NCCN Guidelines® Insights: Merkel Cell Carcinoma, Version 1.2024

Featured Updates to the NCCN Guidelines

Authors:
Chrysalyne D. Schmults Dana-Farber/Brigham and Women’s Cancer Center

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Rachel Blitzblau Duke Cancer Institute

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Sumaira Z. Aasi Stanford Cancer Institute

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Murad Alam Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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Arya Amini City of Hope National Medical Center

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Kristin Bibee The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Diana Bolotin The UChicago Medicine Comprehensive Cancer Center

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Jeremy Bordeaux Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

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Pei-Ling Chen Moffitt Cancer Center

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Carlo M. Contreras The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

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Dominick DiMaio Fred & Pamela Buffett Cancer Center

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Jessica M. Donigan Huntsman Cancer Institute at the University of Utah

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Jeffrey M. Farma Fox Chase Cancer Center

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Karthik Ghosh Mayo Clinic Comprehensive Cancer Center

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Kelly Harms University of Michigan Rogel Cancer Center

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Alan L. Ho Memorial Sloan Kettering Cancer Center

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John Nicholas Lukens Abramson Cancer Center at the University of Pennsylvania

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Susan Manber Publicis Health

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Lawrence Mark Indiana University Melvin and Bren Simon Comprehensive Cancer Center

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Theresa Medina University of Colorado Cancer Center

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Kishwer S. Nehal Memorial Sloan Kettering Cancer Center

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Paul Nghiem Fred Hutchinson Cancer Center

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Kelly Olino Yale Cancer Center/Smilow Cancer Hospital

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Soo Park UC San Diego Moores Cancer Center

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Tejesh Patel The University of Tennessee Health Science Center

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Igor Puzanov Roswell Park Comprehensive Cancer Center

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Jason Rich Siteman Cancer Center at Barnes-Jewish Hospital and Washington UniversitySchool of Medicine

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Aleksandar Sekulic Mayo Clinic Comprehensive Cancer Center

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Ashok R. Shaha Memorial Sloan Kettering Cancer Center

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Divya Srivastava UT Southwestern Simmons Comprehensive Cancer Center

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Valencia Thomas The University of Texas MD Anderson Cancer Center

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Courtney Tomblinson Vanderbilt-Ingram Cancer Center

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Puja Venkat UCLA Jonsson Comprehensive Cancer Center

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Yaohui Gloria Xu University of Wisconsin Carbone Cancer Center

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Siegrid Yu UCSF Helen Diller Family Comprehensive Cancer Center

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Mehran Yusuf O’Neal Comprehensive Cancer Center at UAB

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Beth McCullough National Comprehensive Cancer Network

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Sara Espinosa National Comprehensive Cancer Network

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Full access

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled “Clinical N0 Disease, Locally Advanced MCC.” This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term “nonsurgical” by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.

NCCN Continuing Education

Target Audience: This journal article is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

FL1

Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-24-002-H01-P

PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until January 10, 2025. PAs should only claim credit commensurate with the extent of their participation.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/94819; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.

Release date: January 10, 2024; Expiration date: January 10, 2025

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • • Integrate into professional practice the updates to the NCCN Guidelines for Merkel Cell Carcinoma

  • • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Merkel Cell Carcinoma

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

Individuals Who Provided Content Development and/or Authorship Assistance:

The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.

Rachel Blitzblau, MD, PhD, Panel Vice Chair

Carlo M. Contreras, MD, Panel Member

Kelly Harms, MD, PhD, Panel Member

Kelly Olino, MD, Panel Member

Beth McCullough, RN, BS, Guidelines Layout Specialist, NCCN

Sara Espinosa, PhD, Oncology Scientist/Medical Writer, NCCN

The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.

Chrysalyne D. Schmults, MD, MS, Panel Chair, has disclosed receiving grant/research support from Castle Biosciences, Regeneron Pharmaceuticals, and sanofi-aventis U.S.; serving as an officer, director, or any other fiduciary role for Chronicle Medical Software; owning equity interest/stock options in Chronicle Medical Software; and having ownership/partnership/principle in Chronicle Medical Software.

Paul Nghiem, MD, PhD, Panel Member, has disclosed serving as a scientific advisor for EMD Serono; receiving grant/research support from EMD Serono; and serving as a consultant for EMD Serono.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels

This activity is supported by educational grants from AstraZeneca; Bristol Myers Squibb; Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC; and Seagen. This activity is supported by a medical education grant from Exelixis, Inc. This activity is supported by an independent educational grant from Merck & Co., Inc., Rahway, NJ, USA.

Overview

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine neoplasm with roughly 3,000 cases annually in the United States with increasing incidence projected to reach >5,000 cases yearly by 2030.14 The increase in incidence is due to not only the aging of the population and improved recognition and diagnosis but also changes in environmental risk factors.2 Patients who are immunocompromised, such as those with solid organ transplants, lymphoproliferative malignancies (eg, chronic lymphocytic leukemia), or HIV infections, are at higher risk for MCC incidence, recurrence, and poor outcomes.57 MCC tumors grow rapidly and have a significant risk of occult metastasis to the draining nodal basin, as well as distant sites in nearly one-third of patients.816 A recent study demonstrated a 40% 5-year recurrence rate in MCC.17 Additionally, MCC has had a historically high mortality rate exceeding that of melanoma, prior to the use of systemic immunotherapy.1719

The pathogenesis of MCC is still under investigation, with 2 proposed pathways leading to tumor formation. One proposed etiology is ultraviolet exposure–related, leading to critical mutations in both TP53 and RB1, and tumorogenesis.8,2024 The other is thought to be virally mediated with integration of the Merkel cell polyomavirus into the host cell genome leading to truncation of the large viral T-cell antigen.2527 Regardless of the etiology, MCC is treated with a combination of surgery, radiation, and systemic immunotherapy, which has markedly improved patient prognosis.

A major update in Version 1.2024 of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MCC is a reorganization to better define groups of patients and their potential treatment options. The NCCN Skin Cancer Excluding Melanoma Panel has made changes across all 4 disease groups reviewed by the panel to this effect.

Clinical N0 Disease: Local MCC Only, Surgically Resectable

Management of the primary MCC tumor requires multidisciplinary consultation. For primary tumors that are deemed surgically resectable, the recommended surgical margin may vary based on recommendations for adjuvant radiation therapy (RT). For example, excision of a smaller MCC tumor with a 1- to 2-cm margin may be sufficient management if clear margins are obtained and no adverse risk factors are identified.28 For larger tumors in which a 1- to 2-cm margin is not feasible due to the resulting size of the surgical wound, excision with a <1-cm margin with planned adjuvant RT may be recommended. In addition, adjuvant RT is recommended in the presence of adverse features such as tumor size of >1 cm, immunosuppression, head/neck site, or the presence of lymphovascular invasion. It is well accepted that adjuvant RT reduces local recurrence, and it has recently been shown that narrow margin excision (≤1.0 cm) when combined with adjuvant RT has a low rate of local recurrence.2931 However, given the marked sensitivity of MCC to RT, particularly in the setting of residual microscopic disease, and the desire for timely administration of adjuvant RT, the latest version of the NCCN Guidelines for MCC have been updated to reflect a shift in the treatment paradigm (see MCC-2).32 This change is now reflected in the guidelines as a “Preferred” designation for adjuvant RT in the treatment of microscopically positive margins where re-excision is an additional treatment option. Adjuvant RT is similarly a treatment for “Narrow clinical margin (<1 cm) excision and/or adverse risk factors,” which was revised from “Adverse risk factors” during this update.31 Importantly, for primary site management, a multidisciplinary approach facilitates maximization of treatment effect with the minimization of treatment morbidity.

F1

Sentinel lymph node biopsy (SLNB) is an important staging tool for identifying subclinical nodal metastases, which is valuable for accurate staging, and impacts subsequent treatment decisions.24,33,34 Given the benefits of SLNB, the panel clarified that it should be performed whenever possible, prior to removal of the primary tumor. This is particularly important in the cases of head and neck MCC given the concern that resection and reconstruction prior to performing a SLNB may impact the accuracy of subsequent nodal basin mapping. Based on this discussion, the following statement was added to the guideline: “It is recommended, regardless of surgical approach, that every effort is made to coordinate surgical management such that SLNB is performed prior to or at the time of definitive excision” (see MCC-2A). This addition clarifies the timing for SLNB with respect to surgical management of the primary tumor. The approach facilitates SLN mapping prior to surgical disruption of lymphatics surrounding the primary tumor.31

F2

Clinical N0 Disease: Locally Advanced MCC When Curative Surgery and Adjuvant RT Are Not Feasible

The panel also discussed the need to better define instances when patients would be deemed as not good surgical candidates, or “nonsurgical,” and to clarify management in these patients. The panel described nonsurgical status as being due to patient-related factors, such as competing severe medical comorbidities even in the setting of resectable disease, or to tumor-related features, namely locally advanced disease.

To better categorize these treatment options, the panel created a new clinical node–negative (N0) page for locally advanced MCC when curative surgery and curative RT are not feasible (see MCC-3). After a multidisciplinary discussion, the favored treatment option includes neoadjuvant immunotherapy with an anti–PD-1 agent (see “Systemic Therapy for MCC” section) for patients who are surgical candidates. If a treatment response is seen and the tumor is amenable to resection, either wide local excision or, more rarely, Mohs can be pursued with consideration for SLNB. The “Clinical N0 Disease, Locally Advanced MCC” algorithm page (MCC-3) also outlines options for patients with surgically resectable disease. For tumor progression on neoadjuvant immunotherapy and patients with locally advanced primary tumors who are not deemed surgical candidates due to medical comorbidities, RT for durable local control or systemic therapy is recommended (see MCC-3).

F3

Clinical N+ Disease: Regional MCC/In-Transit Disease

The AJCC TNM staging system is used to classify clinical and pathologic cancer stages, define prognosis, and provide guidance for appropriate treatment options.35,36 The 8th edition of this staging system for MCC defines in-transit lesions as discontinuous from primary tumor, located between the primary tumor and the draining regional nodal basin or distal to the primary tumor site.13,35 In previous versions of the NCCN Guidelines, in-transit disease was not identified as a distinct clinical subgroup and treatment recommendations were not specified.

After the panel reviewed the current organization of the clinical node–positive (N+) stage, an additional management algorithm was created for in-transit disease to delineate alternative treatment options when compared with regionally nodal positive MCC (see MCC-4). After initial classification of an N+ disease, further imaging is recommended to evaluate for distant disease. If distant metastatic disease is absent, recommendations for patients with a primary tumor and a clinically detectable regional lymph node metastasis include management of the primary tumor and the nodal basin. Metastatic disease in the nodal basin should be confirmed with a fine-needle aspiration or core biopsy. Multidisciplinary consultation is recommended and lymph node dissection with RT is preferred; additional treatment options include lymph node dissection alone, RT alone, clinical trial preferred if available, and the consideration of neoadjuvant immunotherapy.

F4

For management of in-transit disease, diagnosis confirmation with biopsy is recommended. Following confirmation, treatment options for in-transit disease include multidisciplinary consultation, clinical trial, and surgery or RT, as well as systemic therapy if curative surgery and/or RT are not feasible. Although the panel has made these general treatment recommendations for in-transit disease, it is important to note that due to the rarity of this clinical scenario and the lack of high-quality peer-reviewed primary literature, these recommendations are based on expert opinion.3740 This lack of large studies has led to individualized treatment decisions with the input of a multidisciplinary team at a high-volume treatment center.

Systemic Therapy for MCC

During the Version 1.2024 update to the NCCN Guidelines for MCC, the panel reformatted the systemic therapy pages, expanding the settings covered to provide greater clarity in defining regimens for local, regional, and disseminated disease. The panel discussed each of the currently available regimens to provide clinicians with a more comprehensive list of systemic therapies, incorporating changes from the algorithm as well as new FDA approvals. The regimens in the guidelines most impacted by this update are avelumab, nivolumab, pembrolizumab, and retifanlimab-dlwr. Following is a summary of each regimen as well as the updates made in this version. The goal of the panel is to provide a framework of available regimens that allow clinicians to select optimal treatments through informed decisions.

Regimens

Avelumab

Current recommendations for the use of avelumab in local (N0) and regional (N+) disease are based on 2 retrospective multi-institutional studies to assess treatment outcomes. In Bhatia et al,41 advanced-stage (IIIB/IV) avelumab-treated MCC (n=90) was studied in 6 US academic medical centers with a median follow-up of 20.8 months (95% CI, 19.1–24.2) and median duration of treatment of 13.5 months (95% CI, 6.4–30.6). Patients treated with avelumab had a 73% (95% CI, 64%–83%) objective response rate (ORR), median progression-free survival (PFS) of 24.4 months (95% CI, 8.31–not estimable [NE]), and median overall survival (OS) of 30.7 months (95% CI, 11.2–NE).41

SPEAR-Merkel was an additional retrospective observational study of metastatic MCC (mMCC) and locally advanced MCC response to first-line avelumab treatment, which included selected patients treated by the US Oncology Network from 2017 to 2019.42 For mMCC (n=19) the median OS was 20.2 months (95% CI, 10.0–not reached [NR]), PFS was 10 months (95% CI, 2.8–NR), and response rate was 63.2% (95% CI, 38.4%–83.7%).42 Median OS and PFS were not reached in the locally advanced MCC (n=9) group; however, a response rate of 66.7% (95% CI, 29.9%–92.5%) was recorded.42

Recommendations for the use of avelumab in the metastatic setting are based on data from the JAVELIN Merkel 200 trial, an open-label multicenter prospective clinical trial testing avelumab in patients with histologically confirmed and measurable stage IV distant MCC.4349 Patients in Part A of the trial, whose mMCC had progressed after ≥1 previous lines of chemotherapy (n=88), had a median follow-up of 65.1 months (range, 60.8–74.1 months), a median OS of 12.6 months (95% CI, 7.5–17.1 months), and 5-year OS rates of 26% (95% CI, 17%–36%).46 For the trial Part B cohort of mMCC cases treated with avelumab as first-line therapy (n=116), the median follow-up was 21.2 months (range, 14.9–36.6 months), the objective response rate was 39.7% (95% CI, 30.7%–49.2%), median PFS was 4.1 months (95% CI, 1.4–6.1), and median OS was 20.3 months (95% CI, 12.4–NE).48 A 2022 update to the Part B cohort reported a median follow-up of 54.3 months (range, 48.0–69.7 months) as well as a 4-year OS rate of 38% (95% CI, 29%–47%), where the median OS was 38.7 months (n=21; 95% CI, 11.3–NE) for patients with PD-L1–positive tumors and 16.1 months (n=87; 95% CI, 9.6–42.0) for those with PD-L1–negative tumors.49

Nivolumab

The recommendation for the use of nivolumab in the neoadjuvant setting is supported by data from the CheckMate 358 phase I/II trial that enrolled patients with resectable stage IIA–IV MCC (n=39) who received ≥1 doses of nivolumab.50 Surgery was completed in 36 patients with a 47.2% (n=17) pathologic complete response rate. In 54.5% (n=18/33) of radiologically evaluable cases, there were tumor reductions ≥30%.50 The median follow-up for this cohort was 20.3 months (range, 0.5–39.7 months); however, median recurrence-free survival and OS were not reached in this study.50

Pembrolizumab

A phase II, single-arm multicenter trial tested pembrolizumab in patients with distant metastatic or locoregional MCC not amenable to definitive surgery or RT with no prior MCC systemic therapy treatment (n=50).5153 After a median follow-up of 31.8 months (range, 0.4–56.9 months), the ORR was 58% (95% CI, 43.2%–71.8%) with a 30% complete response (n=15; 95% CI, 17.9%–44.6%) and 28% partial response (n=14; 95% CI, 16.2%–42.5%).53 For this study, the median PFS was 16.8 months (95% CI, 4.6–43.4) and the 3-year estimated PFS rate was 39.1%.53 Although the median OS was not reached, the 3-year OS rate was 59.4% for all participants and 89.5% for patients with responsive disease (complete and partial response).53

Retifanlimab-dlwr

Retifanlimab-dlwr was studied in the POD1UM-201, an open-label, single-arm, multicenter, phase II trial for patients with unresectable locally advanced or mMCC.54 This study tested retifanlimab-dlwr in patients whose disease was chemotherapy-naïve or chemotherapy-refractory and had no prior therapy with anti–PD-1/L1 regimens such as those previously discussed. Current data are available for the chemotherapy-naïve group (n=87), of which the first 65 patients were assessed. These patients had an ORR of 46.2% (n=30), with 12.3% (n=8) having complete response and 33.8% (n=22) a partial response. Additionally, the disease control rate for this group was 53.8% (n=35).

Local Disease N0

The systemic therapy page has undergone significant changes during this update as the panel elected to reorganize the regimens and provide consistency with the corresponding algorithm page. Some of the differences include new regimens, addition of existing regimens to new disease classifications, and changes in NCCN categories of preference. Adjuvant systemic therapy is not recommended outside of a clinical trial for primary resectable disease. However, systemic therapies are recommended for primary locally advanced and recurrent locally advanced MCC if curative surgery and curative RT are not feasible. The panel has given all regimens for local disease a NCCN 2A category of evidence, signifying there is uniform NCCN consensus that the intervention is appropriate based on lower-level evidence (see MCC-D 1 of 4). For primary locally advanced MCC, avelumab and pembrolizumab are “Preferred” regimens, retifanlimab-dlwr is in the “Other Recommended Regimen” category, and neoadjuvant nivolumab has been added as a “Useful in Certain Circumstances” option. For recurrent locally advanced MCC, pembrolizumab and retifanlimab-dlwr are recommended as “Preferred” regimens and avelumab as an “Other Recommended Regimen.”

F5

Regional Disease N+

All regimens recommended for regional disease have a NCCN 2A category of evidence (see MCC-D 2 of 4). The regimens for primary regional disease have not undergone any adjustments during this update. The panel noted that adjuvant chemotherapy is not routinely recommended because the survival benefit has not been demonstrated in available retrospective studies.

F6

For primary regional disease, surgery and RT is the “Preferred” treatment recommendation. However, certain clinical scenarios may warrant systemic therapy and carboplatin ± etoposide, cisplatin ± etoposide, or neoadjuvant nivolumab, which are recommended as “Useful in Certain Circumstances.”

Therapies recommended for recurrent regional disease if curative surgery and curative RT are not feasible include pembrolizumab and retifanlimab-dlwr, which are now designated as “Preferred” treatment options. Additionally, avelumab was added to this disease classification as an “Other Recommended Regimen.”

Disseminated Disease M1

In disseminated disease, all the “Preferred” regimens are NCCN category 2A regimens (see MCC-D 3 of 4). Among these therapy options, the only change was the addition of retifanlimab-dlwr, which was moved from “Other Recommended Regimens” to “Preferred” because the panel considered the data available comparable to that of avelumab, nivolumab, and pembrolizumab.

F7

The regimens recommended for disseminated disease if anti–PD-1 or anti–PD-L1 therapy is contraindicated or if disease has progressed on anti–PD-1 or anti–PD-L1 monotherapy have not been affected during this review of the guidelines and continue to be viable options under the category of “Useful in Certain Circumstances.”

Summary

The NCCN Guidelines for MCC has undergone significant changes in Version 1.2024, as the panel deliberated and finalized the reorganization of patient groups to better provide specific treatment options. Some updates include the clarification of nonsurgical eligibility for clinical N0 disease, addition of locally advanced MCC as a clinical distinction, inclusion of in-transit disease treatment guidelines, and an overhaul of the systemic therapy pages. Each modification is intended to facilitate the development of individualized informed decisions in a multidisciplinary clinical team. The panel hopes these recommendations will be incorporated into routine practice, with the ultimate goal of improving patient outcomes for MCC.

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    Sridharan V, Muralidhar V, Margalit DN, et al. Merkel cell carcinoma: a population analysis on survival. J Natl Compr Canc Netw 2016;14:12471257.

  • 15.

    Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: report of 10 cases and review of the literature. J Am Acad Dermatol 2000;43:755767.

  • 16.

    Medina-Franco H, Urist MM, Fiveash J, et al. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 2001;8:204208.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    McEvoy AM, Lachance K, Hippe DS, et al. Recurrence and mortality risk of Merkel cell carcinoma by cancer stage and time from diagnosis. JAMA Dermatol 2022;158:382389.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Santamaria-Barria JA, Boland GM, Yeap BY, et al. Merkel cell carcinoma: 30-year experience from a single institution. Ann Surg Oncol 2013;20:13651373.

  • 19.

    Hitchcock CL, Bland KI, Laney RG 3rd, et al. Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural history, diagnosis, and treatment. Ann Surg 1988;207:201207.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Lai JH, Fleming KE, Ly TY, et al. Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors. Hum Pathol 2015;46:12901296.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Suárez AL, Louis P, Kitts J, et al. Clinical and dermoscopic features of combined cutaneous squamous cell carcinoma (SCC)/neuroendocrine [Merkel cell] carcinoma (MCC). J Am Acad Dermatol 2015;73:968975.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Miller RW, Rabkin CS. Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 1999;8:153158.

  • 23.

    Agelli M, Clegg LX, Becker JC, et al. The etiology and epidemiology of Merkel cell carcinoma. Curr Probl Cancer 2010;34:1437.

  • 24.

    Tarantola TI, Vallow LA, Halyard MY, et al. Prognostic factors in Merkel cell carcinoma: analysis of 240 cases. J Am Acad Dermatol 2013;68:425432.

  • 25.

    Rollison DE, Giuliano AR, Becker JC. New virus associated with Merkel cell carcinoma development. J Natl Compr Canc Netw 2010;8:874880.

  • 26.

    Batinica M, Akgül B, Silling S, et al. Correlation of Merkel cell polyomavirus positivity with PDGFRα mutations and survivin expression in Merkel cell carcinoma. J Dermatol Sci 2015;79:4349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Paulson KG, Lewis CW, Redman MW, et al. Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: a prospective validation study. Cancer 2017;123:14641474.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Frohm ML, Griffith KA, Harms KL, et al. Recurrence and survival in patients with Merkel cell carcinoma undergoing surgery without adjuvant radiation therapy to the primary site. JAMA Dermatol 2016;152:10011007.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Bhatia S, Storer BE, Iyer JG, et al. Adjuvant radiation therapy and chemotherapy in Merkel cell carcinoma: survival analyses of 6908 cases from the National Cancer Database. J Natl Cancer Inst 2016;108:djw042.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Lewis KG, Weinstock MA, Weaver AL, et al. Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol 2006;142:693700.

  • 31.

    Tarabadkar ES, Fu T, Lachance K, et al. Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: analysis of 188 cases of localized disease and proposed management algorithm. J Am Acad Dermatol 2021;84:340347.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Rush Z, Fields RC, Lee N, et al. Radiation therapy in the management of Merkel cell carcinoma: current perspectives. Expert Rev Dermatol 2011;6:395404.

  • 33.

    Servy A, Maubec E, Sugier PE, et al. Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy. Ann Oncol 2016;27:914919.

  • 34.

    Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol 2011;29:10361041.

  • 35.

    Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. Springer International Publishing; 2017.

  • 36.

    Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017;67:9399.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Zeitouni NC, Giordano CN, Kane JM 3rd. In-transit Merkel cell carcinoma treated with isolated limb perfusion or isolated limb infusion: a case series of 12 patients. Dermatol Surg 2011;37:357364.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Hindmarch JJ, Coker DJ, Waugh R, et al. Treatment of in-transit Merkel cell carcinoma by isolated limb infusion with cytotoxic drugs. J Surg Case Rep 2022;2022:rjac172.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Kiyohara T, Shijimaya T, Miyamoto M, et al. In-transit recurrence of Merkel cell carcinoma associated with Bowen’s disease: the first reported case successfully treated by avelumab. J Dermatol 2019;46:440443.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Rusheen J, Clune J, Ariyan S, et al. Case report: metastatic Merkel cell carcinoma presenting seven years after loco-regional disease resection of primary tumor with interval in-transit and nodal metastases. Front Oncol 2023;13:1217816.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Bhatia S, Nghiem P, Veeranki SP, et al. Real-world clinical outcomes with avelumab in patients with Merkel cell carcinoma treated in the USA: a multicenter chart review study. J Immunother Cancer 2022;10:e004904.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Cowey CL, Liu FX, Kim R, et al. Real-world clinical outcomes with first-line avelumab in locally advanced/metastatic Merkel cell carcinoma in the USA: SPEAR-Merkel. Future Oncol 2021;17:23392350.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016;17:13741385.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Kaufman HL, Russell JS, Hamid O, et al. 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. J Immunother Cancer 2018;6:7.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    D’Angelo SP, Russell J, Lebbé C, et al. 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. JAMA Oncol 2018;4:e180077.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    D’Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): updated overall survival data after >5 years of follow-up. ESMO Open 2021;6:100290.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    D’Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J Immunother Cancer 2020;8:e000674.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    D’Angelo SP, Lebbé C, Mortier L, et al. 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. J Immunother Cancer 2021;9:e002646.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    D’Angelo S, Lebbé C, Mortier L, et al. First-line avelumab treatment in patients with metastatic Merkel cell carcinoma: 4-year follow-up from the JAVELIN Merkel 200 trial. J Immunother Cancer 2022;10(Suppl 2):Abstract 604.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Topalian SL, Bhatia S, Amin A, et al. Neoadjuvant nivolumab for patients with resectable Merkel cell carcinoma in the CheckMate 358 trial. J Clin Oncol 2020;38:24762487.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 2016;374:25422552.

  • 52.

    Nghiem P, Bhatia S, Lipson EJ, et al. Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy. J Clin Oncol 2019;37:693702.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Nghiem P, Bhatia S, Lipson EJ, et al. Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. J Immunother Cancer 2021;9:e002478.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Grignani G, Rutkowski P, Lebbe C, et al. A phase 2 study of retifanlimab in patients with advanced or metastatic Merkel cell carcinoma (MCC) (POD1UM-201). J Immunother Cancer 2021;9(Suppl 2):Abstract 545.

    • PubMed
    • Search Google Scholar
    • Export Citation

NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© 2024 National Comprehensive Cancer Network® (NCCN®). All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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    Jacobs D, Huang H, Olino K, et al. Assessment of age, period, and birth cohort effects and trends in Merkel cell carcinoma incidence in the United States. JAMA Dermatol 2021;157:5965.

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    Fitzgerald TL, Dennis S, Kachare SD, et al. Dramatic increase in the incidence and mortality from Merkel cell carcinoma in the United States. Am Surg 2015;81:802806.

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    Olsen CM, Pandeya N, Whiteman DC. International increases in Merkel cell carcinoma incidence rates between 1997 and 2016. J Invest Dermatol 2021;141:25962601.e1.

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    Kaae J, Hansen AV, Biggar RJ, et al. Merkel cell carcinoma: incidence, mortality, and risk of other cancers. J Natl Cancer Inst 2010;102:793801.

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    Clarke CA, Robbins HA, Tatalovich Z, et al. Risk of Merkel cell carcinoma after solid organ transplantation. J Natl Cancer Inst 2015;107:dju382.

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    Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 2008;58:375381.

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    Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 2003;49:832841.

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    Hodgson NC. Merkel cell carcinoma: changing incidence trends. J Surg Oncol 2005;89:14.

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    Lemos BD, Storer BE, Iyer JG, et al. Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system. J Am Acad Dermatol 2010;63:751761.

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    Albores-Saavedra J, Batich K, Chable-Montero F, et al. Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol 2010;37:2027.

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  • 13.

    Harms KL, Healy MA, Nghiem P, et al. Analysis of prognostic factors from 9387 Merkel cell carcinoma cases forms the basis for the new 8th Edition AJCC Staging System. Ann Surg Oncol 2016;23:35643571.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Sridharan V, Muralidhar V, Margalit DN, et al. Merkel cell carcinoma: a population analysis on survival. J Natl Compr Canc Netw 2016;14:12471257.

  • 15.

    Akhtar S, Oza KK, Wright J. Merkel cell carcinoma: report of 10 cases and review of the literature. J Am Acad Dermatol 2000;43:755767.

  • 16.

    Medina-Franco H, Urist MM, Fiveash J, et al. Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 2001;8:204208.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    McEvoy AM, Lachance K, Hippe DS, et al. Recurrence and mortality risk of Merkel cell carcinoma by cancer stage and time from diagnosis. JAMA Dermatol 2022;158:382389.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Santamaria-Barria JA, Boland GM, Yeap BY, et al. Merkel cell carcinoma: 30-year experience from a single institution. Ann Surg Oncol 2013;20:13651373.

  • 19.

    Hitchcock CL, Bland KI, Laney RG 3rd, et al. Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural history, diagnosis, and treatment. Ann Surg 1988;207:201207.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Lai JH, Fleming KE, Ly TY, et al. Pure versus combined Merkel cell carcinomas: immunohistochemical evaluation of cellular proteins (p53, Bcl-2, and c-kit) reveals significant overexpression of p53 in combined tumors. Hum Pathol 2015;46:12901296.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Suárez AL, Louis P, Kitts J, et al. Clinical and dermoscopic features of combined cutaneous squamous cell carcinoma (SCC)/neuroendocrine [Merkel cell] carcinoma (MCC). J Am Acad Dermatol 2015;73:968975.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Miller RW, Rabkin CS. Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 1999;8:153158.

  • 23.

    Agelli M, Clegg LX, Becker JC, et al. The etiology and epidemiology of Merkel cell carcinoma. Curr Probl Cancer 2010;34:1437.

  • 24.

    Tarantola TI, Vallow LA, Halyard MY, et al. Prognostic factors in Merkel cell carcinoma: analysis of 240 cases. J Am Acad Dermatol 2013;68:425432.

  • 25.

    Rollison DE, Giuliano AR, Becker JC. New virus associated with Merkel cell carcinoma development. J Natl Compr Canc Netw 2010;8:874880.

  • 26.

    Batinica M, Akgül B, Silling S, et al. Correlation of Merkel cell polyomavirus positivity with PDGFRα mutations and survivin expression in Merkel cell carcinoma. J Dermatol Sci 2015;79:4349.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Paulson KG, Lewis CW, Redman MW, et al. Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: a prospective validation study. Cancer 2017;123:14641474.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Frohm ML, Griffith KA, Harms KL, et al. Recurrence and survival in patients with Merkel cell carcinoma undergoing surgery without adjuvant radiation therapy to the primary site. JAMA Dermatol 2016;152:10011007.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Bhatia S, Storer BE, Iyer JG, et al. Adjuvant radiation therapy and chemotherapy in Merkel cell carcinoma: survival analyses of 6908 cases from the National Cancer Database. J Natl Cancer Inst 2016;108:djw042.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Lewis KG, Weinstock MA, Weaver AL, et al. Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol 2006;142:693700.

  • 31.

    Tarabadkar ES, Fu T, Lachance K, et al. Narrow excision margins are appropriate for Merkel cell carcinoma when combined with adjuvant radiation: analysis of 188 cases of localized disease and proposed management algorithm. J Am Acad Dermatol 2021;84:340347.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Rush Z, Fields RC, Lee N, et al. Radiation therapy in the management of Merkel cell carcinoma: current perspectives. Expert Rev Dermatol 2011;6:395404.

  • 33.

    Servy A, Maubec E, Sugier PE, et al. Merkel cell carcinoma: value of sentinel lymph-node status and adjuvant radiation therapy. Ann Oncol 2016;27:914919.

  • 34.

    Schwartz JL, Griffith KA, Lowe L, et al. Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol 2011;29:10361041.

  • 35.

    Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. Springer International Publishing; 2017.

  • 36.

    Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017;67:9399.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Zeitouni NC, Giordano CN, Kane JM 3rd. In-transit Merkel cell carcinoma treated with isolated limb perfusion or isolated limb infusion: a case series of 12 patients. Dermatol Surg 2011;37:357364.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Hindmarch JJ, Coker DJ, Waugh R, et al. Treatment of in-transit Merkel cell carcinoma by isolated limb infusion with cytotoxic drugs. J Surg Case Rep 2022;2022:rjac172.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Kiyohara T, Shijimaya T, Miyamoto M, et al. In-transit recurrence of Merkel cell carcinoma associated with Bowen’s disease: the first reported case successfully treated by avelumab. J Dermatol 2019;46:440443.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Rusheen J, Clune J, Ariyan S, et al. Case report: metastatic Merkel cell carcinoma presenting seven years after loco-regional disease resection of primary tumor with interval in-transit and nodal metastases. Front Oncol 2023;13:1217816.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Bhatia S, Nghiem P, Veeranki SP, et al. Real-world clinical outcomes with avelumab in patients with Merkel cell carcinoma treated in the USA: a multicenter chart review study. J Immunother Cancer 2022;10:e004904.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Cowey CL, Liu FX, Kim R, et al. Real-world clinical outcomes with first-line avelumab in locally advanced/metastatic Merkel cell carcinoma in the USA: SPEAR-Merkel. Future Oncol 2021;17:23392350.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 2016;17:13741385.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Kaufman HL, Russell JS, Hamid O, et al. 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. J Immunother Cancer 2018;6:7.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    D’Angelo SP, Russell J, Lebbé C, et al. 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. JAMA Oncol 2018;4:e180077.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    D’Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): updated overall survival data after >5 years of follow-up. ESMO Open 2021;6:100290.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    D’Angelo SP, Bhatia S, Brohl AS, et al. Avelumab in patients with previously treated metastatic Merkel cell carcinoma: long-term data and biomarker analyses from the single-arm phase 2 JAVELIN Merkel 200 trial. J Immunother Cancer 2020;8:e000674.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    D’Angelo SP, Lebbé C, Mortier L, et al. 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. J Immunother Cancer 2021;9:e002646.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    D’Angelo S, Lebbé C, Mortier L, et al. First-line avelumab treatment in patients with metastatic Merkel cell carcinoma: 4-year follow-up from the JAVELIN Merkel 200 trial. J Immunother Cancer 2022;10(Suppl 2):Abstract 604.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Topalian SL, Bhatia S, Amin A, et al. Neoadjuvant nivolumab for patients with resectable Merkel cell carcinoma in the CheckMate 358 trial. J Clin Oncol 2020;38:24762487.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 2016;374:25422552.

  • 52.

    Nghiem P, Bhatia S, Lipson EJ, et al. Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy. J Clin Oncol 2019;37:693702.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Nghiem P, Bhatia S, Lipson EJ, et al. Three-year survival, correlates and salvage therapies in patients receiving first-line pembrolizumab for advanced Merkel cell carcinoma. J Immunother Cancer 2021;9:e002478.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Grignani G, Rutkowski P, Lebbe C, et al. A phase 2 study of retifanlimab in patients with advanced or metastatic Merkel cell carcinoma (MCC) (POD1UM-201). J Immunother Cancer 2021;9(Suppl 2):Abstract 545.

    • PubMed
    • Search Google Scholar
    • Export Citation
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