Paul Nghiem, MD, PhD
A recent report regarding pembrolizumab (Keytruda) for advanced Merkel cell carcinoma ushered in a more optimistic era in the treatment of this rare but often lethal skin cancer.1 The ASCO Post spoke with one of the field’s leaders, Paul Nghiem, MD, PhD—the first author of the study—about the changing landscape for the disease and his personal management of these patients. Our interview is a follow-up to Dr. Nghiem’s commentary in the Journal of Oncology Practice, which focused on this tumor’s abundant immunogenicity.2
Dr. Nghiem is the George F. Odland Endowed Chair in Dermatology at the University of Washington and affiliate investigator at the Fred Hutchinson Cancer Research Center in Seattle.
Overall Outlook
Given the ability of pembrolizumab to extend survival for some patients with advanced Merkel cell carcinoma, what’s the overall outlook in this malignancy?
A sea change is coming in how we will manage this cancer. A substantial subset of patients with advanced disease—about 50%—will now do well on monotherapy with a checkpoint inhibitor.1 So for advanced disease, much is changing. In terms of management of early disease, surgery and radiation already offered good efficacy.
Recurrence Risk
You mentioned in your article in Journal of Oncology Practice that recurrence is common, even after apparently rendering patients disease-free after surgery and radiotherapy. How is this so?
A sea change is coming in how we will manage [Merkel cell carcinoma]. A substantial subset of patients with advanced disease—about 50%—will now do well on monotherapy with a checkpoint inhibitor.— Paul Nghiem, MD, PhD
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It has to do with the characteristics of this cancer. Much more commonly than melanoma, Merkel cell carcinoma microscopically metastasizes to the lymph nodes and to distant sites.
The average melanoma (0.6-mm Breslow depth) and the average Merkel cell carcinoma (1.7 cm in diameter) pose strikingly different risks of spread. One in three such Merkel cell carcinoma patients has microscopic nodal involvement on sentinel lymph node biopsy, compared to fewer than 1 in 50 patients with an average melanoma. There is thus a 20- to 30-fold higher chance that the average Merkel cell carcinoma has metastasized to the nodes, and a 2- or 3-fold higher chance of distant metastasis and death.
Sentinel Node Biopsy
Is lymph node dissection important in newly diagnosed patients?
Most people agree that sentinel node biopsy is a sensitive staging test, and if regional nodes are positive, that either surgery or radiation (but not both) needs to be done in the draining nodal basin.
CD8 Profile
You mentioned that the presence of CD8 T cells confers virtually a 100% probability of survival. Is this information useful clinically?
Both virus-positive and virus-negative Merkel cell carcinomas can have robust intratumoral infiltration of CD8 T cells. This is associated with 100% survival, independent of stage.3 Among 300 of our patients analyzed in this way, for those with robust CD8 infiltration, none have died.
Merkel Cell Carcinoma Overview
- Merkel cell carcinoma is a rare but often lethal skin cancer that is much more likely to metastasize than melanoma.
- In a pivotal study of 26 patients with advanced Merkel cell carcinoma, 56% responded to treatment with pembrolizumab.
- Patients who have disease progression on anti–PD-1/PD-L1 agents can be treated with combinations of checkpoint inhibitors and intralesional therapies, ideally on a clinical trial.
- The management of early disease is typically very effective and based on surgery and radiotherapy.
- The Merkel cell polyomavirus oncoprotein serology test is useful in surveillance, as it helps detect recurrences in seropositive patients and suggests regular imaging is important for seronegative patients, whose tumors are more likely to recur.
- A new data set is informative as to stage-specific survival and can be accessed online at www.merkelcell.org/prognosis/index.php.
So you might say this would be a great test, but we don’t use it in our patients. Why not? Because it makes no difference therapeutically to the one in five patients who has this favorable CD8 profile. Such patients need to receive the same treatment as other patients, regardless of CD8 infiltration status. Disease can recur in such patients, but if it does, we can cure it. Because the CD8 profile really doesn’t change our management, we don’t routinely do this test.
Optimal Management
What’s the optimal approach, then, for managing the newly diagnosed Merkel cell carcinoma patient?
In most cases of Merkel cell carcinoma (about 80%), Merkel cell polyomavirus is clonally integrated in the tumor cells, and viral oncoproteins drive oncogenesis. There is increasing evidence that these patients do somewhat better than polyomavirus-negative patients. What this means clinically is that the 20% of patients who are virus-negative might need more careful monitoring for recurrence.
Several early management concepts are important. One is the serologic assessment of antibodies to the viral oncoproteins, the Merkel virus serology test (www.merkelcell.org/sero), which has been shown to be useful for two things: It identifies patients who do not make such antibodies, who are at higher risk and need to be followed more closely; and for patients who do have antibodies, the test aids in early detection of recurrence.
It is important to perform the serology test within 3 months of the patient demonstrating measurable disease. This is because after the lesion has been resected, these antibodies start to disappear (most patients lose detectable antibodies by 9 months after treatment unless they have a recurrence). The Merkel virus serology test is working well for us in our clinic; an increasing titer prompts us to order a scan. It is sensitive and specific, and it allows us to reduce the number of routine surveillance scans we perform.
The other thing that’s changing our management is the availability of a data set for recurrence-free survival, on a per-stage level (www.merkelcell.org/prognosis/index.php). These are unpublished data from 467 patients in our Seattle cohort, whom we have followed since shortly after their initial Merkel cell carcinoma diagnosis, and we find it very helpful in guiding surveillance intensity. There are huge differences among the stages in terms of recurrence-free, disease-specific, and overall survival, and the risk of recurrence falls quickly. By 3 years from diagnosis, most stages of Merkel cell carcinoma have plateaued, and 80% of the risk has disappeared. These are the first data we have had for stage-specific relapse-free survival. We now routinely use these stage-specific data to make decisions with the patient regarding ongoing disease surveillance intensity and their residual risk over the months and years after their diagnosis.
Advanced Disease
Is there a way in which early disease management impacts the treatment of advanced disease?
Yes, because we want to catch recurrences early. Serologic testing and imaging during the high-risk period after diagnosis helps do this. With the newer immunotherapies, most physicians believe we have a better chance for a good outcome if we treat “grapes and walnuts” (in terms of tumor size) rather than “lemons and grapefruits.” We have the capacity to catch recurrent disease earlier with serologic testing and scanning. I’m confident that patients with smaller tumors do better with immunotherapy than those with larger tumors.
Catching disease early is primarily important for immunotherapy, and it matters less for chemotherapy, which typically works well regardless of tumor volume but rarely provides durable benefit. While immunotherapy can help many patients with advanced disease, there is still a subset of older patients with many comorbidities who would not want aggressive therapy, so surveillance can be much less involved for those patients. For immune-suppressed patients who would not benefit from immunotherapy, we would focus on chemotherapy, which typically shrinks Merkel cell carcinoma tumors for about 3 months, even if they are very large.
Checkpoint Inhibitors
Should essentially all patients with advanced disease receive an anti–PD-1/PD-L1 (programmed cell death protein 1/programmed cell death ligand 1) agent now, or is there a way to select these patients?
Our big challenge is to be able to predict which patients will do well. After a couple of years of research in this area, we have learned there will not be a quick, definitive answer to this question anytime soon. For the moment, patients who test either positive or negative for the Merkel cell polyomavirus can respond to these drugs, as can patients with and those without PD-L1 expression in the tumor.
While we might see some trends in response, there is nothing more predictive than about 60% vs 40%; therefore, we will often try checkpoint inhibition in any patient with advanced disease who is not immunosuppressed or does not have other contraindications. We can tell such patients that we have a good shot at helping them with one agent.
Subsequent Options
When anti–PD-1 pathway blockade fails, what can the clinician try next?
That is currently a wide open question. The obvious possibility is to enroll patients on clinical trials. We have data in mouse models, and to some degree in Merkel cell carcinoma patients, showing that immunotherapy combinations can be synergistic and that toxicity is not more than additive.
A number of combination trials—for example, a trial of ipilimumab (Yervoy) plus nivolumab (Opdivo) and another with adoptive T-cell therapy plus an anti–PD-L1 agent—are underway. Other trials may well combine checkpoint inhibitor therapy with intralesional therapies (the oncolytic immunotherapy talimogene laherparepvec [Imlygic] or interferon, which are approved in melanoma) and/or radiation therapy with a checkpoint inhibitor. These intralesional therapies upregulate major histocompatibility complex 1, which is suppressed in 80% of Merkel cell carcinoma cases and is probably part of the mechanism of immune evasion.
While it’s far better to enroll patients and capture the data in clinical trials, when that is not possible, these patients can also be treated with combination therapies in the clinic. In our clinic, we have had at least one striking case in which single-checkpoint inhibition failed and the addition of another checkpoint inhibitor (ipilimumab) led to an excellent result in a dire situation. ■
Disclosure: Dr. Nghiem has served in a consulting or advisory role for and has received travel funding from EMD Serono and has received research funding from Bristol-Myers Squibb.
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