Avelumab (Bavencio)

Merkel cell carcinoma, also known as primary cutaneous neuroendocrine carcinoma,¹ was characterized in 1972.² It is a rare but challenging neuroendocrine cancer of the skin that may sometimes be misdiagnosed as basal cell carcinoma.³ The differential diagnosis may include lymphoma, small cell melanoma, metastatic small cell lung cancer to the skin, and other cutaneous small round cell neoplasms.¹ Confirming a diagnosis, therefore, requires histopathologic and immunohistochemical studies. Unfortunately, this malignancy is aggressive, frequently metastatic, and the prognosis is generally poor. More than one third of patients (33% to 46%) die of their disease.^4,5

In many cases, Merkel cell polyomavirus is a contributing factor to the development of Merkel cell carcinoma⁶; somatic mutations induced by ultraviolet light exposure and subsequent DNA damage likely also contribute to the development of the disease.⁷ There is a higher incidence of Merkel cell carcinoma among immunosuppressed individuals, such as those who have received organ transplants or have HIV infection,⁸ and it is strongly associated with advancing age. It is seldom seen in patients younger than age 40 but increases in incidence among the elderly (80 years and older).^9,10

More Aggressive Than Melanoma

Although relatively rare, according to Shailender Bhatia, MD, Associate Professor at the University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Merkel cell carcinoma is “the most aggressive skin cancer.” Almost half (45%) of patients with Merkel cell carcinoma will eventually develop metastatic disease. The median survival for patients presenting with metastatic Merkel cell carcinoma is about 1 year, and almost all patients with metastatic disease will die within 5 years.¹¹ The incidence of Merkel cell carcinoma is increasing more than that of melanoma,¹² likely as a result of general increases in longevity (Merkel cell carcinoma is a disease of older age), which may be associated with higher cumulative ultraviolet light exposure and weakening of the immune system.

Around 80% of the cases of Merkel cell carcinoma in the United States are associated with polyomavirus and expression of viral antigens, which confer immunogenicity to the cancer cells.

“Around 80% of the cases of Merkel cell carcinoma in the United States are associated with polyomavirus and expression of viral antigens, which confer immunogenicity to the cancer cells,” Dr. Bhatia told JNCCN 360. In virus-negative cases, “the mutational burden is unusually high, potentially from intense sun exposure, and may involve many neoantigens, which may also contribute to a robust immune response.”

Diagnosis is usually made by a dermatologist as a result of investigating a skin lesion. Of note, Merkel cell carcinoma may initially appear to be nonspecific and not particularly alarming, Dr. Bhatia explained. However, within a short period (days or weeks), “the lesion starts behaving aggressively, with rapid growth that prompts the dermatologist to obtain a biopsy.” When the pathology report indicates “Merkel cell carcinoma,” patients are unlikely to be familiar with the diagnosis, “and often it is the first case for many of [the] physicians, too,” Dr. Bhatia observed.  

Emergence of Immunotherapy for Merkel Cell Carcinoma

Until recently, chemotherapies were the only systemic therapy options for stage IV Merkel cell carcinoma. Response rates to chemotherapy are highly variable. Even if the tumor initially responds well to chemotherapy (objective response rate, ~55%), the duration of response is usually short, and disease progression is seen within as few as 3 months.¹³

On the basis of the high immunogenicity seen in Merkel cell carcinoma, researchers designed a clinical trial to evaluate the immune checkpoint inhibitor avelumab, in patients with stage IV Merkel cell carcinoma who experienced disease progression on at least one line of chemotherapy; however, many patients had been treated with multiple lines before enrolling on the trial.¹⁴

“What we observed,” Dr. Bhatia said, “was that avelumab worked well for a proportion of patients: about one-third of patients had objective responses. The most promising finding, however, was that for those patients who achieved response, it was long-lasting. We now have longer term data with at least 3-year follow-up, and it appears that most of the responders are continuing to benefit, without progression of disease.”¹⁵ Although some patients continue treatment beyond 2 or 3 years, most discontinue treatment. Nevertheless, benefit appears to remain unchanged, Dr. Bhatia reported, even after treatment is completed.

We now have longer term data with at least 3-year follow-up, and it appears that most of the responders are continuing to benefit, without progression of disease.

The current version of the NCCN Clinical Practice Guidelines in Oncology for Merkel Cell Carcinoma¹⁶ recommends avelumab, pembrolizumab, or nivolumab as preferred options for systemic therapy for the treatment of stage IV metastatic disease. Treatment in the context of a clinical trial is another preferred option, and radiation and surgery may also be considered for patients with advanced disease.

Second-Line vs Front-Line Treatment

It seemed that many lines of previous treatment were correlated with a lower likelihood of response in the first part of the JAVELIN Merkel 200 trial.^14,15 Moreover, although avelumab was effective in some patients with Merkel cell carcinoma, even after chemotherapy,^14,15 the best response rates, Dr. Bhatia pointed out, are seen in those who were chemotherapy-naive, ie, in the front-line setting.¹⁷

“We believe that chemotherapy negatively affects the immune system, decreasing the effectiveness of immune checkpoint inhibitor therapy,” Dr. Bhatia told JNCCN 360. “It looks like the response rate goes down as the number of previous lines of chemotherapy increases. This seems to be generally true with immune checkpoint inhibitors. In chemotherapy-naive patients, the response rates are roughly between 50% and 60%. In contrast, those who received one line of chemotherapy were in the 40% response range, and those who received more than one line of chemotherapy had the lowest response rates, in the 20% range. We can speculate that chemotherapy affects subsequent immunotherapy, either by rendering the cancer cells less immunogenic in some way or by weakening the host immune system, making the immune cells less able to respond vigorously.”

Dr. Bhatia also observed that the rate of moderate or severe immune-related adverse events with avelumab is higher in chemotherapy-naive patients (~20%) than in patients who had received prior chemotherapy (~5%). “This finding supports the notion that immunotherapy should be the first systemic therapy patients receive, unless there is a contraindication,” he explained.

A Role for Biomarkers?

Dr. Bhatia and other investigators were surprised by the observation that polyomavirus status did not appear to affect the likelihood of response to avelumab. It had been anticipated that patients with virus-positive Merkel cell carcinoma would have higher rates of response to avelumab due to the presence of T antigens, “but this was not the case,” Dr. Bhatia said.

“We now understand that virus-negative cases probably have a high mutational burden, which is characterized by the presence of numerous neoantigens.”¹² Similarly, PD-1/ PD-L1 is proving to be an imperfect biomarker in this setting, he noted. Although there may be a higher chance of responding to avelumab if the tumor has high expression of PD-L1, “clinically, patients with virus-negative or PD-L1–negative tumors have also responded quite well to treatment.”

Administration of Avelumab

Most oncologists and their clinical staff are familiar with the administration of immune checkpoint inhibitors. Avelumab is similar to other agents in the class, Dr. Bhatia said, but there are a few things to keep in mind.

Initially, avelumab was approved at the dose of 10 mg/kg, but in late 2018, a flat dose of 800 mg every 2 weeks was approved,^18,19 “making things easier for the infusion staff.” According to Dr. Bhatia, “there’s a slightly higher risk of mostly mild infusion reactions with avelumab during the first few cycles.” To ensure safety and tolerability, premedications, such as acetaminophen and antihistamine (eg, diphenhydramine), are recommended in the labeling for the first four infusions.¹⁹

“Of course, patients are monitored during infusion while they are in the clinic, but we also educate patients about delayed reactions that might develop after they have left the clinic. We instruct them to have diphenhydramine available and to go to an urgent care or emergency department if the reaction is serious,” Dr. Bhatia told JNCCN 360.  

The corticosteroids worked well for these patients, preventing infusion reactions, and they were on avelumab for more than 2 years, with ongoing outstanding responses several years later.

With this prophylactic plan, most patients are able to continue treatment. Occasionally, infusion reactions remain problematic. “I have approached these cases by adding corticosteroid medications,” Dr. Bhatia said. “It may seem a bit counterintuitive because these medications suppress the immune system, which is a mechanism that seems to oppose the activity of the primary treatment. Nevertheless, in my clinical experience, periodic exposure to corticosteroids prior to infusion does not seem to majorly interfere with the effectiveness of the immune checkpoint inhibitor,” he explained. “In fact, two of the best responders in the JAVELIN trial experienced infusion reactions, and the only way to enable them to continue with treatment was to administer corticosteroids. The corticosteroids worked well for these patients, preventing infusion reactions, and they were on avelumab for more than 2 years, with ongoing outstanding responses several years later,” Dr. Bhatia reported.

Patient Education and Preparation

“Because we are with a Center of Excellence for Merkel cell carcinoma, patients come to us from all over the country and certainly from the wider tristate region,” noted Jeannie Warner, RN, OCN, Clinical Nurse Coordinator on the Renal, Melanoma Team with Dr. Bhatia at the Seattle Cancer Care Alliance.

“One of the first things we review is the patient’s treatment history,” Ms. Warner said. If he or she has received chemotherapy, “I explain how immunotherapy with immune checkpoint inhibitors is different. Chemotherapy attacks all rapidly dividing cells, including normal cells, which results in hair loss, nausea, and immunocompromise. Immunotherapy is quite different, I explain: it allows the patient’s own immune system to see the cancer for the first time and to develop the cells to attack it. And then I share with patients why they may see side effects that are immune related.”

The First Dose of Avelumab…and Thereafter

Ms. Warner and her cancer care team have experience using avelumab to treat patients with Merkel cell carcinoma. “We describe what patients may experience with the first treatment, what they may feel on a day-to-day basis, and what types of more serious immune-related adverse events may occur. I always explain that the first treatment may trigger a generalized inflammatory reaction that feels like having the flu. During the first 24 hours after avelumab infusion, the patient may feel feverish, achy, and exhausted, but treatment with 500 to 650 mg of acetaminophen, fluids, and rest will alleviate most of the discomfort.” Some patients experience mild gastrointestinal changes during the first 24 hours after the first infusion. They may have decreased appetite, increased heartburn, or a mild change in bowel function. If anything more significant or dramatic occurs, the team needs to be alerted, Ms. Warner stressed.

Ms. Warner also describes what patients might expect on a daily basis. With rare exceptions, avelumab is well tolerated and does not interfere with daily activities. The team encourages patients to remain as active as possible and to maintain a healthy lifestyle. Patients are instructed to let the team know if they experience considerably more fatigue than usual. “Feeling just slightly tired is normal, but significant fatigue is something we want to hear about.”

Patients also need to hear about changes that may occur in the skin, the most common of which is dryness resulting in itching. “We urge patients to moisturize their skin and use sunscreen when exposed to sun. This is particularly important for men because moisturizing is not necessarily a part of their regular routine,” Ms. Warner pointed out. If a good moisturizing lotion does not improve the dryness of the skin and the itchiness is bothersome, “we encourage patients to be in touch with the team,” she reiterated.

Immune-Related Adverse Events

Most of the time, immune checkpoint inhibitors are tolerated well and do not seriously compromise patients’ quality of life. Nevertheless, the possibility of immune-related adverse events exists. Patients should be educated about what to look for and the importance of promptly reporting any symptoms.

“I have found that patients are sometimes reluctant to ‘bother’ us, especially when symptoms develop between visits,” Dr. Bhatia acknowledged. “Some trial protocols give these drugs every 4 weeks or even every 6 weeks. We need to emphasize to patients that we want to hear from them between visits. We have good guidelines regarding immune-related adverse events, both with regard to the severity of symptoms and to effective management.²⁰ Moreover, community oncologists are encouraged to establish relationships with their academic counterparts, especially for cases where management of serious symptoms becomes challenging,” Dr. Bhatia suggested.

The most important piece of information for patients and families—regardless of where they are receiving treatment—is how to reach their care team 24/7.

To introduce the subject of serious toxicities, Ms. Warner starts with a simple explanation of how immune therapies work. “I tell patients that immune checkpoint inhibitors exert their activity by ramping up or ‘taking the brakes off’ the immune system,” she explained. As a result, the inflammatory response may be triggered in healthy organs, and that can be a concern. “I point out there is a 10% to 15% chance of [a serious] reaction, so the likelihood is fairly low. Nevertheless, if there is a significant issue and it occurs at 10:00 PM on a Friday night, we don’t want the patient to wait until Monday. We underscore the importance of early reporting, regardless of timing. The most important piece of information for patients and families—regardless of where they are receiving treatment—is how to reach their care team 24/7. The sooner we know about these symptoms and side effects, the better. This message is reinforced many times during the first visit and then at subsequent visits,” Ms. Warner told JNCCN 360. 

Patient Monitoring and Communication With the Care Team

Using a head-to-toe approach, the team reviews signs of inflammation that patients should be aware of, emphasizing that any organ or system may be affected: skin, eyes, nervous system, respiratory system, gastrointestinal tract, kidney, liver, joints, and muscles. “We have a comprehensive, clear handout that outlines what the inflammatory response in each system may look like, but the key point is that patients should be aware of their baseline,” Ms. Warner observed. “We want to know when something is different, when a change is noticed.” If a person usually has a headache once a week and after treatment, still has a headache once a week, “I would not be concerned,” she said. But if that person started to develop a headache every day, “I’d want to know about it.”

Another important point for patients and families to understand is that the inflammatory response, in the form of a side effect, can occur after completion of therapy. Therefore, even if the patient sailed through therapy with minimal or no reactions, an inflammatory response may sometimes emerge 3 to 6 months later. This is especially pertinent in the adjuvant setting, when the number of infusions is limited.

In real life, Ms. Warner cautioned, this translates to letting community providers know that the patient had been on (or is currently receiving) immunotherapy. For instance, patients who present to the emergency department or primary care provider need to let their oncology team know what’s going on, even if active treatment has been discontinued for months. These drugs are relatively new, especially for community practitioners. Therefore, although neurologists and cardiologists may be familiar with chemotherapy-induced adverse events, they may be less familiar with the inflammatory conditions associated with immune checkpoint inhibitors, Ms. Warner observed.

Investigative Therapies and Research Network

For those with either intrinsic or acquired resistance, there are several investigative efforts underway to test combinations of drugs.²¹ For instance, there is a strong interest in combining intratumoral injection of immune-stimulatory agents with systemic immune checkpoint inhibition (ClinicalTrials.gov identifier NCT02819843). Another promising potential combination is avelumab plus virus-specific chimeric antigen receptor T cells. In addition, avelumab is being combined with allogeneic genetically modified natural killer cells plus an interleukin-15 superagonist.

Merkel cell carcinoma is a rare disease, and most clinicians may have little if any experience in treating it. Dr. Bhatia encourages professionals to contact the network of researchers and clinicians at academic centers who can serve as a key resource for education and guidance: https://merkelcell.org. He also encourages clinicians to contact him (sbhatia@uw.edu) for help with challenging cases.

DISCLOSURES

Shailender Bhatia, MD, has served as a consultant or advisor to Genentech, Bristol-Myers Squibb, EMD Serono, and Sanofi Genzyme. His institution has received research support from EMD Serono, Bristol-Myers Squibb, Merck, OncoSec Medical, Immune Design, NantKwest, and Novartis.

Jeannie Warner, RN, OCN, reported no conflicts of interest.

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