Neoadjuvant nivolumab induces response in resectable Merkel cell carcinoma
Nivolumab administered 4 weeks before surgery induced pathologic complete responses and radiographic tumor regressions in about half of a cohort of patients with Merkel cell carcinoma, according to results of the phase 1/phase 2 CheckMate 358 study published in Journal of Clinical Oncology.
These early markers of response predicted improved RFS. The treatment approach also appeared tolerable, researchers noted.
“Merkel cell carcinoma appears to respond very rapidly to anti-PD-1 immunotherapy in some patients with advanced disease,” Suzanne L. Topalian, MD, associate director of the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, said in a press release. “This led us to test whether anti-PD-1 could be effective if given for a brief period before surgery. Using this approach, we found that patients who had substantial tumor regressions on CT scans or in pathology studies of surgically removed tumor specimens had extended cancer [RFS] that was statistically significant.
“Radiographic and pathologic tumor regressions following neoadjuvant anti-PD-1 therapy are, therefore, potential new, early markers that will help us predict what a patient’s long-term outcome will be,” she added. “This is critical information for oncologists planning treatment strategies for their patients.”
Incidence of Merkel cell carcinoma — a rare and aggressive skin cancer — is increasing in the United States.
Cytotoxic chemotherapy used to be the primary systemic therapy for advanced disease. Initial responses to chemotherapy occur in about 60% of cases; however, durability is usually disappointing, with 95% of patients experiencing progression within 1 year.
The PD-1/PD-L1 immunosuppressive pathway often is upregulated in Merkel cell carcinoma, and previous trials of PD-1 and PD-L1 inhibitors have shown high response rates with significant durability in advanced disease. Because of this, immunotherapy is now preferred over chemotherapy for eligible patients, and interest has grown in studying these drugs in earlier stages of disease.
To that end, Topalian and colleagues assigned 39 patients (median age, 68 years; range, 22-88) with stage IIA to stage IV resectable Merkel cell carcinoma to nivolumab (Opdivo, Bristol-Myers Squibb) dosed at 240 mg IV on days 1 and 15, with surgery planned for day 29.
Researchers assessed tumor regression radiographically and microscopically, and they used pretreatment tumor biopsies to assess Merkel cell polyomavirus status, PD-L1 expression and tumor mutational burden.
Safety and tolerability of neoadjuvant nivolumab served as the primary endpoint.
Eighteen patients experienced any-grade treatment-related adverse events, with three patients experiencing grade 3 or grade 4 events. Researchers observed no unexpected toxicities.
Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2).
Among the 36 patients who underwent surgery, 17 (47.2%) achieved pathologic complete response. Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions of 30% or greater.
Responses occurred regardless of Merkel cell polyomavirus, PD-L1 or tumor mutational burden status.
Median RFS and OS had not been reached after median follow-up of 20.3 months.
RFS correlated significantly with pathologic complete response and radiographic response at the time of surgery, according to researchers. No patient with a pathologic complete response experienced tumor relapse during observation.
“To our knowledge, this is the first attempt to look at the role of anti-PD-1 therapy before surgery in patients with Merkel cell carcinoma who are candidates for complete surgical removal of their tumor,” Topalian said in a press release. “We know that, historically, many of these patients would subsequently relapse after standard surgical and postoperative treatments. Even if we think we’re removing all of the existing tumor at the time of surgery, in many patients the tumor has already spread to other parts of the body, at microscopic sites of metastasis that are too tiny to be detected with scans.” – by John DeRosier
Disclosures: Topalian reports stock ownership in, a consultant/advisory role with, and travel expenses from Five Prime Therapeutics, as well as stock ownership in Dragonfly Therapeutics, a consultant/advisory role with Immunocore and research funding and/or travel expenses from Bristol-Myers Squibb and Merck. She also reports an immediate family member has stock or other ownership interests in, holds consultant/advisory roles with, receives research funding from or has other relationships with several companies. Please see the study for all other authors’ relevant financial disclosures.