CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: May 09, 2023
Expiration: May 08, 2024
Merkel Cell Carcinoma
Zeynep Eroglu, MD:
There are several notable characteristics of patients with MCC. Patients with MCC tend to be older than 70 years of age.11 Similar to BCC and cSCC, immunosuppression and UV exposure from the sun are also risk factors for MCC. Merkel cell polyomavirus positivity is also a risk factor for MCC.
Patients with metastatic MCC have a much worse prognosis. The historic 5-year survival rate for these patients is approximately 14%.
Surgery remains the standard treatment for those with resectable primary MCC, similar to BCC and cSCC. Radiation also may be used in the adjuvant setting or if complete surgery is not feasible. Historically and before the advent of immunotherapy, chemotherapy was used for MCC with very poor outcomes. Typically, the median time to progression was only approximately 3-8 months.
However, we now have 3 FDA-approved immunotherapy drugs for MCC: avelumab, pembrolizumab, and retifanlimab, which was just recently approved.15,26,27
JAVELIN Merkel 200: Avelumab in Metastatic Merkel Cell Carcinoma
Zeynep Eroglu, MD:
In phase II JAVELIN Merkel 200 trial, avelumab (an anti–PD-L1 antibody) was evaluated in patients with metastatic MCC.28-30 This trial had 2 cohorts. Part A of the trial enrolled patients (n = 88) who received avelumab in the second-line setting, whereas Part B evaluated avelumab in the first-line setting (n = 116). In this trial, avelumab 10 mg/kg was given every 2 weeks until disease progression, unacceptable toxicity, or withdrawal.
The primary endpoints were the best overall response for Part A and the durable response rate for Part B.
JAVELIN Merkel 200: Response
Zeynep Eroglu, MD:
The response rate with avelumab treatment in Part A was 33% with avelumab with a CR rate of 10%.28 The median DoR was quite prolonged at 40 months.
In the treatment-naive Part B, the response rate was 40%, the CR was 19%, and the median DoR was much shorter at approximately 18 months.29 Of note, many of the responses were seen quite early, typically within the first 2 months (median 6.1 weeks).
JAVELIN Merkel 200 (Part A and Part B): Survival
Zeynep Eroglu, MD:
In Part A, with second-line avelumab, the 3-year PFS rate was 21%, whereas the 3-year OS rate was 32%.28,30 In a longer follow-up, the 5-year OS rate was 26% with a median OS of 12.6 months.30
In Part B, first-line avelumab treatment resulted in a 1-year PFS rate of 31%, whereas the 1-year OS rate was 60%.29 The median PFS was 4 months, and the median OS was 20.3 months.
Based on the results of the JAVELIN Merkel 200 trial, avelumab was approved by the FDA for adult and pediatric patients 12 years of age or older with metastatic MCC.26
JAVELIN Merkel 200: Survival
JAVELIN Merkel 200 (Part A): Safety
Zeynep Eroglu, MD:
The safety of avelumab in MCC was similar to what we would expect with the use of immunotherapy drugs, with most patients having manageable irAEs.28 Approximately 11% of patients had a TRAE that was grade ≥3. The most common TRAEs were fatigue (25%), diarrhea (12.5%), nausea (12.5%), and rash (9%).
CITN-09/KEYNOTE-017: Pembrolizumab as First-line Therapy in Advanced Merkel Cell Carcinoma
Zeynep Eroglu, MD:
Pembrolizumab is another anti–PD-1 antibody that is approved by the FDA as of 2018 for patients with recurrent locally advanced MCC or metastatic MCC.15 The approval was based on the results of the KEYNOTE-017 trial, which was a phase II study that enrolled patients (N = 50) with distant, metastatic, or locoregional MCC.31 Again, eligibility for this study required surgery and radiation to no longer be options for the patients. Patients received pembrolizumab for up to 2 years with the primary endpoint being ORR.
CITN-09/KEYNOTE-017: Response
Zeynep Eroglu, MD:
The ORR was 58% with a CR of 15%. The median DoR was not reached at the time of reporting.
Analyses were carried out to measure any association between PD-L1 expression or Merkel cell polyoma viral status with response to pembrolizumab in MCC, but there was no clinically significant correlation. The viral status of the MCC did not appear to predict benefits with immunotherapy drugs. Outcomes with immunotherapy have been similar across both viral and nonviral MCCs, despite these 2 subtypes having some distinct genomic profiles. Therefore, we do not typically test PD-L1 expression or other biomarkers currently when deciding to treat patients with immunotherapy with MCC.
CITN-09/KEYNOTE-017: Survival
Zeynep Eroglu, MD:
The 3-year PFS rate was 39%, whereas the median PFS was 16.8 months. The 3-year OS rate was close to 60%, with the median OS not yet reached. There are far better outcomes with immunotherapy drugs in MCC as compared with chemotherapy drugs, which had a median PFS of 3-8 months.
As for optimal treatment duration, we do not have great data on this. Typically, in these studies, patients were treated for up to 2 years. Again, we can consider potentially stopping earlier if there is a CR, after approximately a year. Because of the aggressive biology of MCC and the high risk of relapse, we recommend close follow-up when patients come off immunotherapy. This constitutes typically doing scans at least every 3-6 months for the first few years, and then potentially, the frequency of imaging can be reduced. Regular skin examinations are necessary for all the NMSCs we discussed. In addition, lymph node examinations are also very important in the postimmunotherapy surveillance of patients with MCC, BCC, and cSCC.
CITN-09/KEYNOTE-017: Safety
Zeynep Eroglu, MD:
There were no new safety signals noted in this trial, and AEs were typical as seen with immunotherapy. Thirty percent of patients had grade ≥3 TRAEs. Sixteen percent of patients discontinued the study due to a TRAE, and there was 1 treatment-related death during this trial.
Retifanlimab in Merkel Cell Carcinoma
In March 2023, a new anti–PD-1 inhibitor, retifanlimab, was also approved for patients with metastatic or recurrent locally advanced MCC.27 This approval was based on the phase II PODIUM-201 trial (NCT03599713) that enrolled 65 patients who were chemotherapy naive. Patients received 500 mg IV retifanlimab every 4 weeks for up to 24 months. The reported ORR was 52% at the time of approval, but we await the final publication of this trial.27,32
Nivolumab + Ipilimumab ± SBRT in MCC: Tumor Response
Zeynep Eroglu, MD:
One of the major challenges with MCC, similar to cSCC and BCC, is the limited options available to patients who progress while receiving anti–PD-1/PD-L1 therapy. Chemotherapy could be used in that PD-1 refractory setting, but typically there are very poor outcomes. Switching from one PD-1/PD-L1 antibody to another is typically not beneficial. Because of this, we strongly urge enrollment on clinical trials for such patients.
One recent trial explored the combination of nivolumab and the anti–CTLA-4 ipilimumab with or without stereotactic body radiation (SBRT) in advanced MCC.33 Ipilimumab was given at 1 mg/kg every 6 weeks with every-2-week nivolumab 240 mg. Both drugs were continued for up to 2 years of this trial.
This study had 2 cohorts and enrolled 50 patients. One cohort included patients (n = 24) who did not have prior immunotherapy therapy. This cohort demonstrated a 100% ORR. The second cohort consisted of patients (n = 26) refractory to prior PD-1/PD-L1 therapy. In this cohort, the ORR was approximately 30%. The trial also looked at whether SBRT added any benefit to the immunotherapy, but there was no difference seen with the addition of SBRT.
Ipilimumab + Nivo ± SBRT in MCC: Progression-Free Survival
Zeynep Eroglu, MD:
The median PFS in the immunotherapy-naive groups was not reached in this analysis. The median PFS was approximately 3-4 months for those with prior immunotherapy who received nivolumab plus ipilimumab with or without SBRT.
Thus, combination of nivolumab plus ipilimumab is a potential option to consider for patients with MCC, particularly those with MCC refractory to upfront anti–PD-1 therapy.
Select Ongoing Studies in Merkel Cell Carcinoma
Zeynep Eroglu, MD:
Additional studies are exploring the use of various immunomodulatory agents such as interleukin (IL)-12, IL-15, and IL-17 alone or in combination with immunotherapy drugs as well as the use of oncolytic viruses in MCC. Ongoing trials also are looking at radiation therapy, toll-like receptor agonists, and the use of adoptive cell therapies. Again, patients with MCC who are refractory to immunotherapy should be encouraged to enroll on ongoing clinical trials.
CheckMate 358: Neoadjuvant Nivolumab in Resectable MCC
Zeynep Eroglu, MD:
Immunotherapy also has been considered in the neoadjuvant setting in MCC. The CheckMate 358 trial investigated up to 2 doses of neoadjuvant nivolumab including 1 cohort of 39 patients with MCC.34 To be eligible, these patients had to have resectable MCC.
There was a pCR rate of 47%, at a median follow-up of 20 months, and the median relapse-free survival and OS rates were not yet reached. There were 3 patients who could not undergo the planned surgery for their resectable disease. One had disease progression before surgery and 2 had AEs. This is something important to be aware of when using neoadjuvant therapy: the small risk that a tumor may become unresectable.
We typically only encourage the use of neoadjuvant approaches in the NMSCs in clinical trials when available. If clinical trials are not available, using a multidisciplinary team approach involving surgeons, radiologic oncologists, and medical oncologists is critical to identify appropriate patients.
ADMEC-O: Adjuvant Nivolumab in MCC
Zeynep Eroglu, MD:
Moving to the adjuvant setting, the ADMEC-O study was a phase II trial comparing a year of adjuvant nivolumab with observation in 179 postsurgical patients with MCC.35 At 2 years, 87% of patients receiving nivolumab were disease-free compared with 74% on observation only. However, this was not a statistically significant difference, and the OS data from the study are not yet mature.
Select Adjuvant Immunotherapy Trials in Advanced Merkel Cell Carcinoma
Zeynep Eroglu, MD:
Here are 2 other ongoing trials looking at the use of adjuvant immunotherapy in MCC. The STAMP trial (NCT03712605) is evaluating pembrolizumab vs observation in patients with completely resected MCC. In this trial, radiation therapy was optional in either arm.
The ADAM trial (NCT03271372) is looking at adjuvant avelumab vs placebo in patients who completed definitive surgery or primary radiation therapy. The primary endpoint for both of these trials is relapse-free survival. We eagerly await data from these studies to see what the role of immunotherapy in the adjuvant setting may be for MCC.
In summary, immunotherapy with anti–PD-1/PD-L1 therapy would be our preferred systemic therapy option for advanced MCC. We will need more data from the neoadjuvant and adjuvant studies for MCC, cSCC, and BCC to determine the optimal use of immunotherapy drugs in those settings. As mentioned previously, we strongly encourage ongoing enrollment on clinical trials for earlier-stage and advanced NMSCs to address some of the current treatment gaps that we have for our patients.
MCC Key Takeaways
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