Growing incidence of Merkel cell carcinoma draws researchers’ attention
A dramatic increase in the rate of Merkel cell carcinoma has attracted new attention to this rare and aggressive skin cancer.
Incidence of the disease jumped 95% in the United States between 2000 and 2013, driven largely by the growing proportion of Americans aged older than 60 years.
“This cancer has an almost bizarre sensitivity to age,” Paul T. Nghiem, MD, PhD, professor of dermatology at University of Washington School of Medicine and affiliate investigator at Fred Hutchinson Cancer Research Center, said during an interview with HemOnc Today. “Although most cancers are a bit associated with increasing age, Merkel cell carcinoma is 17,000 times more likely among those aged older than 70 years than those aged 20 years.
“A major factor in the increase of cases is immunosenescence — as people age, the human body is less able to recognize and control things that our immune system was once able to control at a younger age,” Nghiem added.
The rising incidence of Merkel cell carcinoma has prompted more research into new therapies for the skin cancer, with immunotherapies and other emerging treatments showing promise.
HemOnc Today spoke with skin cancer experts about the potential explanations for the increase in Merkel cell carcinoma cases in the U.S. and across the world, how the treatment landscape is evolving and how these changes have been represented in treatment guidelines, and emerging therapies under investigation that may continue to change the way Merkel cell carcinoma is treated.
Incidence and outcomes
Nghiem and colleagues assessed and projected Merkel cell carcinoma incidence trends using SEER data on 6,600 cases in the U.S. from 2000 through 2013.
Their results showed an incidence rate of 0.7 cases per 100,000 person-years in 2013, equating to 2,488 cases per year.
Of note, incidence increased exponentially with age, ranging from 0.1 cases per 100,000 person-years for those aged 40 to 44 years, to one case per 100,000 person-years for those aged 60 to 64 years, and to 9.8 cases per 100,000 person-years for those aged 85 years and older.
Further, with a 95% increase in incidence from 2000 to 2013, Merkel cell carcinoma is widely outpacing other cancers. For instance, incidence of solid tumors increased by 15% during that time period, and melanoma incidence increased by 57%.
Nghiem and colleagues hypothesized that, because of the strong link between risk and older age, this trend of increasing incidence will persist through 2025. They predicted the number of newly diagnosed Merkel cell carcinoma cases would rise from 2,488 in 2013 to 2,835 in 2020 and to 3,284 in 2025.
Although the increase may be explained by some degree of subtle immune suppression among the aging baby boomer population, the trend also appears driven by years of prolonged UV light exposure.
Advances in diagnostic testing also may have led to increased detection, as Merkel cell carcinoma is a disease that historically has been misdiagnosed, often due to the lack of symptoms and characteristic features.
“We are seeing DNA damage from sunbathing and tanning bed activities that occurred more than 20 years ago, and when that DNA damage accumulates to a certain point, it causes cancer,” Suzanne Louise Topalian, MD, associate director of Bloomberg-Kimmel Institute for Cancer Immunotherapy, told HemOnc Today. “The other possibility is that awareness is increasing. More skin examinations are being performed and more novel diagnostic tools are available.”
Survival depends greatly on disease stage. Five-year relative survival rates are 78% for those with localized disease, 51% for those with regional disease and 17% for those with distant disease, according to SEER statistics.
Treatment for Merkel cell carcinoma traditionally has included surgery followed by radiotherapy for localized disease, and chemotherapy for more widespread disease. However, chemotherapy has limited benefit for patients with advanced disease.
“Chemotherapy treatments were adapted from those used to treat small cell lung cancer and often had significant side effects or were not appropriate for elderly patients with Merkel cell carcinoma, particularly if they had other medical problems,” Alexander D. Guminski, MD, PhD, associate professor of medicine at The University of Sydney School of Medicine in Australia, told HemOnc Today. “Patients who responded to chemotherapy often had rapid recurrence of their tumors, sometimes even before the next cycle of treatment was due to start.”
Historically, more than 40% of patients with Merkel cell carcinoma develop widespread metastatic disease, with a median life expectancy of approximately 9 months with chemotherapy, according to Topalian.
“This was an area of significant unmet need,” she said. “Because Merkel cell carcinoma is a very rare disease, until recently, it had not received a lot of attention from ‘big pharma’ in terms of developing new treatments.”
A lot of the recent attention directed toward Merkel cell carcinoma has been focused on use of immunotherapy for the disease.
Merkel cell carcinoma is immunogenic — meaning it might be a prime target for immunotherapy — and trials have shown efficacy of PD-1 inhibitors as first-line or later therapy.
“Scientific advances in Merkel cell carcinoma within the past 2 to 3 years have revolutionized treatment for this disease,” Topalian said. “It is one of the most remarkable success stories that have come out of all the work that has been done with PD-1 pathway-blocking agents in cancer.”
The first indication that the immune system was significant in controlling Merkel cell carcinoma arose about a decade ago, according to Nghiem, when he and colleagues found that patients with Merkel cell carcinoma with either a moderate or a significant amount of killer-infiltrating T cells did not die of the disease, and stage was not a factor in mortality.
“Around that time, the disease-causing virus was identified, and we knew this cancer had a lot of reasons for the immune system to detect it,” Nghiem recalled.
That virus — Merkel cell polyomavirus — causes about 80% of these cancers, with the remaining 20% caused by UV exposure and DNA damage.
“We began studying virus-specific immune responses and found they were common in patients, but we also found evidence of exhaustion and dysfunction selectively in the tumor-specific T cell compared with T cells specific to other viruses, such as cytomegalovirus,” Nghiem said. “This obviously suggested we should be looking to see if blockade of the PD-1 pathway would be beneficial.”
In parallel, Lipson and colleagues from Johns Hopkins published data showing that Merkel cell carcinomas often express PD-L1, the major ligand for the PD-1 inhibitory receptor on T cells.
Based on this knowledge, Nghiem and colleagues conducted the single-arm JAVELIN Merkel 200 trial to evaluate the use of avelumab (Bavencio; EMD Serono, Pfizer) — an anti–PD-L1 monoclonal antibody — among patients with metastatic Merkel cell carcinoma who underwent at least one previous chemotherapy regimen.
Updated 2-year data from that trial — published last year in Journal for ImmunoTherapy of Cancer — showed that one-third (33%) of patients who received avelumab experienced complete or partial tumor shrinkage, with 74% of responses lasting at least 1 year. At 1 year, 30% (95% CI, 21-41) of patients achieved PFS and 52% (95% CI, 41-62) achieved OS, with a median OS of 12.9 months (95% CI, 7.5-not estimable).
Earlier findings from JAVELIN Merkel 200 led to FDA accelerated approval of avelumab in 2017, representing the first FDA-approved first- or second-line treatment for patients aged 12 years and older with metastatic Merkel cell carcinoma.
This was followed by the approval of pembrolizumab (Keytruda, Merck) — an anti-PD-1 monoclonal antibody — in December 2018. The decision was based, in part, on data from the multicenter, nonrandomized, open-label Cancer Immunotherapy Trials Network-09/KEYNOTE-017 trial.
In that trial, Nghiem and colleagues treated 50 patients with recurrent locally advanced or metastatic Merkel cell carcinoma with 2 mg/kg pembrolizumab every 3 weeks for up to 2 years. Patients had not previously received systemic therapy for advanced disease.
At median follow-up of 14.9 months, the objective response rate was 56% (95% CI, 41-70), which included a 24% complete response rate. Researchers observed ORRs of 59% in virus-positive tumors and 53% in virus-negative tumors. Among the 28 responders, median duration of response was not reached (range, 5.9-34.5+ months).
Median PFS was 16.8 months (95% CI, 4.6-not estimable), with a 2-year PFS rate of 48.3%. Median OS was not reached, and 68.7% of patients achieved 2-year OS.
Experts with whom HemOnc Today spoke agreed that chemotherapy had been suboptimal for meeting treatment goals for advanced Merkel cell carcinoma, and that immunotherapy agents have greatly enhanced the disease’s treatment paradigm.
“In 2018, everything flipped — chemotherapy was no longer preferred and immunotherapy was strongly preferred [for] eligible patients,” Nghiem said. “Although chemotherapy would shrink the tumor in about two-thirds of cases, it provided long-term control in only about 5%. Now, with immunotherapy, the data show more than 50% of patients achieve persistent benefit.”
Although researchers knew very early that Merkel cell carcinoma would have been the prime disease target for immunotherapy, pharmaceutical companies were slow to support research in this area, according to Jurgen C. Becker, MD, PhD, professor in the department of translational oncology at University Duisburg-Essen in Germany.
“I tried to convince pharmaceutical companies to test these agents in Merkel cell carcinoma, but this was not done at that time,” Becker told HemOnc Today. “In this perspective, it was momentous that Dr. Nghiem and colleagues conducted a clinical trial that completely changed the field. It is because of people like him who took the initiative that we are finally seeing improvements in survival for these patients.”
However, these agents come with limitations.
“One major limitation is that only half of patients respond to therapy,” Becker said. “Another limitation is that the responses to immunotherapy are less durable — there is a significant proportion of earlier secondary resistance. Thus, improvements are needed for these patients with primary and secondary resistance.”
Immediate changes to guidelines
Publication of the groundbreaking data on avelumab and pembrolizumab led to immediate changes in National Comprehensive Cancer Network guidelines for Merkel cell carcinoma, which have been dubbed the “gold standard” of recommendations for treatment of the disease.
“The NCCN guidelines are the dominant recommendations that everybody pays attention to here in the United States, because they have quickly caught up with recent data,” Nghiem said.
Although the guidelines for earlier stages of Merkel cell carcinoma have not changed much in terms of the recommendations for surgery and adjuvant radiation therapy, the guidelines for advanced-stage disease have changed dramatically.
Above all, immunotherapy is now recommended for patients with advanced Merkel cell carcinoma without medical contraindications.
The guidelines also focus on a blood test shown to be effective for early detection of Merkel cell carcinoma.
“Half of the overall population of patients with Merkel cell carcinoma make antibodies against the Merkel cell polyomavirus oncoprotein,” Nghiem said. “In those patients, antibody levels decrease quickly if the cancer is not coming back, whereas the levels increase quickly if the cancer is coming back. This blood test can detect disease recurrence very early on, even sometimes before scans, and can spare the patient exposure to radiation from scans.
“We make great use of this test at our institution, which we give at baseline to all patients,” Nghiem added. “It has changed the way we follow patients and helps to diagnose Merkel cell carcinoma early, when we have more time to treat it.”
The NCCN guidelines encourage clinical trial participation as a key recommendation, especially for those with advanced or recurrent disease.
“There are so many different clinical trials that are ongoing for patients with Merkel cell carcinoma,” Topalian said. “Clinical trials are always something that oncologists, as well as patients, should think about if it is right for them in their particular situation.”
Other guidelines from Fred Hutchinson Cancer Research Center and the American Academy of Dermatology aim to help clinicians navigate immunotherapy for Merkel cell carcinoma.
“The guidelines, in general, are intended to convey the latest and greatest treatment recommendations in Merkel cell carcinoma, especially for clinicians who may not be dealing with the disease all the time or may not have time to review all the literature that is needed to optimize care,” Shailender Bhatia, MD, associate professor in the department of medicine at University of Washington and Seattle Cancer Care Alliance, told HemOnc Today.
Emerging treatment approaches
Because not everyone responds to anti-PD-1 immunotherapy — and those who do might experience resistance — additional therapies that target different pathways remain needed.
Determining how to predict who may develop resistance and finding effective new therapies for patients with resistance are key goals for the community of physicians who treat Merkel cell carcinoma.
“Unfortunately, not all patients respond to checkpoint inhibitors and some patients experience acquired resistance,” Guminski said. “Patients with active autoimmune disease, such as inflammatory bowel disease, may be contraindicated to receive current immunotherapy. New approaches are greatly needed for these patients.”
Bhatia echoed this sentiment.
“The biggest challenge right now is that while these drugs are working so well in a group of patients, they are not working for everybody,” he said. “For patients with autoimmune diseases or those who may have received an organ transplant, stimulating the immune system can be dangerous. We need nonimmunotherapy options for these patients that will not trigger exacerbation of their underlying diseases. We also have patients who do not respond to immunotherapy at all — patients with primary intrinsic resistance to immunotherapy. So, we definitely need better options for various groups of patients.”
To address these needs, other clinical trials designed to assess treatments for Merkel cell carcinoma are underway.
Ipilimumab (Yervoy, Bristol-Myers Squibb) — a monoclonal antibody that works to activate the immune system by targeting CTLA-4 — is being tested in combination with anti-PD-1 and anti PD-L1 drugs among patients with Merkel cell carcinoma.
Early results from the phase 1/phase 2 CheckMate 358 trial — presented at American Association for Cancer Research Annual Meeting in 2017 — also suggested that nivolumab (Opdivo, Bristol-Myers Squibb), a PD-1 inhibitor, may have efficacy for patients with Merkel cell carcinoma. Among 25 evaluable patients, ORR was 64% and appeared higher for treatment-naive patients than those who had received one to two prior systemic therapies (73% vs. 50%).
Other trials aim to offer further insight into the use of intratumoral injections of genetically altered viruses for Merkel cell carcinoma, whereas others are examining the possibility of combining checkpoint inhibitors with more traditional therapies.
“Combinations of checkpoint inhibitors and other mechanisms of activating T cells, such as engineered patient-derived T cells, are being explored, and combinations of immunotherapy with radiotherapy or radionuclide treatment, such as Lutetium-178, are also being tested,” Guminski said. “Better immunotherapy treatments will come from a better understanding of the biology of Merkel cell carcinoma and from understanding the nature and kinetics of response to current immunotherapy. Given that many patients with Merkel cell carcinoma are elderly, effective new treatments will need to be convenient and have minimal toxicity.”
Clinical trials also aim to address secondary resistance in Merkel cell carcinoma, Becker said.
“We are currently testing a drug for secondary resistance in patients in order to reintroduce some of the antigen processing that has been recognized as one of the escape mechanisms in Merkel cell carcinoma,” he said. “A lot of ongoing trials in Europe, the United States and Australia are working to address the situation of secondary resistance, and we will soon see who will be the first to report the results. My hope is that we can overcome secondary resistance and gain a better understanding of the disease, which is limited because there are no good data that show the natural course of the disease.”
Adjuvant trials also are ongoing to test the role of immune checkpoint inhibitors in early disease stages to prevent progression. For example, researchers of the ADEMC-O trial in Germany are comparing adjuvant ipilimumab or nivolumab with observation in completely resected Merkel cell carcinoma. A similar effort in the U.S. is the ADAM trial — the first phase 3 trial in this disease — which is testing avelumab vs. placebo for patients with the highest risk for recurrence after surgery plus radiation.
Nghiem and said that an area ripe for improvement is appropriate surveillance for disease recurrence.
“This is an area that we are particularly focused on,” Nghiem said. “Merkel cell carcinoma has a high risk for recurrence, at least threefold higher than melanoma, and that risk is concentrated during the first 2 to 3 years after diagnosis. Patients need to be watched closely during that time, especially now that there are potentially curative or effective therapies that can induce durable benefit.”
There are many aspects of treating Merkel cell carcinoma that require multidisciplinary teams, Nghiem added.
“My plea to the community of clinicians treating these patients is that upon diagnosis, patients should have at least one consultation visit to a center focused on Merkel cell carcinoma — there are many of these centers located across the United States,” he said. “Patients with Merkel cell carcinoma should receive multidisciplinary care that involves surgeons, radiation oncologists, medical oncologists, dermatologists, etc, to all play roles in their treatment trajectory.”
Bhatia said the work in Merkel cell carcinoma is not yet complete.
“Clinical trials are the preferred approach for patients, whenever feasible, and we need to offer this to our patients,” he said. “Even though patients are benefiting tremendously from these recent treatment advances, we need to continue to improve our therapies and work toward cure and not just prolonging survival in our patients.” – by Jennifer Southall
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For more information:
Jurgen C. Becker, MD, PhD, can be reached at University Duisburg-Essen, Forsthausweg 2, Duisburg, North Rhine-Westphalia 47057; email: firstname.lastname@example.org.
Shailender Bhatia, MD, can be reached at Seattle Cancer Care Alliance, 825 Eastlake Ave. E, Seattle, WA 98109; email: email@example.com.
Alexander D. Guminski, MD, PhD, can be reached at The University of Sydney School of Medicine, Edward Ford Building A27, The University of Sydney New South Wales 2006; email: firstname.lastname@example.org.
Paul T. Nghiem, MD, PhD, can be reached at University of Washington, 850 Republican St., Brotman Room 240, Seattle, WA 98109; email: email@example.com.
Suzanne Louise Topalian, MD, can be reached at Johns Hopkins University, 1550 Orleans St., Baltimore, MD 21287; email: firstname.lastname@example.org.
Disclosures: Becker, Bhatia, Guminski and Nghiem report no relevant financial disclosures. Topalian reports research grants from Bristol-Myers Squibb, consulting fees from Merck and that an immediate family member is a consultant for MedImmune/AstraZeneca.