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Treatment of recurrent and metastatic Merkel cell carcinoma

Treatment of recurrent and metastatic Merkel cell carcinoma
Authors:
Song Youn Park, MD
Paul T Nghiem, MD, PhD
Patricia Tai, MB, BS, DMRT, FRCR, FRCPC
Ann W Silk, MD, MS
Section Editors:
June K Robinson, MD
Michael B Atkins, MD
Deputy Editor:
Melinda Yushak, MD, MPH
Literature review current through: Jan 2024.
This topic last updated: Sep 12, 2023.

INTRODUCTION — Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy that predominantly affects older adults with light skin types. Patients with MCC have a high propensity to develop recurrent or metastatic disease.

Among all patients with MCC, less than ten percent present with distant metastatic disease at the time of diagnosis [1]. Patients with locoregional MCC who have completed initial therapy have a 20 to 75 percent chance of recurrent or metastatic disease depending on stage at diagnosis, with a majority occurring within three years of diagnosis [2,3]. For those who recur, the proportion with initial distant, nodal, or local involvement is 52, 27, and 21 percent [4]. Recurrences are generally associated with a poor prognosis [3].

The management of locoregionally recurrent and metastatic MCC is discussed here. The staging, treatment, and surveillance of locoregional MCC and the clinical features and initial diagnosis of MCC are reviewed separately.

●(See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma".)

●(See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma".)

LOCOREGIONALLY RECURRENT DISEASE — Locoregionally recurrent MCC is defined as local, in-transit, or nodal recurrences without metastatic involvement of distant organs. Among patients who were initially diagnosed with stage I to II MCC, the risk of locoregional recurrence is approximately 10 to 30 percent [3,5,6].

Patients with locoregionally recurrent disease should be assessed for metastatic disease. Those with clinical or radiographic evidence of metastatic disease should be evaluated for systemic therapy. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'Imaging studies' and 'Metastatic disease' below.)

For most patients with locoregionally recurrent disease and no evidence of metastatic disease, we suggest initial treatment with locoregional therapies (eg, surgery and/or radiation therapy [RT]) rather than systemic therapy. The use of systemic therapy for locoregionally recurrent MCC is evolving and clinical trial enrollment is encouraged, where available (www.clinicaltrials.gov).

Local and in-transit recurrences — Although data are limited, local recurrences (tumors that recur within two centimeters of the original surgical margin) and in-transit recurrences are likely related to tumor escape through lymphovascular channels.

The optimal approach to patients with a local or in-transit recurrence is undefined. For such patients, we offer definitive local therapy (surgery and/or RT), using a similar approach to those with treatment-naïve disease. This offers patients the possibility of curative-intent therapy, especially those with resectable or slowly progressive disease. Patients who complete definitive local therapy may subsequently be observed or enrolled in clinical trials evaluating adjuvant systemic therapy; multidisciplinary discussion is necessary for such patients. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'Staging work-up and management' and "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'Adjuvant systemic therapy'.)

Patients with a resectable local or in-transit recurrence should be re-evaluated for definitive local therapy using surgical resection with or without RT. Definitive RT is also an appropriate treatment option, given that MCC is a radiosensitive tumor. For example, a hypofractionated radiotherapy regimen of 50 Gy with 70 kV-x-rays (10 fractions of 5 Gy within five weeks) was used to successfully treat a recurrent MCC of the eyelid [7].

Nodal recurrences — Patients with MCC can develop recurrent disease involving regional lymph nodes [6,8,9]. Nodal involvement, either at initial presentation or recurrence, is associated with a higher risk of subsequent distant metastases [10,11].

The optimal approach to patients with nodal recurrences is undefined. For patients with nodal recurrences, we offer curative-intent locoregional therapy (surgery and/or RT), using a similar approach to those with treatment-naïve disease who have clinically evident regional lymph nodes. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'Clinically evident regional lymph nodes'.)

Patients may also be evaluated for neoadjuvant immunotherapy prior to locoregional therapy, although this approach is seldom used by UpToDate contributors and remains investigational. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'What is the role of neoadjuvant immunotherapy?'.)

Patients who complete locoregional therapy may either be observed or enrolled in clinical trials, particularly those evaluating adjuvant immunotherapy. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'Adjuvant systemic therapy'.)

Patients for whom curative-intent surgery and/or RT is not feasible can be evaluated for systemic therapy with immune checkpoint inhibitors (ICIs), although further studies are necessary to evaluate this approach. (See 'Initial therapy' below.)

METASTATIC DISEASE — Most patients with metastatic (stage IV) disease (table 1 and table 2) are treated with systemic therapy. Clinical factors that influence treatment options include sites of disease involvement, symptoms, age, comorbidities, and available agents. Clinical trial enrollment is encouraged, where available (www.clinicaltrials.gov). Patients who are ineligible for systemic therapy may be offered alternative locoregional approaches and/or best supportive care. (See 'Locoregional therapies' below.)

Clinical presentation — Patients with metastatic (stage IV) disease (table 1 and table 2) can present with distant metastases to the skin, subcutaneous tissue, lymph nodes, or other visceral sites that are detected on clinical evaluation and/or imaging studies. MCC is an aggressive malignancy; in observational studies, approximately one-third of patients who receive initial therapy subsequently develop metastatic disease [3,10]. Patients can also present with de novo metastatic disease at initial diagnosis. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'Imaging studies'.)

Biopsy — Prior to initiating therapy, a tissue biopsy of the metastatic site should be obtained to confirm the diagnosis unless it is contraindicated due to anatomic location or patient's general condition. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Histopathology'.)

Initial therapy — For patients with advanced or metastatic MCC, we suggest initial treatment with single-agent immunotherapy (ie, immune checkpoint inhibitors [ICI]) rather than chemotherapy (algorithm 1). Single-agent immunotherapy is typically better tolerated than most chemotherapy regimens and can induce clinically meaningful, durable responses in patients with metastatic MCC. For select patients with widely metastatic, symptomatic disease burden, some UpToDate experts offer a brief course (up to two cycles) of chemotherapy to decrease tumor burden prior to initiating ICI therapy. However, data are limited for this approach and some studies suggest lower response rates when immunotherapy is used as subsequent therapy after chemotherapy [12] versus initial therapy [13]. (See 'Chemotherapy' below.)

The optimal therapy is not defined, as these agents have not been directly compared in randomized trials. We suggest either avelumab or pembrolizumab (table 3), both of which have durable responses in long-term follow-up studies and are approved for the treatment of MCC. Other acceptable options include retifanlimab and nivolumab. Eligibility criteria for immunotherapy are discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations", section on 'Defining immunotherapy eligibility'.)

Avelumab — Avelumab is effective with durable responses in both treatment-naïve and chemotherapy-refractory metastatic disease. Objective response rates (ORRs) for avelumab range between 40 and 73 percent [12-18], with some studies suggesting durable median overall survival (OS) as long as three years [18].

Avelumab is administered at 800 mg intravenously (IV) every two weeks until disease progression or unacceptable toxicity. Elective discontinuation of immunotherapy (eg, in the setting of a complete treatment response) requires further prospective evaluation. Among patients with advanced MCC who discontinued avelumab electively or due to treatment toxicity, observational studies have demonstrated high rates of disease progression (approximately 30 percent or more) [19,20]. However, these results are difficult to interpret due to the inclusion of patients with variable treatment duration, disease responses, and reasons for treatment discontinuation (eg, complete response, toxicity, patient choice).

Avelumab is associated with a risk of infusion reaction. Patients should be premedicated with acetaminophen and an antihistamine prior to the first four infusions and subsequently as needed [21]. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Infusion-related reactions'.)

●Treatment-naïve disease – In a single-arm, open-label phase II trial (JAVELIN Merkel 200, part B), 116 patients with metastatic MCC who had not previously received systemic therapy were treated with avelumab (10 mg/kg every two weeks) [13,14]. At median follow-up of 21 months, the ORR was 40 percent, and the durable response rate (treatment response for at least six months) was 30 percent [13]. Median progression-free survival (PFS) and OS was 4 and 20 months, respectively. Avelumab was well tolerated, with a grade ≥3 toxicity rate of 18 percent and no treatment-related deaths.

●Chemotherapy-refractory disease – In part A of the phase II JAVELIN Merkel 200 trial, 88 patients with metastatic MCC who received one or more lines of prior cytoxic chemotherapy were treated with avelumab (10 mg/kg every two weeks) [12,15-17]. At median follow-up 29 months, the ORR was 33 percent, including a complete response rate of 11 percent. Two-year PFS was 26 percent [16] and five-year OS was 26 percent [17].

The rate of infusion-related reactions was 17 percent of patients; all were grade 1 or 2 [15]. Grade 3 toxicity rate was 5 percent, with no grade 4 or 5 toxicities reported. (See "Toxicities associated with immune checkpoint inhibitors", section on 'Infusion-related reactions'.)

Based on these data, the US Food and Drug Administration (FDA) [22] and the European Medicine Agency (EMA) approved avelumab to treat adult and pediatric patients 12 years and older with metastatic MCC.

Pembrolizumab — Pembrolizumab (table 3) is also effective with durable responses in metastatic MCC.

In an open-label phase II trial (KEYNOTE-017), 50 patients with advanced unresectable MCC who were systemic therapy-naïve were treated with pembrolizumab (2 mg/kg every three weeks) for up to two years [23-25]. Forty-three patients (86 percent) had stage IV disease and seven patients (14 percent) had stage IIIB disease. A majority of patients had received prior surgery (84 percent) or RT (70 percent).

At a median follow-up of 32 months, the ORR was 58 percent, including complete and partial response rates of 30 and 28 percent, respectively [25]. Among the patients with treatment response, 73 percent still had durable responses at three years. Three-year PFS and OS were 39 and 54 percent, respectively. The grade ≥3 toxicity rate was 30 percent.

The FDA has approved pembrolizumab to treat adult and pediatric patients with recurrent, locally advanced, or metastatic MCC [26].

Retifanlimab — Retifanlimab a PD-1 inhibitor, is effective with durable responses in treatment-naïve metastatic MCC. Although retifanlimab is one available initial treatment option with regulatory approval in this population, it is not among our preferred agents due to the short study follow-up time, limited experience with this agent, and the availability of other therapies.

Retifanlimab was evaluated in an open-label phase II trial (POD1UM-201) of 65 patients with systemic-therapy naïve, recurrent locally advanced or metastatic MCC [27]. Patients were allowed to have had prior surgery (72 percent) or radiation therapy (38 percent). The study did not enroll patients with active autoimmune disease or those with medical conditions that required immunosuppression, but it did allow enrollment of patients living with HIV whose disease was controlled on antiretroviral therapy. Retifanlimab was administered at 500 mg IV every four weeks until disease progression, unacceptable toxicity, or for up to two years.

In preliminary results, at median follow-up of approximately eight months, the objective response rate was 52 percent, including a complete and partial response rate of 18 and 34 percent [27,28]. Among the 34 patients with an objective response. the median duration of response ranged from 1 to more than 25 months; durable responses lasting one year or longer were seen in 21 patients (62 percent). The most common toxicities included fatigue, musculoskeletal pain, pruritus, diarrhea, rash, pyrexia, and nausea.

Based on these data, the FDA granted accelerated approval to retifanlimab for the treatment of adult patients with recurrent locally advanced or metastatic MCC [27].

Nivolumab — Nivolumab (table 4) is one available initial treatment option in patients with treatment-naïve metastatic MCC, but it is not among our preferred agents since data on treatment durability are limited and other effective treatments are available.

In preliminary results of a phase I/II trial (CheckMate 358), 25 patients with advanced MCC who had received ≤2 prior systemic chemotherapies were treated with nivolumab (240 mg IV every two weeks) [29]. At median follow-up of 26 weeks, among the 22 response-evaluable patients, the ORR was 68 percent, with ongoing responses in 13 of 15 patients (87 percent). The ORRs for treatment-naïve patients versus those with one to two prior systemic therapies were 71 and 63 percent, respectively. At three months, PFS and OS were 82 and 92 percent, respectively. The grade ≥3 toxicity rate was 20 percent.

Ineligible for immunotherapy — Patients who are ineligible for or unable to tolerate immunotherapy may be offered initial treatment with chemotherapy or enrollment in clinical trials, where available (www.clinicaltrials.gov). (See 'Chemotherapy' below and 'Investigational approaches' below.)

Agents not used

●Nivolumab plus ipilimumab – We do not typically use nivolumab plus ipilimumab as initial treatment for most patients with metastatic MCC. Initial data suggest similar benefit for this combination compared with single-agent immunotherapy, which have established favorable outcomes in treatment-naïve MCC [30]. Studies are limited for duration of response and OS with nivolumab plus ipilimumab. Combination immunotherapy also has more toxicity than single-agent immunotherapy. (See "Toxicities associated with immune checkpoint inhibitors".)

A randomized phase II trial of 50 patients evaluating the addition of stereotactic body radiation (SBRT) to nivolumab plus ipilimumab suggested high ORR (100 percent) and complete response rates (54 percent) for nivolumab plus ipilimumab alone (without radiation therapy [RT]) in a subgroup of 13 patients with systemic treatment-naïve metastatic MCC [31]. (See 'Nivolumab plus ipilimumab' below.)

However, in preliminary results from a separate randomized phase I/II trial (CheckMate 358) of 68 patients with MCPyV positive advanced MCC, initial therapy with nivolumab plus ipilimumab demonstrated a similar ORR compared with nivolumab monotherapy (58 versus 64 percent) [30].

●Ipilimumab – We do not offer ipilimumab monotherapy as initial therapy for metastatic MCC. Data are limited for the safety and efficacy of this approach [32,33], and other immunotherapy options are available that are better tolerated.

Subsequent therapy

Nivolumab plus ipilimumab — For patients with metastatic MCC who progress on single-agent immunotherapy, we suggest nivolumab plus ipilimumab rather than chemotherapy (algorithm 1).

Initial observational data were mixed for the activity of nivolumab plus ipilimumab in metastatic MCC who have progressed on prior single-agent immunotherapy, with some studies suggesting effective, durable responses [34-36] while others suggested minimal benefit [37].

A subsequent randomized, open-label phase II trial evaluating nivolumab plus ipilimumab (with or without RT) suggested ORRs of approximately 40 percent in patients with disease refractory to single-agent immunotherapy [31]. In this study, 50 patients with advanced MCC were randomly assigned to either nivolumab (240 mg IV every two weeks) plus low-dose ipilimumab (1 mg/kg IV very six weeks) or nivolumab plus ipilimumab and SBRT administered at 24 Gy in three fractions to ≥1 tumor site. The study enrolled 24 patients were systemic-therapy naïve (13 to immunotherapy alone and 11 to immunotherapy plus RT) and 26 patients who had received prior single-agent immunotherapy (12 to immunotherapy alone and 14 to immunotherapy plus RT). Among those 26 patients, 21 progressed while on initial immunotherapy, two progressed after discontinuation of initial immunotherapy with response, and three received ICI as adjuvant therapy.

At median follow-up of 15 months, the addition of SBRT to nivolumab plus ipilimumab did not improve ORR (52 versus 72 percent) [31]. However, among the 26 patients who had received prior single-agent immunotherapy, nivolumab plus ipilimumab (with or without RT) resulted in ORR and complete response rates (CRR) of 31 and 15 percent, respectively.

●For the subgroup of 12 patients treated with nivolumab plus ipilimumab alone (without RT) who had received prior immunotherapy, ORR and CRR were 42 and 25 percent, respectively.

●For the subgroup of 14 patients treated with nivolumab plus ipilimumab and RT who had received prior immunotherapy, ORR and CRR were 21 and 7 percent, respectively.

●The grade ≥3 toxicity rate for nivolumab plus ipilimumab was 36 percent.

Further data on durability of response and OS with nivolumab plus ipilimumab are necessary. The results of this study in patients with systemic therapy-naïve disease are discussed above. (See 'Agents not used' above.)

Chemotherapy — For patients with metastatic disease who progress on or are ineligible for immunotherapy, we offer systemic chemotherapy or enrollment in clinical trials. Options for chemotherapy include a platinum (carboplatin or cisplatin) plus etoposide [9,38,39]; cyclophosphamide plus doxorubicin, and vincristine (CAV) [9,40]; and topotecan [40]. Chemotherapy regimens used for metastatic MCC are typically patterned after those used for small cell carcinoma of the lung. (See "Extensive-stage small cell lung cancer: Initial management", section on 'Rationale for addition of immune checkpoint inhibitors to chemotherapy' and "Treatment of refractory and relapsed small cell lung cancer".)

For most patients receiving chemotherapy, we prefer carboplatin plus etoposide. In studies performed prior to the era of ICIs, carboplatin and etoposide had reported response rates of approximately 60 percent [9,39]. A weekly dosing of carboplatin (area under the curve of 2.0) can be used to reduce toxicity [38]. Single agent oral etoposide has also been successfully used in older adults [41].

Chemotherapy has a high response rate and can rapidly reduce tumor burden. However, responses are not durable, the impact on OS is uncertain, and patients are at risk for significant treatment related toxicity (including death) [9,40]. There are no randomized trials of chemotherapy in patients with metastatic MCC.

In one retrospective series of 103 patients with distant metastases treated with a wide range of chemotherapy regimens (including CAV and platinum plus etoposide), ORRs were high (up to 76 percent) [9]. However, the median duration for complete and partial responses were short (six and three months, respectively) and the rate of treatment-related deaths was 3 percent.

Locoregional therapies — For patients with metastatic disease that is symptomatic or nonresponsive to systemic therapy, options include local treatment of the symptomatic primary tumor and/or regional nodes with surgery or RT. If impending organ damage (eg, spinal cord compression or superior vena cava obstruction) is suspected at any time during treatment, RT should be initiated promptly.

RT is a particularly effective modality for palliation, as MCC is a very radiosensitive tumor. The dose is typically delivered in multiple (between 5 and 20) fractions. Single-fraction RT is one well-tolerated option for patients with symptomatic tumor masses. In a retrospective analysis of 93 tumors treated with single-fraction radiotherapy, the ORR was 94 percent, including a complete response rate of 45 percent [42]. Other palliative RT options include brachytherapy [43].

INVESTIGATIONAL APPROACHES — There is interest in developing novel therapies to treat advanced and metastatic disease. Patients interested in these treatments should be enrolled in clinical studies, where available.

●Somatostatin receptor-based therapy – Somatostatin receptor-based therapy, such as peptide receptor radionuclide therapy and somatostatin analogs have been investigated in advanced and metastatic MCC. Like other neuroendocrine tumors, MCC possesses receptors for somatostatin. These receptors can be demonstrated in vivo by somatostatin receptor-based diagnostic imaging (indium-111 pentetreotide single-photon emission computed tomography [OctreoScan] or gallium Ga-68 DOTATATE positron emission tomography scanning) [44-48]. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Somatostatin receptor-based imaging'.)

•Lutetium Lu-177 dotatate – Peptide receptor radionuclide therapy with Lutetium Lu-177 dotatate has been used to successfully treat metastatic MCC [48,49]. As examples, in patients with disease progression on avelumab, Lu-177 in combination with immunotherapy (such as pembrolizumab [50] or nivolumab plus ipilimumab [51]) has demonstrated significant treatment responses.

Lu-177 dotatate is approved by the US Food and Drug Administration (FDA) for the treatment of somatostatin-receptor positive gastroenteropancreatic neuroendocrine tumors, which is discussed separately. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Lutetium Lu-177 dotatate' and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Lutetium-177 dotatate'.)

•Somatostatin analogs – Somatostatin analogs (octreotide and lanreotide) have also been studied in MCC [44-47,52]. Case reports have demonstrated objective responses and durable progression-free survival (PFS) with these agents [47,48].

The use of somatostatin analogues in gastroenteropancreatic neuroendocrine tumors is discussed separately. (See "Metastatic well-differentiated gastrointestinal neuroendocrine (carcinoid) tumors: Systemic therapy options to control tumor growth", section on 'Radiolabeled somatostatin analogs' and "Metastatic well-differentiated pancreatic neuroendocrine tumors: Systemic therapy options to control tumor growth and symptoms of hormone hypersecretion", section on 'Somatostatin analogs'.)

●Pazopanib – Pazopanib is active in metastatic MCC [53-55]. In a phase II trial (UKMCC-01) of 16 patients with metastatic MCC, pazopanib demonstrated clinical benefit rate in nine patients (56 percent), including three with partial responses and six with stable disease [56].

●Intratumoral talimogene laherparepvec – Intratumoral talimogene laherparepvec (T-VEC) is an investigational option that can be used when other treatments are not feasible. In observational studies, T-VEC has demonstrated complete responses in treatment-naïve patients and those with recurrent disease [57,58].

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Non-melanoma skin cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Patients with Merkel cell carcinoma (MCC) have a high propensity to develop locoregionally recurrent or metastatic disease. (See "Staging, treatment, and surveillance of locoregional Merkel cell carcinoma", section on 'Prognosis'.)

●Locoregionally recurrent disease – Most patients with locoregionally recurrent MCC (ie, local, in-transit, or nodal recurrences without metastatic involvement of distant organs), we suggest initial treatment with salvage locoregional therapies (eg, surgery and/or radiation therapy [RT]) rather than systemic therapy (Grade 2C). The use of systemic therapy for locoregionally recurrent MCC is evolving, and clinical trial enrollment is encouraged, where available (www.clinicaltrials.gov). (See 'Locoregionally recurrent disease' above.)

●Initial therapy for metastatic disease – For patients with advanced or metastatic MCC, we suggest initial treatment with single-agent immunotherapy rather than chemotherapy (Grade 2C) (algorithm 1). Immunotherapy is better tolerated and can induce clinically meaningful, durable responses. However, for select patients with widely metastatic, symptomatic disease burden, some UpToDate experts offer a brief course (up to two cycles) of chemotherapy to decrease tumor burden prior to initiating immune checkpoint inhibitor (ICI) therapy, although data are limited for this approach. (See 'Initial therapy' above.)

•Preferred agents – We suggest either avelumab or pembrolizumab (table 3) (Grade 2C), both of which have durable responses in long-term follow-up studies and are approved for the treatment of MCC. Other acceptable options include retifanlimab and nivolumab. (See 'Avelumab' above and 'Pembrolizumab' above.)

●Subsequent therapy for metastatic disease

•Nivolumab plus ipilimumab – For patients with metastatic MCC who progress on single-agent immunotherapy, we suggest nivolumab plus ipilimumab rather than chemotherapy (Grade 2C). (See 'Nivolumab plus ipilimumab' above.)

•Systemic chemotherapy – For patients with metastatic disease who progress on or are ineligible for immunotherapy, we offer systemic chemotherapy or enrollment in clinical trials. Options for chemotherapy include a platinum (carboplatin or cisplatin) plus etoposide; cyclophosphamide plus doxorubicin, and vincristine (CAV); and topotecan. (See 'Chemotherapy' above.)

●Locoregional therapies – For patients with metastatic disease that is symptomatic or nonresponsive to systemic therapy, options include local treatment of the symptomatic primary tumor and/or regional nodes with surgery or RT. If impending organ damage (eg, spinal cord compression or superior vena cava obstruction) is suspected at any time during treatment, RT should be initiated promptly. (See 'Locoregional therapies' above.)

●Investigational approaches – Clinical trials are encouraged in all patients, where available. Investigational approaches include somatostatin receptor-based therapy and pazopanib. (See 'Investigational approaches' above.)

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  30. Saiag P, Blom A. Combined nivolumab and ipilimumab in non-resectable Merkel cell carcinoma. Lancet 2022; 400:976.
  31. Kim S, Wuthrick E, Blakaj D, et al. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial. Lancet 2022; 400:1008.
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  33. Winkler JK, Dimitrakopoulou-Strauss A, Sachpekidis C, et al. Ipilimumab has efficacy in metastatic Merkel cell carcinoma: a case series of five patients. J Eur Acad Dermatol Venereol 2017; 31:e389.
  34. LoPiccolo J, Schollenberger MD, Dakhil S, et al. Rescue therapy for patients with anti-PD-1-refractory Merkel cell carcinoma: a multicenter, retrospective case series. J Immunother Cancer 2019; 7:170.
  35. Glutsch V, Kneitz H, Gesierich A, et al. Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma. Cancer Immunol Immunother 2021; 70:2087.
  36. Khaddour K, Rosman IS, Dehdashti F, Ansstas G. Durable remission after rechallenge with ipilimumab and nivolumab in metastatic Merkel cell carcinoma refractory to avelumab: Any role for sequential immunotherapy? J Dermatol 2021; 48:e80.
  37. Shalhout SZ, Emerick KS, Kaufman HL, et al. A Retrospective Study of Ipilimumab Plus Nivolumab in Anti-PD-L1/PD-1 Refractory Merkel Cell Carcinoma. J Immunother 2022; 45:299.
  38. Poulsen M, Walpole E, Harvey J, et al. Weekly carboplatin reduces toxicity during synchronous chemoradiotherapy for Merkel cell carcinoma of skin. Int J Radiat Oncol Biol Phys 2008; 72:1070.
  39. Pectasides D, Moutzourides G, Dimitriadis M, et al. Chemotherapy for Merkel cell carcinoma with carboplatin and etoposide. Am J Clin Oncol 1995; 18:418.
  40. Iyer JG, Blom A, Doumani R, et al. Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma. Cancer Med 2016; 5:2294.
  41. Schlaak M, Podewski T, Von Bartenwerffer W, et al. Induction of durable responses by oral etoposide monochemotherapy in patients with metastatic Merkel cell carcinoma. Eur J Dermatol 2012; 22:187.
  42. Iyer JG, Parvathaneni U, Gooley T, et al. Single-fraction radiation therapy in patients with metastatic Merkel cell carcinoma. Cancer Med 2015; 4:1161.
  43. Garibyan L, Cotter SE, Hansen JL, et al. Palliative treatment for in-transit cutaneous metastases of Merkel cell carcinoma using surface-mold computer-optimized high-dose-rate brachytherapy. Cancer J 2013; 19:283.
  44. Meier G, Waldherr C, Herrmann R, et al. Successful targeted radiotherapy with 90Y-DOTATOC in a patient with Merkel cell carcinoma. A Case Report. Oncology 2004; 66:160.
  45. Kau R, Arnold W. Somatostatin receptor scintigraphy and therapy of neuroendocrine (APUD) tumors of the head and neck. Acta Otolaryngol 1996; 116:345.
  46. di Bartolomeo M, Bajetta E, Buzzoni R, et al. Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group. Cancer 1996; 77:402.
  47. Cirillo F, Filippini L, Lima GF, et al. [Merkel cell tumor. Report of case and treatment with octreotide]. Minerva Chir 1997; 52:1359.
  48. Salavati A, Prasad V, Schneider CP, et al. Peptide receptor radionuclide therapy of Merkel cell carcinoma using (177)lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: a potential novel treatment based on molecular pathology. Ann Nucl Med 2012; 26:365.
  49. Basu S, Ranade R. Favorable Response of Metastatic Merkel Cell Carcinoma to Targeted 177Lu-DOTATATE Therapy: Will PRRT Evolve to Become an Important Approach in Receptor-Positive Cases? J Nucl Med Technol 2016; 44:85.
  50. Aicher A, Sindrilaru A, Crisan D, et al. Short-Interval, Low-Dose Peptide Receptor Radionuclide Therapy in Combination with PD-1 Checkpoint Immunotherapy Induces Remission in Immunocompromised Patients with Metastatic Merkel Cell Carcinoma. Pharmaceutics 2022; 14.
  51. Ferdinandus J, Fendler WP, Lueckerath K, et al. Response to Combined Peptide Receptor Radionuclide Therapy and Checkpoint Immunotherapy with Ipilimumab Plus Nivolumab in Metastatic Merkel Cell Carcinoma. J Nucl Med 2022; 63:396.
  52. Fakiha M, Letertre P, Vuillez JP, Lebeau J. Remission of Merkel cell tumor after somatostatin analog treatment. J Cancer Res Ther 2010; 6:382.
  53. Davids MS, Charlton A, Ng SS, et al. Response to a novel multitargeted tyrosine kinase inhibitor pazopanib in metastatic Merkel cell carcinoma. J Clin Oncol 2009; 27:e97.
  54. Tarabadkar ES, Thomas H, Blom A, et al. Clinical Benefit from Tyrosine Kinase Inhibitors in Metastatic Merkel Cell Carcinoma: A Case Series of 5 Patients. Am J Case Rep 2018; 19:505.
  55. Knepper TC, Panchaud RA, Muradova E, et al. An analysis of the use of targeted therapies in patients with advanced Merkel cell carcinoma and an evaluation of genomic correlates of response. Cancer Med 2021; 10:5889.
  56. Nathan PD, Gaunt P, Wheatley K, et al. UKMCC-01: A phase II study of pazopanib (PAZ) in metastatic Merkel cell carcinoma. J Clin Oncol 2016; 34S: ASCO #9542.
  57. Hirotsu KE, Hua V, Tran AT, et al. Complete remission from intralesional talimogene laherparepvec for regionally advanced Merkel cell carcinoma in an immunocompromised solid organ transplant patient. JAAD Case Rep 2021; 13:144.
  58. Casale F, Tchanque-Fossuo C, Stepenaskie S, Durkin J. Complete response of Merkel cell carcinoma with talimogene laherparepvec (TVEC) monotherapy. Dermatol Online J 2022; 28.
Topic 139691 Version 8.0

References

1 : Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System.

2 : Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System.

3 : Recurrence and Mortality Risk of Merkel Cell Carcinoma by Cancer Stage and Time From Diagnosis.

4 : Merkel cell carcinoma: 30-year experience from a single institution.

5 : Natural history of merkel cell carcinoma following locoregional recurrence.

6 : Patterns of Metastasis in Merkel Cell Carcinoma.

7 : [Primary radiotherapy of recurrent Merkel cell carcinoma of the eyelid. Case report and review of the literature].

8 : Merkel cell carcinoma of the skin.

9 : Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases.

10 : Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance.

11 : Recurrence and Survival in Patients With Merkel Cell Carcinoma Undergoing Surgery Without Adjuvant Radiation Therapy to the Primary Site.

12 : Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial.

13 : First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study.

14 : Efficacy and Safety of First-line Avelumab Treatment in Patients With Stage IV Metastatic Merkel Cell Carcinoma: A Preplanned Interim Analysis of a Clinical Trial.

15 : Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.

16 : Two-year efficacy and safety update from JAVELIN Merkel 200 part A: A registrational study of avelumab in metastatic Merkel cell carcinoma progressed on chemotherapy

17 : Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): updated overall survival data after>5 years of follow-up.

18 : Real-world clinical outcomes with avelumab in patients with Merkel cell carcinoma treated in the USA: a multicenter chart review study.

19 : Durability of response to immune checkpoint inhibitors in metastatic Merkel cell carcinoma after treatment cessation.

20 : Response durability after cessation of immune checkpoint inhibitors in patients with metastatic Merkel cell carcinoma: a retrospective multicenter DeCOG study.

21 : Response durability after cessation of immune checkpoint inhibitors in patients with metastatic Merkel cell carcinoma: a retrospective multicenter DeCOG study.

22 : Response durability after cessation of immune checkpoint inhibitors in patients with metastatic Merkel cell carcinoma: a retrospective multicenter DeCOG study.

23 : Durable Tumor Regression and Overall Survival in Patients With Advanced Merkel Cell Carcinoma Receiving Pembrolizumab as First-Line Therapy.

24 : PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma.

25 : Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma.

26 : Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma.

27 : Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma.

28 : 545 A phase 2 study of retifanlimab in patients with advanced or metastatic merkel cell carcinoma (MCC) (POD1UM-201).

29 : Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC)

30 : Combined nivolumab and ipilimumab in non-resectable Merkel cell carcinoma.

31 : Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial.

32 : Adjuvant ipilimumab compared with observation in completely resected Merkel cell carcinoma (ADMEC): A randomized, multicenter DeCOG/ADO study.

33 : Ipilimumab has efficacy in metastatic Merkel cell carcinoma: a case series of five patients.

34 : Rescue therapy for patients with anti-PD-1-refractory Merkel cell carcinoma: a multicenter, retrospective case series.

35 : Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma.

36 : Durable remission after rechallenge with ipilimumab and nivolumab in metastatic Merkel cell carcinoma refractory to avelumab: Any role for sequential immunotherapy?

37 : A Retrospective Study of Ipilimumab Plus Nivolumab in Anti-PD-L1/PD-1 Refractory Merkel Cell Carcinoma.

38 : Weekly carboplatin reduces toxicity during synchronous chemoradiotherapy for Merkel cell carcinoma of skin.

39 : Chemotherapy for Merkel cell carcinoma with carboplatin and etoposide.

40 : Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma.

41 : Induction of durable responses by oral etoposide monochemotherapy in patients with metastatic Merkel cell carcinoma.

42 : Single-fraction radiation therapy in patients with metastatic Merkel cell carcinoma.

43 : Palliative treatment for in-transit cutaneous metastases of Merkel cell carcinoma using surface-mold computer-optimized high-dose-rate brachytherapy.

44 : Successful targeted radiotherapy with 90Y-DOTATOC in a patient with Merkel cell carcinoma. A Case Report.

45 : Somatostatin receptor scintigraphy and therapy of neuroendocrine (APUD) tumors of the head and neck.

46 : Clinical efficacy of octreotide in the treatment of metastatic neuroendocrine tumors. A study by the Italian Trials in Medical Oncology Group.

47 : [Merkel cell tumor. Report of case and treatment with octreotide].

48 : Peptide receptor radionuclide therapy of Merkel cell carcinoma using (177)lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: a potential novel treatment based on molecular pathology.

49 : Favorable Response of Metastatic Merkel Cell Carcinoma to Targeted 177Lu-DOTATATE Therapy: Will PRRT Evolve to Become an Important Approach in Receptor-Positive Cases?

50 : Short-Interval, Low-Dose Peptide Receptor Radionuclide Therapy in Combination with PD-1 Checkpoint Immunotherapy Induces Remission in Immunocompromised Patients with Metastatic Merkel Cell Carcinoma.

51 : Response to Combined Peptide Receptor Radionuclide Therapy and Checkpoint Immunotherapy with Ipilimumab Plus Nivolumab in Metastatic Merkel Cell Carcinoma.

52 : Remission of Merkel cell tumor after somatostatin analog treatment.

53 : Response to a novel multitargeted tyrosine kinase inhibitor pazopanib in metastatic Merkel cell carcinoma.

54 : Clinical Benefit from Tyrosine Kinase Inhibitors in Metastatic Merkel Cell Carcinoma: A Case Series of 5 Patients.

55 : An analysis of the use of targeted therapies in patients with advanced Merkel cell carcinoma and an evaluation of genomic correlates of response.

56 : UKMCC-01: A phase II study of pazopanib (PAZ) in metastatic Merkel cell carcinoma.

57 : Complete remission from intralesional talimogene laherparepvec for regionally advanced Merkel cell carcinoma in an immunocompromised solid organ transplant patient.

58 : Complete response of Merkel cell carcinoma with talimogene laherparepvec (TVEC) monotherapy.

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