/link]
[link url="http://thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30364-3/fulltext"]The Lancet Oncology article summary[/link]