Merkel Cell Carcinoma

Introduction

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer driven by integrated Merkel cell polyomavirus (MCPyV) or UV signature mutations. MCC is associated with advanced age (> 70 years), fair skin, male sex, and immunosuppression.^1,2 Here we review the characteristics and management of MCC.

Epidemiology

In the United States (U.S.), MCC incidence is 0.7 per 100,000.² MCC incidence is higher in countries having more UV exposure, with Australia and New Zealand rates being 2.5 and 0.96 per 100,000 respectively.³ Most MCC cases develop on UV-exposed skin with 42.6% of cases presenting on the head and neck, followed by 24.1%, 14.5%, and 9.4% of cases occurring on the upper limbs, lower limbs, and trunk. Fair skin is also a risk factor for MCC, with close to 90% of cases occurring in white patients.⁴

MCC is a disease of advanced age, with the median age of diagnosis being over 75 years-old and less than 10% of patients presenting under age 50.^1,5 Male sex is also an MCC risk factor, as 63% of cases occur in men.⁴ MCC risk is notably higher in immunosuppressed populations, yet most patients with MCC do not have a diagnosis of immunosuppression.^1,5

Pathogenesis

MCC’s name stems from its resemblance to Merkel cells, which are touch sensors in the basal epidermis. MCC probably does not arise from normal Merkel cells, but its precise cell of origin is currently unknown.^1,5 The majority of MCC cases in the U.S. are positive for MCPyV, a small double-stranded DNA polyomavirus. Episomal MCPyV skin infection is pervasive and asymptomatic. Commensal MCPyV infection is associated with low expression levels of viral oncogenes such as the large T antigen (LT) and small T antigen (ST). Virus-positive MCC (VP-MCC) occurs through clonal integration of MCPyV DNA into the host genome and a truncating mutation in LT. Integrated MCPyV is replication deficient but expresses high levels of ST and truncated LT, both of which are thought to be involved in VP-MCC transformation.⁵

Virus negative (VN)-MCC tumors are typically caused by chronic UV exposure as evidenced by a high tumor mutational burden and enrichment of somatic UV-signature mutations.⁵ Although VP-MCC tumors lack enrichment of UV-signature mutations, they are nonetheless found at higher frequency on chronically sun exposed skin, suggesting an indirect role for UV in VP-MCC pathogenesis.^1,5

Diagnosis

MCC typically presents as a rapidly-growing, erythematous to violaceous skin nodule, although it may present in a skin-draining lymph node with no cutaneous primary.⁵ Diagnosis requires histopathological evaluation of tissue biopsy by an experienced pathologist. Immunohistochemistry for neuroendocrine markers such as INSM1, chromogranin A, or synaptophysin is often used to support the diagnosis.^6,7 MCC typically stains with pan-cytokeratin and neurofilament antibodies, but the most commonly used MCC marker is cytokeratin 20 (CK20). A paranuclear dot-like staining pattern for CK20 or other intermediate filaments is highly supportive of an MCC diagnosis.^5,7

Staging

The American Joint Committee on Cancer (AJCC) staging system for MCC (8^th edition) uses primary tumor size (2 cm threshold) and invasion to define Stages I and II. Stage III reflects nodal involvement or in-transit skin metastases. Stage IV requires distant metastasis with the most common sites being skin, non-regional lymph nodes, liver, bone, pancreas, and lung.⁸ Because occult nodal disease is common in MCC, sentinel lymph node biopsy (SLNB) is recommended for most patients.⁵ Recent literature also suggests that baseline imaging with fluorodeoxyglucose-PET/computed tomography (PET/CT) or CT should be considered before surgery. In a retrospective study involving 492 patients without clinical involvement of regional lymph nodes, 13.2% experienced an upstage in their MCC after baseline imaging. The same study reported that baseline imaging identified distant metastatic MCC in 10.8% of 92 patients with clinically involved regional nodes.⁹ Another study of 23 patients similarly concluded that baseline PET/CT imaging led to a change in MCC staging in 39% of patients.¹⁰ For MCC, PET/CT appears to be more sensitive than CT alone.⁹ In addition to finding smaller lesions, PET/CT detects bone and bone marrow metastases missed by CT scans.¹¹

Prognosis

Tumor stage, advanced age, male sex and virus status correlate with MCC prognosis. Approximate 5-year survival for stage I MCC is 62.8%, stage II is 34.8–54.6%, stage III is 26.8–40.3%, and stage IV is 13.5%.¹ However, more contemporary data suggest that prognosis has improved in recent years, likely due to the use of immunotherapy for advanced disease.⁴ Men with MCC are approximately 50% more likely to die from their disease than women.⁴ Similarly, advancing age is linked to increasingly lower survival.^3,4 Although VP-MCC is associated with better outcomes than VN-MCC,¹² clinical testing of tumors for MCPyV is not routinely performed.

Host immune status also impacts MCC outcomes. MCC is associated with earlier onset and poorer prognoses in immunosuppressed patient populations.¹³ The importance of the immune response in MCC is further supported by the fact that heightened levels of intratumor and peritumoral CD8+ T cells, tumor-infiltrating MCPyV-specific T cells, and PD-(L)1 expression all correlate with more positive outcomes.^14–16

An online MCC recurrence risk calculator that accounts for age, sex, tumor stage, primary site, immune status, and time since diagnosis is available at https://merkelcell.org/prognosis/recur/.¹⁷

Discussion

Emerging Biomarkers of MCC Tumor Burden

Blood based biomarker testing has the potential to predict prognosis, assess treatment response, and monitor for MCC recurrence while potentially sparing patients unnecessary imaging and biopsies. Both serology-based tests (e.g. AMERK) and circulating tumor DNA (ctDNA) are particularly promising (see Table 1). Optimally, a baseline assessment of one of these biomarkers would occur before treatment.

Table 1.

Comparison of emerging MCC peripheral blood biomarkers for surveillance. WGS, whole genome sequencing. ICI, immune checkpoint inhibitor.

	AMERK18,19	Signatera (ctDNA)20–22
Assay	Serology for MCPyV ST antibodies	WGS + bespoke PCR
Positivity rate at diagnosis	~50%	90+%
Levels after treatment	Falls in 2–3 mo	Undetectable immediately
Effect of ICI	Possible impact	None
MCPyV requirement	+	None
Worse prognosis with	Negative test at diagnosis	Still + after treatment
Surveillance frequency	Every 3 months	Every 3 months
Recurrence detection	Rising titers	Rising levels

The AMERK test detects circulating antibodies against the MCPyV ST oncoprotein and is specific to VP-MCC. When detected, the titers correlate with tumor burden, falling after excision and rising in progressive disease, sometimes before clinical detection of recurrence.¹⁸ In a study of 219 patients with MCC, 52% had positive AMERK titers. An increasing oncoprotein titer had a 66% positive predictive value for clinically evident recurrence whereas a decreasing titer had a negative predictive value of 97%. The UW MCC group, who developed AMERK, now routinely tests patients newly diagnosed with MCC with reassessment every 3 months for the first 3–4 years in those with positive baseline titers. Increasing titers prompt clinical and radiological evaluation.¹⁹ Patients with undetectable AMERK titers at the time of diagnosis have higher risk of recurrence and may benefit from increased surveillance.¹⁹ Given that immunotherapy can impact antibody production, it is possible that AMERK results may be altered in patients receiving immunotherapy. An additional serological test of antibodies to MCPyV oncoprotein is under investigation in a large prospective MCC cohort in Europe (NCT04705389).

Quantifying ctDNA can also be used to assess recurrence risk, treatment response, and monitor for progression. MCC cells can release DNA as they die and ctDNA levels in the blood approximate real-time tumor burden, regardless of MCPyV status.²⁰ Signatera is the most widely used commercial ctDNA platform for MCC. It uses whole genome sequencing of the tumor to identify patient-specific DNA sequence variants. Next, custom PCR primers are designed for targeted sequencing of multiple variants from the patient’s blood.²⁰ In some patients serially assessed with Signatera, positive ctDNA results preceded a clinical diagnosis of recurrence, allowing for earlier therapeutic intervention. Additionally, among 75 patients with negative ctDNA tests during post-treatment surveillance, none experienced recurrence.^21,22 In contrast to the AMERK test, all patients with clinically evident MCC at diagnosis were found to have positive ctDNA testing.²²

Treatment

The standard of care for locally advanced or metastatic MCC (mMCC) has changed significantly over time. Given MCC’s rarity, randomized controlled trials are uncommon. As a result, patients with MCC benefit from evaluation by a multidisciplinary tumor board and consideration of clinical trials. We will highlight the current consensus on MCC treatment based on the NCCN and SITC guidelines with special attention to clinical dilemmas and areas actively assessed in current research (see Table 2). A graphical summary of treatment guidelines is provided in Figure 1.

Table 2.

Ongoing Merkel cell carcinoma

Intervention	Agent	Trial	EE
Adjuvant Immunotherapy
Anti PD-L-1	Avelumab	ADAM (NCT03271372)	100
	Avelumab	I-MAT (NCT04291885)	132
Anti-PD-1 1 RT/anti-CTLA4	Nivolumab 1 RT/ipilimumab	NCT03798639	7
Neoadjuvant Immunotherapy
Anti-PD-1	Pembrolizumab	STAMP (NCT03712605)	280
	Pembrolizumab	NCT05496036	15
Anti-PD-1 1 VEGFR	Pembrolizumab 1 Lenvatinib	NCT04869137	26
Refractory to PD-(L)1 Inhibition
Anti-PD1 1 anti-LAG3 1 anti-TIM3	Retifanlimab 1 Tuparstobart 1 Verzistobart	NCT06056895	20
Anti-PD-1 1 RT	Avelumab CART	NCT04792073	18
	Pembrolizumab 1 PRRT	NCT05583708	18
ATRi	Tuvusertib Avelumab	MATRiX (NCT05947500)	50
MDM2i	Navtemadlin 1 Avelumab	NCT03787602	115
HDACi	Dominostat Avelumab	NCT04393753	19
First Line Systemic Therapy
Anti-PD-1 1 RT	Avelumab 1 PRRT/EBRT	NCT04261855	38
	Pembrolizumab SBRT	NCT03304639	9
Anti-PD-1 1 platinum chemo	Pembrolizumab 1 cisplatin/carboplatin and etoposide	NCT06086288	35
	Retifanlimab 1 platinum-etoposide	NCT05594290	36
Targeted Therapy
DNA vaccine	ITI-3000	NCT05422781	6
Gene modified immune cells	aNK and ALT-803	NCT02465957	24
Surveillance Biomarkers
Biomarkers	ctDNA 1 miR375	SUMMERTIME (NCT04705389)	150
Radiation Therapy
RT vs surgery	Radical RT vs surgery	NCT05253144	64
RT	Hypofractionated RT	NCT05100095	RT

Abbreviations: aNK, activated NK-92 natural killer cells; CART, comprehensive ablative radiation therapy; EBRT, external beam radiation therapy; EE, estimated enrollment; PRRT, peptide receptor radionuclide therapy; RT; radiation therapy; SBRT, stereotactic body radiation.

Clinical trials from clinicaltrials.gov.

Figure 1.

MCC Treatment Algorithm. *PET/CT is preferred. ^†ctDNA^21,22 and AMERK¹⁹ have demonstrated promising early results but are not yet recommended by treatment guidelines. ^‡For patients ineligible for surgery. ^§If clinical suspicion remains high. ^¶If high risk for false negative SLNB.

Abbreviations: SLNB, sentinel lymph node biopsy; RT, radiotherapy; ICI, immune checkpoint inhibition; FNA, fine needle aspiration; Bx, biopsy; CLND, complete lymph node dissection.

Surgery

Per NCCN guidelines, surgical excision of the primary tumor is first line therapy in MCC.^23,24 1-2cm surgical margins are recommended with narrower margins if adjuvant RT is performed.^23,24 Surgical excision may be performed by Mohs micrographic surgery (MMS) or wide local excision (WLE). In a retrospective study of 2359 patients with MCC in the SEER registry, there was no difference in MCC-specific survival between the MMS and WLE groups. However, patients undergoing MMS were less likely to receive a SLNB. Overall, patients in both the MMS and WLE groups who received a SLNB demonstrated improved survival.²⁵ This underscores the importance of performing SLNBs in conjunction with MMS. A benefit of WLE over MMS is that SLNB can be conducted concurrently.

Radiation Therapy

Prompt adjuvant radiation to the primary tumor site and, if involved, the regional lymph node basin is standard of care and reduces time to locoregional recurrence (LR) and improves disease free survival (DFS) when compared to surgery alone.^23,24 The use of adjuvant RT is associated with an overall survival benefit in patients with stage I/II MCC (HR 0.783, P < 0.02).²⁶ However, if stage I tumors are resected with negative margins and the patient is deemed low risk (primary tumor <1cm, no immunosuppression, not on the head and neck, and no lymphovascular invasion), foregoing adjuvant RT may be considered.^23,24 A recent retrospective study found no difference in LR in non-head and neck stage I MCC treated without RT.²⁷

The approach for RT in nodal disease is less well-defined. Regional RT may be considered for clinically evident nodes, patients who are clinically node negative but at high risk for nodal disease, as a monotherapy for positive SLNB, or as adjuvant after LN dissection.²⁴

In the U.S., RT monotherapy is typically reserved as palliative care in nonsurgical candidates.²⁴ In a systematic review of definitive RT for nonsurgical candidates with macroscopic locoregional disease, 34.9% of patients were disease-free at final follow up.²⁸ MCC outcomes of definitive RT versus surgery are currently being assessed in patients without metastases beyond the regional lymph nodes (NCT05253144).

Data for RT dosing in MCC is limited and current recommendations are based on RT use in similar cancers. NCCN recommends conventionally fractionated adjuvant RT (50 Gy in 2Gy doses) in cases with negative resection margins.²⁴ Single fraction (SF, 8 Gy) can be used in the palliative setting and may be an alternative to conventional dosing to decrease patient morbidity. In a retrospective study of stage I/II MCC patients with at least one high risk feature receiving adjuvant SF RT, no local reoccurrences were observed at a median follow up of 2.3 years.²⁹ The safety profile was favorable, with no side effects greater than grade 1 observed.²⁹ An additional hypofractionated, reduced dosing regimen using 10 fractions of 3.6 Gy is under investigation (NCT05100095).

Lymph Nodes

SLNB is recommended for all patients with MCC. Even if clinically node negative, patients still have a 30% risk of occult nodal disease.²³ In patients that are clinically node positive, a fine-needle aspiration or core biopsy is indicated. Patients with clinically enlarged nodes and negative biopsy results may still benefit from an excisional biopsy if at high risk for nodal disease. Patients with a positive FNA or core biopsy and no metastatic disease on imaging may receive a nodal dissection with or without RT.²⁴

Immunotherapy

MCC is an immunogenic cancer, as demonstrated by an increased incidence in patients with immunosuppression and a dramatic response to immunotherapy.^13,30 PD-(L)1 immune checkpoint inhibitors (ICI) are recommended as a first line (1L) treatment in locally advanced, recurrent or mMCC.^23,30 Avelumab, pembrolizumab and retifanlimab are currently FDA approved for MCC based on trial results detailed in Table 3. Nivolumab is not FDA-approved for MCC but has been tested in clinical trials with positive results (see Table 3). ICI immunotherapy has a similar safety profile in patients with MCC as in patients with melanoma and other solid cancers.³⁰

Table 3.

Results of the landmark immunotherapy clinical trials for MCC.

Trial	Overview	Participants (N)	ORR (%)	OS	Median DOR
JAVELIN A55,56	2L avelumab for advanced chemo refractory MCC	88	33.0	26.0% (5-year)	NR
JAVELIN B42	1L avelumab for treatment naïve mMCC	116	39.7	20.3m (median)	18.2 m
KEYNOTE-017	1L pembrolizumab for advanced unresectable MCC	50	58.057	59.4% (3-year)58	NR59
PODIUM-20160*	1L retifanlimab for advanced/metastatic chemo naïve MCC	65	46.2	NR	NR
CheckMate 35861	1L nivolumab vs nivolumab + ipilimumab in recurrent or mMCC	68	60.0 N vs 58.1 N/I	80.7m N vs 29.8m N/I (median)	60.6m N vs 25.9m N/I
Kim et al. 202248	Nivolumab + ipilimumab ± SBRT in advanced ICI naïve MCC	24	100 N/I vs 100 N/I +SBRT	NR	NE
	Nivolumab + ipilimumab ± SBRT in advanced MCC with previous ICI	26	42.0 N/I vs 21.0 N/I +SBRT	14.9m vs 9.7 m (median)	15m vs 5m

^*Updated results on the full cohort of 101 patients were presented at the European Society for Medical Oncology Annual Meeting in 2023 and will be published shortly.

Abbreviations: ORR, objective response rate; OS, overall survival; DOR, duration of response; 2L, second line; NR, not reached; 1L, first line; mMCC, metastatic Merkle cell carcinoma; N, nivolumab; N/I, nivolumab and ipilimumab; m, months; NE, not estimable; SBRT, stereotactic body radiation therapy; ICI, immune checkpoint inhibitors

Considerations for Selecting an Immunotherapy

The optimal first-line immunotherapy for MCC has not yet been determined as head-to-head trials are lacking. Heterogeneity in clinical trial designs limits drug comparisons. Of the landmark immunotherapy trials so far, objective response rate (ORR) ranges from 33% for second line (2L) avelumab up to 100% for 1L nivolumab with ipilimumab (see Table 3). However, attempting to estimate response rates for these agents based on their small landmark studies is problematic as values often differ from real world use.

Avelumab was the first ICI approved for MCC and it also has the most real-world data reported. Prior to avelumab’s FDA approval, a worldwide expanded access program allowed for the compassionate use of the drug outside of clinical trials. In a global cohort with 240 patients, real-world ORR (rwORR) was 46.7% and was consistent across 1L (n=15) and 2L (n=225) subgroups. In patients with a response, median duration of treatment was 7.9 months.³¹ Several avelumab-treated cohorts in the United States have been studied with rwORR ranging between 53.57–75.3% in the 1L setting and between 35.0–64.7% in the 2L setting.^32–34 Overall, survival has also been reported in cohorts from England, Germany, Israel, and Japan, ranging from 13.3 to 52.0 months for stage III and IV patients receiving 1L or 2L therapy.^35–38 No new safety signals arose in the real world studies. These studies suggest a more favorable ORR for avelumab than was seen in the JAVELIN trial.

Significantly less real-world MCC data is available on other immunotherapies. Two cohort studies examine the ORR to anti-PD(L)-1 ICI overall. In 36 patients treated at the Moffit Cancer Center with various regimens of pembrolizumab, avelumab, nivolumab or combination therapy, rwORR was 44%.³⁹ Notably, many patients received other systemic therapies prior to ICI. In 18 patients treated at 3 German clinical centers, 6 (33%) received nivolumab with a ORR of 43% and 8 received pembrolizumab with a ORR of 29%.⁴⁰ In a case series of 7 patients receiving 1L pembrolizumab, ORR was 66.7%. At a median follow up of 16.5 months, three 3 out of 4 responses were durable.⁴¹ Moving forward, we hope to see real-world efficacy and safety data on larger cohorts of patients treated with pembrolizumab, retifanlimab, or nivolumab.

Besides ORR, there are many other factors to consider when choosing an ICI. In terms of safety, side effect profiles are similar across the ICI agents and consistent with what is expected for the PD-(L)1 inhibitor class. An exception is avelumab, which displays a higher incidence of low-grade infusion reactions, with 73.5% (n=25) of patients receiving 1L therapy experiencing reactions upon their first infusion.⁴² Another difference between approved ICI drugs is dosing schedules. Avelumab is administered every 2 weeks, with pembrolizumab administered every 3 weeks and retifanlimab administered every 4 weeks.

Adjuvant and Neoadjuvant Immunotherapy

With the high therapeutic efficacy of ICIs in treating advanced MCC, there is considerable interest in the potential of neoadjuvant and adjuvant immunotherapy to reduce recurrence risk in patients with resectable disease. SITC guidelines recommend patients with resectable MCC at high risk for recurrence be enrolled in clinical trials of neoadjuvant or adjuvant immunotherapy.³⁰ Neoadjuvant immunotherapy is theorized to stimulate more robust anti-tumor T cell responses due to more available tumor antigen, and it has the potential to decrease surgical morbidity by reducing tumor size before resection. On the other hand, surgical resection is delayed by neoadjuvant therapy, which may allow for disease progression to the point where surgery is no longer possible. Serious adverse events related to neoadjuvant therapy could potentially delay surgery even further.⁴³ Adjuvant therapy is thought to decrease disease recurrence by eliminating micrometastases after surgery and may counter the postoperative immunosuppressive environment.⁴⁴ Given the positive results of neoadjuvant and adjuvant ICI use in high-risk resectable melanoma,⁴⁵ it is reasonable to wonder whether a similar clinical benefit can be observed in MCC.

Nivolumab has been tested as a monotherapy for resectable MCC in both the neoadjuvant and adjuvant setting. In the CheckMate 358 trial, 36 patients with stage IIA to IV MCC received neoadjuvant nivolumab prior to surgery and 47.2% achieved a pathologic complete response.⁴⁶ Nivolumab was also tested in the adjuvant setting for completely resected MCC lesions of any stage. In 118 patients who received adjuvant nivolumab, interim data analysis demonstrated DFS rates of 85% at 12 months and 77% at 24 months, compared to 77% at 12 months and 73% at 24 months for in the observation group. Overall survival data were not mature, and the final survival analysis is pending.⁴⁷

Further research on neoadjuvant or adjuvant ICI use in resectable MCC is needed before changes are made to clinical practice. Several ongoing prospective clinical trials address this question. Adjuvant nivolumab versus nivolumab with ipilimumab is under investigation for high risk or node positive MCC (NCT03798639). Adjuvant avelumab is being assessed in stage III (NCT03271372) and stage I to III MCC (NCT04291885). Pembrolizumab is under investigation in the adjuvant setting for patients with stage I to III MCC (NCT03712605) in the neoadjuvant-adjuvant setting alone (NCT05496036) and in combination with lenvatinib, a VEGR receptor inhibitor (NCT04869137). Neoadjuvant retifanlimab (NCT05594290) and cemiplimab (NCT04975152) are being tested as well.

Patients Refractory to PD-(L)1 Inhibition

Although immunotherapy is highly efficacious, almost half of patients with advanced MCC have tumors that are refractory to 1L anti-PD-(L)1 drugs. There are few effective therapeutic options for these patients, as switching from one anti-PD-(L)1 therapy to another is unlikely to be beneficial.³⁰ The addition of anti-CTLA-4 therapy to anti-PD-(L)1 therapy is a promising option. Kim et al. demonstrated an ORR of 31% in 26 patients with MCC and previous ICI who were treated with 2L nivolumab and ipilimumab, with no benefit from the addition of SBRT.⁴⁸ Additional retrospective studies have reported response rates of 31% and 50% to combination nivolumab and ipilimumab therapy for MCC refractory to prior anti-PD-(L)1 therapy.^49,50 Notably, patients had heterogenous treatment histories, with some having additional systemic therapies in between their initial anti-PD(L)1 treatment and the combination therapy.

Advancing effective treatments for anti-PD(L)1 resistant MCC is a key focus in current clinical trials. Active studies focus on the addition of new RT regimens (NCT04792073, NCT05583708), targeted therapies (NCT05947500, NCT03787602, NCT03787602), triplet immunotherapy (NCT06056895) and genetically modified immune cells (NCT03747484) (see Table 2).

When to Discontinue Immunotherapy

The optimal duration of ICI therapy for MCC remains unclear. Retrospective studies have investigated the duration of response after ICI discontinuation for reasons other than disease progression. Stege et al. demonstrated a 60% rate of relapse after ICI discontinuation in 20 patients with mMCC with a median ICI duration of 10 months.⁵¹ In a more recent study by Weppler et al. of 40 patients with mMCC and a median ICI duration of 13.5 months, 35% of patients relapsed at a median follow up of 12.3 months.⁵² Neither study demonstrated a relationship between duration of initial ICI and response durability. However, both studies noted a decreased risk of disease progression in those with a complete response.

Zijilker et al. recently published the first study with a uniform protocol for discontinuation of ICI in MCC. Sixty-five patients with mMCC were treated with avelumab for 1 year if complete response was observed on FDG-PET/CT or until unacceptable toxicity. Of the 25 patients with a complete response, only 2(8%) relapsed.⁵³ In contrast, in the preceding retrospective Stege et al. and Weppler et al. studies, complete responders relapsed at a rate of 33% and 26% respectively.^51,52 However, these studies did not require PET/CT for confirmation of complete response and allowed multiple ICI agents. Another recent study investigated reducing ICI frequency to every 3 months after initial disease control for metastatic melanoma and MCC. Only 5 patients with MCC were included and 100% experienced a 36-month progression-free survival rate after reduced frequency dosing.⁵⁴

Based on these studies, degree of response, rather than treatment duration, seems to be an important predictor of disease progression off ICI. In patients with PET/CT confirmed complete response, a year of ICI may be sufficient.⁵³ Alternative dosing regimens after complete or durable partial responses should be explored. As indefinite ICI is impractical and often unfeasible, larger studies investigating the optimal duration of ICI are required.

Chemotherapy

Historically, chemotherapies were the primary systemic treatments for advanced MCC. Chemotherapy demonstrated response rates comparable to those seen in immunotherapy. Yet responses were not durable, with a median duration of response ranging from 2–9 months.²⁴ As a result, chemotherapy is now reserved as a palliative treatment option or for patients who are ineligible for immunotherapy.⁵

Clinics Care Points

• ○ An MCC diagnosis is confirmed via histopathology, with CK20 immunostaining in a perinuclear dot pattern being most specific.

• ○ All eligible patients should receive a SLNB and most patients should receive PET/CT imaging in their initial staging workup.

• ○ AMERK and ctDNA testing upon diagnosis can be tracked serially to assess tumor burden and monitor for recurrence.

• ○ Locoregional MCC is typically treated with surgical resection and adjuvant RT. Immunotherapy is the mainstay of treatment for advanced disease.

• ○ Multidisciplinary management and clinical trials are preferred for patients with MCC.

Key points:

• MCC is associated with integrated Merkel cell polyomavirus and UV exposure

• Emerging biomarkers have prognostic value, can monitor treatment response, or screen for recurrence

• MCC treatment includes surgical resection and radiation therapy for early-stage disease and immunotherapy for advanced disease

• Clinical dilemmas in MCC treatment include optimal RT dosing, neoadjuvant versus adjuvant immunotherapy, optimal duration of immunotherapy, and second-line treatment options for disease refractory to anti-PD-(L)1 therapy

Synopsis:

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that is highly radiosensitive and immunogenic. Immunotherapy is the primary treatment for advanced disease, and immune checkpoint inhibitors show promise as neoadjuvant or adjuvant therapy in patients with high-risk resectable MCC. Emerging biomarkers of tumor burden are becoming increasingly important in identifying high-risk patients and in post-treatment surveillance. Further research is needed to determine the optimal duration of anti-PD-(L)1 treatment and second-line options for patients with MCC refractory to immunotherapy. This review covers the characteristics and management of MCC including recent innovations and areas of active investigation.