NEW ORLEANS — First-line systemic therapy with the anti–PD-1 antibody pembrolizumab induced a high response rate in patients with advanced Merkel cell carcinoma, according to study results presented at the American Association for Cancer Research Annual Meeting.
Researchers observed responses in patients who had virus-positive and virus-negative tumors.
Paul T. Nghiem
“There had not been a trial before that showed benefit in this cancer, and there actually was a lot of doubt in the pharmaceutical industry that a trial could be positive,” Paul T. Nghiem, MD, PhD, professor of medicine in the division of dermatology at University of Washington School of Medicine, said during a press conference.
Merkel cell carcinoma an aggressive skin cancer linked to ultraviolet light exposure and the Merkel cell polyomavirus affects about 2,000 people per year in the United States. It is most common in those aged older than 50 years. More than 40% of patients develop advanced disease, and median survival in that group is 9.5 months.
There is no FDA-approved treatment, and first-line therapy typically consists of platinum and etoposide. Although approximately 55% of patients respond, those responses are rarely durable. Prior research showed 50% of patients progressed by 3 months and 90% progressed by 10 months.
“A key question was, what is the basis for this poor durability?” Nghiem said. “Is it due to systemic or local immune suppression due to chemotherapy? Rather than trying to suppress immune system and just kill the cancer cells, what if we stimulated the immune system?”
Researchers hypothesized that blocking the programmed death 1 (PD-1) immune inhibitory pathway might be effective because more than half of tumors express PD-L1, and this often predicts improved survival. Merkel cell polyomavirus-specific T cells express PD-1 in about two-thirds of patients.
Nghiem and colleagues conducted a multicenter, single-arm, open-label phase 2 trial to evaluate pembrolizumab (Keytruda, Merck) as first systemic therapy for patients with unresectable or metastatic disease. Patients with systemic immunosuppression or active autoimmune disease were excluded.
Study participants received pembrolizumab 2 mg/kg via IV every 3 weeks for up to 2 years. Objective response rate served as the primary endpoint.
Twenty-six patients received at least one dose of pembrolizumab, and 25 underwent at least one radiologic assessment.
Median follow-up was 7.6 months.
Researchers reported a 56% objective response rate. Four patients (16%) achieved a complete response and 10 patients (40%) achieved a partial response. Another patient achieved an unconfirmed partial response. One demonstrated stable disease and nine (36%) experienced progressive disease.
Twelve of the 14 (86%) confirmed responses were ongoing at the time of data cutoff.
A greater percentage of patients with Merkel cell polyomavirus-positive tumors responded to treatment (62% vs. 44%), but the difference was not statistically significant.
Median PFS was 9 months, compared with a historical median PFS of 3 months for chemotherapy-treated patients. The 6-month PFS rate was 67% (95% CI, 49-86).
Fifteen percent of patients experienced drug-related grade 3 or grade 4 adverse events.
Correlative studies to further investigate the immune responses are ongoing. Researchers intend to expand the trial to include an additional 24 patients in hopes of confirming the results.
“There was a thought to do a randomized trial, but that was going to be too costly,” Nghiem said. “While not randomized ... we are hopeful these kinds of data will encourage the powers that be that this is really a winner.” – by Mark Leiser
Nghiem P, et al. Abstract CT-096. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.
Nghiem reports a consult role with EMD Serono, as well as funding from Bristol-Myers Squibb to perform biomarker studies in clinical trials.
Merkel cell carcinoma is a rare cancer, and it has not responded well to treatment. There have been responses but they have not been durable. This trial of pembrolizumab shows a significant rate of response. Some of those responses have proven to be very durable, and they have offered for some patients a high quality of life.
Understanding the mechanism is clearly important, as some patients have their disease caused by a virus mechanism and others develop it due to ultraviolet exposure, both of which suggest immunotherapy could be a useful approach. It also is important to determine whether we can predict who will respond. A substantial amount of research has been conducted to try to predict responders through biomarkers, but we are still not at the point where that science has been developed.
So, this is a significant step forward in the treatment of this disease. This agent produces a higher response rate, some of which are durable and clinically meaningful. However, we also have to recognize many patients do not respond, and we still have much to learn.