Merkel Cell Cancer

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Merkel Cell Cancer | Johns Hopkins Medicine

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The most important first step in defeating Merkel cell carcinoma is to build a team of MCC specialists.

Proper management of MCC almost always involves several of the following specialties: surgery, dermatology, radiation oncology and medical oncology. Established teams that are expert in the management of MCC exist at all of the centers listed below. Central contact persons from each institution are included in the listings.

Aleksandar Sekulic, MD, PhD

Mayo Clinic | Dept. of Dermatology

James Warneke, MD

University of Arizona Cutaneous Oncology Program | Surgical Oncology

Nathalie C. Zeitouni, MDCM. FRCPC, Mohs and Reconstructive Surgery

Medical Dermatology Specialists

1331 N 7th Street, Suite 250

Phoenix, Arizona 85006

United States

J. Camilo Barreto-Andrade, MD

University of Arkansas for Medical Sciences | Surgical Oncology

John B. Sunwoo, MD, FACS

Stanford University & VA Palo Alto | Head & Neck Surgery

Kathryn Bollin, MD

Scripps MD Anderson | Hematology/Oncology

Kim Margolin, MD, Clinical Professor

City of Hope | Medical Oncology

Ling Gao, MD, PhD

UC Irvine Health | Department of Dermatology

Lisa Zaba MD, PhD

Stanford Cancer Center South Bay | Dept. of Dermatology

Ralph Massey, MD

The Skin Cancer Group | Dept. of Mohs Micrographic & Dermatologic Surgery

Seaver L. Soon, MD

Scripps Green Hospital

Siegrid S. Yu, MD

University of California, San Francisco | Dermatologic Surgery (Mohs Micrographic Surgery and Cutaneous Oncology)

1701 Divisadero Street, 3rd Floor

San Francisco, California 94143

United States

Sunil A. Reddy, MD

Stanford Cancer Institute/Stanford Hospital | Medical Oncology

Harriet Kluger, MD

Yale Cancer Center | Medical Oncology

Amod A. Sarnaik, MD, FACS

H. Lee Moffitt Cancer Center and Research Institute | Surgical Oncology

Andrew Brohl, MD

Moffitt Cancer Center | Medical Oncology

Evan Wuthrick, MD

H. Lee Moffitt Cancer Center | Radiation Oncology

Guilherme Rabinowits, MD

Miami Cancer Institute | Medical Oncology

John Strasswimmer, MD, PhD

Boca Raton and Bethesda Hospitals: Baptist Health Cancer Institute

Jonathan Zager, MD, FACS

H. Lee Moffitt Cancer Center and Research Institute | Surgical Oncology

Kenneth Y Tsai, MD, PhD

H. Lee Moffitt Cancer Center | Dermatology

Natalia Jaimes, MD

Sylvester Comprehensive Cancer Center / University of Miami Health System

Vernon K. Sondak, MD

H. Lee Moffitt Cancer Center and Research Institute | Surgical Oncology

Ragini Kudchadkar, MD

Emory University Hospital | Medical Oncology

Ajay V. Maker, MD, FACS

Creticos Cancer Center at Advocate Illinois Masonic Medical Center & University of Illinois at Chicago | Surgical Oncology

Jaehyuk Choi, MD PhD

Robert H. Lurie Comprehensive Cancer Center of Northwestern University | Department of Dermatology

Chicago, Illinois 60611

United States

Sunandana Chandra, MD, MS

Robert H. Lurie Comprehensive Cancer Center of Northwestern University | Medical Oncology

Chicago, Illinois 60611

United States

Evan J. Lipson, MD

Johns Hopkins | Medical Oncology

Linda C Wang, MD, JD

Wang Dermatology | Medical & Surgical Dermatology

Ann W. Silk, MD, MS

Dana-Farber Cancer Institute

Charles H. Yoon, MD, PhD

Dana-Farber/Brigham and Women's Cancer Center| Surgical Oncology

Danielle N. Margalit, MD, MPH

Dana-Farber/Brigham and Women's Cancer Center| Radiation Oncology

David Miller, MD, PhD

Massachusetts General Hospital

Manisha Thakuria, MD

Dana-Farber/Brigham and Women's Cancer Center | Cutaneous Oncology

Reed E. Drews, MD

Beth Israel Deaconess Medical Center | Cutaneous Oncology Program

Kelly Harms, MD, PhD

Michigan Medicine | Cutaneous Surgery and Oncology

Rogel Cancer Center Floor 1, 1500 E. Medical Center Drive

Ann Arbor, Michigan 48109-5902

United States

Clark Clothier Otley, MD

Mayo Clinic | Division of Dermatologic Surgery

James Jakub, MD

Mayo Clinic | Department of Surgery

Ryan Fields, MD, FACS

Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital, Washington University School of Medicine | Surgical Oncology

Janice M. Mehnert, MD

Rutgers Cancer Institute of New Jersey | Medical Oncology

Daniel Coit MD, FACS

Memorial Sloan Kettering Cancer Center

Sherrif F. Ibrahim, MD, PhD

University of Rochester Wilmot Cancer Center | Division of Dermatologic Surgery

Nasreen A. Vohra, MD, FACS

Vidant Medical Center | Dept. of Surgery

Brian Gastman, MD

Cleveland Clinic Foundation | Dermatology and Plastic Surgery Institute

Carlo Contreras, MD

The Ohio State Unviersity Comprehensive Cancer Center | Surgical Oncology

2050 Kenny Road

Columbus, Ohio 43221

United States

Jeremy Bordeaux, MD, MPH

UH Cleveland Medical Center | Department of Dermatology

Thomas P. Trezona, MD, FACS

Sacred Heart Hospital Riverbend| Surgery

Clifford S. Perlis, MD, MBE

Keystone Dermatology Partners

216 Mall Boulevard, Suite 101

King of Prussia, Pennsylvania 19046

United States

Miriam Lango, MD

Fox Chase Cancer Center | Cutaneous Oncology Program

Dylan Lippert, MD

Baylor University Medical Center | Head and Neck Surgical Oncology & Reconstructive Surgery

Frank Saporito, MD

Dallas Skin Cancer Center | Cutaneous Oncology | Dermatologic and Mohs Micrographic Surgery

Mark D. Bonnen, M.D.

Baylor College of Medicine | Dan L. Duncan Comprehensive Cancer Center | Radiation Oncology

Michael K Wong, MD, PhD, FRCPC

UT MD Anderson Cancer Center | Medical Oncology

1400 Holcombe Blvd.

Houston, Texas 77030

United States

Sekwon Jang, MD

Inova Melanoma and Skin Cancer Center | Medical Oncology

Suraj Venna, MD

Inova Melanoma and Skin Cancer Center | Derm-Oncology

David Byrd, MD

Seattle Cancer Care Alliance | Skin Oncology Clinic

Kelly Paulson, MD, PhD

Seattle Cancer Care Alliance | Cellular Immunotherapy

Paul Nghiem, MD, PhD

Seattle Cancer Care Alliance | Skin Oncology Clinic

Shailender Bhatia, MD

Seattle Cancer Care Alliance | Skin Oncology Clinic

Upendra Parvathaneni, MD

Univeristy of Washington Medical Center | Radiation Oncology

Rohit Sharma, MD, FACS

Marshfield Clinic | Surgical Oncology

Julie Howle, MD

Westmead Cancer Care Centre | Medical Oncology

Professor Michael Veness, MD

Westmead Cancer Care Centre | Radiation Oncology

Milton Barros e Silva, MD

AC Camargo Cancer Center

Astrid Blom, MD

CHU Ambroise Pare | Service de Dermatologie Generale et Oncologique

Juergen Becker MD, PhD

Essen University Hospital | Dermatology

Hufelandstrasse 55

Essen 45147


Stephan Grabbe, MD

University of Mainz Medical Center | Dept. of Dermatology

Langenbeckstr. 1

Mainz 55131


Thilo Gambichler, Prof. Dr. med.

St. Josef Hospital | Skin Cancer Center, Dept. of Dermatology, Ruhr-University Bochum




Alexander J. Stratigos, MD, PhD

Center for Melanoma Skin Cancer | Andreas Sygros Hospital for Skin and Venereal Diseases

5 Dragoumi Street

Athens 16121


Eyal Fenig, MD

Herzliya Medical Center | Department of Oncology

7 Ramat Yam St.

Herzliya 4685107


Kotaro Nagase, MD, PhD

Saga University Hospital | Department of Dermatology

5-1-1 Nabeshima

Saga 8498501


Alexander C.J. van Akkooi, MD, PhD

Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital (NKI-AVL) | Dept. of Surgical Oncology

Plesmanlaan 121, 1066 CX



Marloes van Kester, MD, PhD

University Medical Center Groningen | Dept. of Dermatology

Hanzeplein 1

Groningen 9713 GZ


Åse Bratland, MD, PhD

Oslo University Hospital | Department of Oncology

Nydalen, 0424



Piotr Rutkowski, MD, PhD

Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology | Department of Soft Tissue/Bone Sarcoma and Melanoma

Roentgena Str. 5

Warsaw 02-781


Kristina Orlova, MD, PhD

N. N. Blokhin Russian Cancer Research Center | Medical Oncologist & Senior Clinical Researcher

24, Kashirskoye shosse,

Moscow 115478


John Paoli, MD, Assoc. Prof

Sahlgrenska University Hospital

Yi-Hua Liao, MD, PhD

National Taiwan University Hospital | Department of Dermatology

7, Chung-Shan South Rd

Taipei 10002


Andrew Birnie, MD

Kent and Canterbury Hospital

Ethelbert Road

Canterbury CT1 3NG

United Kingdom

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Immunotherapy Appears Better Than Chemotherapy for Aggressive Type of Skin Cancer

Merkel Cell Cancer | Johns Hopkins Medicine

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Posted by: Crystal Williams on: February 8, 2019 | Print This Page

Immunotherapy drug treatment for Merkel cell carcinoma shows better responses, longer survival, leads to FDA approval of drug.

For a patient whose Merkle cell carcinoma had spread to multiple organs, the treatment resulted in substantial tumor regression within 3 months. Credit: Johns Hopkins Kimmel Cancer Center

The first study of the immunotherapy drug pembrolizumab as the initial treatment for patients with a rare but aggressive form of skin cancer known as Merkel cell carcinoma reports better responses and longer survival than expected with conventional chemotherapy.The study, co-led by Suzanne Topalian, M.D.

, associate director of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center, is the longest observation to date of Merkel cell carcinoma patients treated with any anti-PD-1 immunotherapy drug used in the first line.

The findings, published in the Journal of Clinical Oncology, supported the recent (Dec. 19, 2018) U.S. Food and Drug Administration accelerated approval of pembrolizumab, marketed as Keytruda, as a first-line treatment for adult and pediatric patients with advanced Merkel cell carcinoma.

For this study, investigators from the Bloomberg~Kimmel Institute collaborated with researchers from the Fred Hutchinson Cancer Research Center in Seattle, along with 11 other U.S. medical centers. The Bloomberg~Kimmel Institute team includes Topalian, William Sharfman, M.D., Evan Lipson, M.D., Abha Soni, D.O., M.P.H.

, and Janis Taube, M.D., M.Sc.

In the 50-patient study of pembrolizumab as the initial treatment for patients with recurrent, locally advanced or metastatic Merkel cell carcinoma, more than half of the patients (28 patients, 56 percent) had long-lasting responses to the treatment, 12 of whom (24 percent) experienced a complete disappearance of their tumors. Nearly 70 percent of patients in this study were alive two years after starting treatment.

“This is the earliest trial of immunotherapy as a front-line therapy for Merkel cell carcinoma, and it was shown to be more effective than what would be expected from traditional therapies, chemotherapy,” says Topalian, who is a Bloomberg~Kimmel professor of cancer immunotherapy at the Kimmel Cancer Center.

“Immunotherapy provides an effective treatment for patients with Merkel cell carcinoma who before had few options. Immunotherapy is unique in cancer treatment, because it does not directly target cancer cells but rather removes constraints on the immune system’s natural ability to find and destroy cancer cells.

The 50 patients in this study were treated at 13 centers across the United States in a clinical trial conducted by the Cancer Immunotherapy Trials Network, which is sponsored by the National Cancer Institute (NCI).

The Kimmel Cancer Center, where much of the medical science contributing to the development of pembrolizumab unfolded, was a lead institution. Preliminary findings regarding the first 26 patients enrolled in the study were published in the New England Journal of Medicine in 2016.

The study was subsequently amended to add 24 more patients.

The National Institutes of Health (NIH) classifies Merkel cell carcinoma as an “orphan disease,” as it is diagnosed in fewer than 2,000 people annually in the United States.

It typically occurs in older people and those who have suppressed immune systems. About 80 percent of Merkel cell carcinomas are caused by a virus called the Merkel cell polyomavirus.

The remaining cases are attributed to ultraviolet light exposure and other, unknown factors.

In the study, treatment with pembrolizumab worked well against both virus-positive and virus-negative Merkel cell carcinomas, resulting in high response rates and durable progression-free survival in both subtypes. The findings also showed that tumors expressing a PD-1-related protein called PD-L1 tended to respond longer to treatment, although patients whose tumors did not express PD-L1 also responded.

“These findings could be a precursor to developing more effective treatments for other virus-related cancers, which account for about 20 percent of cancers worldwide,” says Sharfman, the Mary Jo Rogers Professor of Cancer Immunology and Melanoma Research.

The non-virus-related subtype is characterized by high numbers of genetic mutations in cancer cells, which has also been shown by the Bloomberg~Kimmel Institute group to be a biomarker of response in various cancers to checkpoint inhibitors such as pembrolizumab.

Pembrolizumab works against Merkel cell carcinoma by blocking PD-1, a molecule on the surface of immune cells that regulates immune responses, turning them on and off. Cancer cells often manipulate PD-1 to send a “stop” signal to the immune system.

Blocking that signal with a checkpoint inhibitor, such as pembrolizumab, initiates a “go” signal, sending immune cells to attack cancer cells. A protein on the surface of cancer cells, called PD-L1, is one mechanism cancer cells use to manipulate PD-1 and disrupt the immune response.

“Under the microscope, PD-L1 looks an armor around the cancer cell,” says Taube, an associate professor of oncology, dermatology and pathology. “Pembrolizumab interrupts PD-1 signaling by blocking the communication between PD-1 and PD-L1, removing the stop signal and re-engaging the immune system to go after cancer cells.

Patients in the just-published study received the immune checkpoint blocking drug pembrolizumab intravenously every three weeks for up to two years. During this time, the status of their cancer was monitored periodically with imaging scans. Overall, most patients tolerated the treatment well. However, 28 percent of patients experienced serious side effects, including one treatment-associated death.

Paul Nghiem, M.D., Ph.D., affiliate investigator in the clinical research division at the Fred Hutchinson Cancer Research Center in Seattle, and professor of medicine in the division of dermatology at the University of Washington School of Medicine, is the principal investigator and first author of the study.

In addition to Topalian, Sharfman, Taube, Lipson, Soni and Nghiem, study investigators included Shailender Bhatia, Ragini Kudchadkar, Andrew Brohl, Phillip Friedlander, Adil Daud, Harriet Kluger, Sunil Reddy, Brian Boulmay, Adam Riker, Melissa Burgess, Brent Hanks, Thomas Olencki, Kim Margolin, Lisa Lundgren, Nirasha Ramchurren, Candice Church, Song Park, Michi Shinohara, Bob Salim, Steven Bird, Nageatte Ibrahim, Steven Fling, Blanca Homet-Moreno, Elad Sharon and Martin Cheever.

The research was supported by the National Cancer Institute (1U01CA154967, K24CA139052, R01CA162522, R01CA142779, T32CA193145), the NIH/NCI Cancer Center Support Grant in Seattle (P30CA015704), Merkel cell carcinoma patient gift fund at the University of Washington, Kelsey Dickson Merkel cell carcinoma challenge grant from the Prostate Cancer Foundation, and Merck.

COI: Lipson reports a consulting or advisory role: Bristol-Myers Squibb, Novartis, EMD Serono, Array BioPharma, Regeneron/Sanofi Genzyme, MacroGenics, Merck, Millennium; research funding: Bristol-Myers Squibb (Inst), Merck (Inst), Sysmex (Inst); patents, royalties, other intellectual property: Method of preventing organ transplantation rejections using agonists to the PD-1 checkpoint pathway (Inst). Sharfman reports honoraria: Bristol-Myers Squibb; consulting or advisory role: Merck, Bristol-Myers Squibb, Novartis, Regeneron; research funding: Bristol-Myers Squibb (Inst), Merck, Novartis. Taube reports consulting or advisory role: Bristol-Myers Squibb, AstraZeneca, Merck, Amgen; research funding: Bristol-Myers Squibb; travel, accommodations, expenses: Bristol-Myers Squibb, AstraZeneca, Merck, Amgen. Topalian reports stock and other ownership interests: Aduro Biotech (I), Compugen (I), Potenza Therapeutics (I), Jounce Therapeutics (I), Five Prime Therapeutics, Tizona Therapeutics (I), DNAtrix (I), FLX Bio (I), WindMIL (I), Dragonfly Therapeutics, Ervaxx (I); consulting or advisory role: Five Prime Therapeutics, Amgen (I), MedImmune (I), Merck, AbbVie, Compugen (I), DNAtrix (I), FLX Bio (I), Tizona Therapeutics (I), WindMIL (I), Dragonfly Therapeutics, Bayer (I), Dynavax (I), Ervaxx (I), Immunomic Therapeutics (I), Janssen Oncology (I); research funding: Bristol-Myers Squibb, Compugen (I), Potenza Therapeutics (I); patents, royalties, other intellectual property: Aduro Biotech (I), Bristol-Myers Squibb (I), Immunomic Therapeutics (I); travel, accommodations, expenses: Bristol-Myers Squibb, Five Prime Therapeutics. (I) = immediate family member, (Inst) = my institution.

Potential conflicts of interest reported by other authors can be found at

Media ContactsLarry Frum443-287-2539

Amy Mone410-614-2915


Merkel Cell Cancer

Merkel Cell Cancer | Johns Hopkins Medicine

Linkedin Pinterest Cancer Skin Biopsies

Merkel cell carcinoma is a rare type of skin cancer. Merkel cells are types of cells in the upper layer of the skin.

The cells are very close to nerve endings, and help the skin sense light touch. Merkel cell carcinoma occurs when these cells grow control. Merkel cell carcinoma can be dangerous because it tends to grow quickly.

It can be hard to treat if it spreads beyond the skin.

Merkel cells are a type of neuroendocrine cell. This means they have features of both nerve cells and hormone-making cells. The cancer is also known as neuroendocrine carcinoma of the skin.                                                                                                                                                                       

What are the risk factors for Merkel cell carcinoma?

The known risk factors for Merkel cell carcinoma include:

  • Exposure to UV rays.  many other types of skin cancer, the risk of Merkel cell carcinoma is higher in people who have been exposed to a lot of UV (ultraviolet) rays from the sun or from other sources tanning beds. People who are treated for psoriasis with UV rays may also have a higher risk.
  • Weakened immune system. People with weakened immune systems, such as people who have had an organ transplant, are at increased risk for this cancer.
  • Light-colored skin. People with lighter skin are at higher risk.
  • Older age. People older than 50 are more ly to get this cancer.
  • Being male. Men are more ly to get Merkel cell carcinoma.

Researchers have found that Merkel cell carcinoma almost always shows infection with a virus known as Merkel cell polyomavirus (MCV). It is not known how the virus may contribute to the growth of this cancer. Most people are infected with this virus at some point. But very few people develop this cancer.

What are the symptoms of Merkel cell carcinoma?

Merkel cell carcinoma tumors are most often found on sun-exposed areas of skin, such as the face, neck, and arms. But they can start anywhere on the body. They usually appear as firm, shiny skin lumps that don't hurt. The lumps may be red, pink, or blue. They tend to grow very quickly.

How is Merkel cell carcinoma diagnosed?

The diagnosis of Merkel cell carcinoma is made with a biopsy. This is a sample of tissue that’s taken and tested in a lab. Tumor samples are removed with a needle or scalpel, or during surgery. They are checked with a microscope to see if cancer cells are present. Diagnosis of Merkel cell carcinoma can be difficult. It can look many other types of cancer.

Early diagnosis and treatment of Merkel cell carcinoma is important to prevent the cancer from spreading. Be aware of any lumps, growths, moles, or other abnormal areas on your skin. Watch for new spots or areas that are changing.

This can include skin marks that grow larger, bleed, crust, or itch. Your healthcare provider may recommend you do a skin self-exam once a month or more. See your healthcare provider if you have any new or changing marks on the skin.


How is Merkel cell carcinoma treated?

Treatment is often done with more than 1 method. Treatment methods include:

  • Surgery to remove the tumor. This may include a border of healthy tissue. Since Merkel cell carcinoma grows fast and often spreads (metastasizes), your provider may also remove nearby lymph nodes.
  • Radiation therapy. This therapy uses X-rays to kill cancer cells and shrink tumors. This may be used after surgery. Or it may be the main treatment if surgery is not an option.
  • Chemotherapy. This treatment is done with medicines. It helps destroy cancer cells in cases where the cancer has spread to other parts of the body.


Immunotherapy drug shrinks tumors in half of patients with rare, virus-linked skin cancer

Merkel Cell Cancer | Johns Hopkins Medicine

In a clinical trial of the immunotherapy drug pembrolizumab, half of 25 patients with a rare type of virus-linked skin cancer experienced substantial tumor shrinkage lasting nearly three times as long, on average, than with conventional chemotherapy. Several patients had no remaining evidence of the disease, known as Merkel cell carcinoma.

Multispectral immunofluorescence showing the interface between Merkel cell tumor cells (orange) and host immune cells (yellow marks CD8+ lymphocytes, red marks CD68+ macrophages). Cell-surface PD-L1 expression (green) is observed on macrophages, lymphocytes and tumor cells, adjacent to PD-1 expression (white) on lymphocytes.

Image : Janis Taube, Johns Hopkins

Results of the study are published online today in the New England Journal of Medicine.

Scientists at the Fred Hutchinson Cancer Research Center and the Johns Hopkins Kimmel Cancer Center, who led the study, say the results could be a harbinger of how some patients with virus-associated cancers—which account for more than 20 percent of cancers worldwide—might respond to certain drugs called immune checkpoint blockers or inhibitors.

“If additional studies with more patients confirm our findings, we will have strong reason to believe that many cancers with virus-linked proteins could be valid targets for immune checkpoint blockade,” says Suzanne Topalian, professor of surgery and oncology and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy.

Merkel cell carcinoma is diagnosed in fewer than 2,000 people annually in the United States.

It tends to occur in older people and those who have suppressed immune systems, says William Sharfman, associate professor of oncology and dermatology and director of cutaneous oncology at the Johns Hopkins Kimmel Cancer Center.

Approximately 80 percent of Merkel cell carcinomas are caused by a virus called Merkel cell polyomavirus. The rest are caused by exposure to ultraviolet light and other unknown factors.

Learn more

Investigators at eight medical centers across the United States examined 26 patients with metastatic or recurrent Merkel cell carcinoma who had not previously received any systemic therapies for advanced disease. All of the patients had received standard therapy with surgery and/or radiation therapy.

Each of the patients received pembrolizumab intravenously every three weeks and received imaging scans every two to three months while receiving the drug.

The researchers identified patients who responded to the drug according to standard oncology benchmarks—that is, patients who showed 30 percent or more shrinkage in measured tumors and no new lesions after two sets of imaging scans at least one month apart.

In the study, 14 of 25 patients (56 percent) whose scans were evaluated responded to the drug. Four of those patients had a complete response, with no remaining radiologic evidence of cancer. Twelve of the 14 continued to respond to the drug after a median follow-up time of 33 weeks.

According to Evan Lipson, assistant professor at the Johns Hopkins Kimmel Cancer Center, about half of patients with Merkel cell carcinoma typically respond to various chemotherapy combinations, but their cancers recur after an average of three months.

“Compared with traditional chemotherapy, about the same percentage of patients responded to pembrolizumab in this study, but these patients' responses were longer lasting,” he says.

Pembrolizumab works to block a protein called PD-1 found on the surface of immune system T cells. The blockade cuts off a molecular “handshake” between the T cells and cancer cells. When the handshake doesn't happen, T cells recognize the cancer cells as foreign and mark them for destruction.

“We're learning that tumor architecture is important to understanding the immune response in cancer,” says Topalian.

Read more from Hopkins Medicine


Is First-Line Avelumab Effective for Metastatic Merkel Cell Carcinoma?

Merkel Cell Cancer | Johns Hopkins Medicine

First-line avelumab monotherapy appears to have antitumor activity and a manageable safety profile in patients with metastatic Merkel cell carcinoma (mMCC), according to the results of an interim analysis of a phase II study. The investigators reported in JAMA Oncology that maturing progression-free survival (PFS) data suggest durable responses.

These findings provide clinical evidence for anti–programmed cell death ligand 1 (PD-L1) treatment, William H. Sharfman, MD, an associate professor of Oncology & Dermatology and the director of Cutaneous Oncology at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, told Cancer Network.

“I think it confirms what we reported in the New England Journal of Medicine, that the anti-PD1 pembrolizumab is active in metastatic Merkel cell [carcinoma]. Avelumab is anti-PDL1, but the same concept [applies],” Sharfman said.

D’Angelo et al found that treatment with avelumab resulted in a confirmed objective response rate of 62.1%. A total of 16 of 18 responses (88.9%) occurred by the first planned post-baseline assessment. Grade 3 treatment-related adverse events (AEs) occurred in 8 of 39 patients (20.5%). 

The JAVELIN Merkel 200 trial showed that avelumab, an anti–PD-L1 antibody, is effective as second-line or later treatment in patients with mMCC. D’Angelo and colleagues are evaluating the efficacy and safety of avelumab as first-line treatment for patients with distant mMCC ( Identifier: NCT02155647).

So far, the JAVELIN Merkel 200 trial has enrolled 39 patients (30 men, 9 women). The median age is 75 years (range, 47–88 years), and the follow-up has been short (median follow-up, 5.1 months).

In responding patients, the estimated proportion with a duration of response of at least 3 months was 93%. The researchers also found that avelumab was generally well-tolerated as a first-line treatment.

No treatment-related deaths and no grade 4 adverse events occurred.

The researchers concluded that this agent is associated with early responses, high response rates, and a manageable safety profile. However, they cautioned that there has been only limited follow-up, and longer follow-up is warranted to evaluate overall survival (OS).

These results have not been compared with other immune checkpoint inhibitors for first-line therapy because data with extended follow-up have not been published for nivolumab and pembrolizumab.

According to the study authors, it is not possible to make comparisons yet on long-term survival outcomes, TRAEs, and the economic impact of different immune checkpoint inhibitors as first-line therapy.

Anthony J. Olszanski, MD, RPh, vice chair of the Department of Hematology/Oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania, said that although the number of patients treated in the current study is small, the findings are consistent with other published data.

“The National Comprehensive Cancer Network (NCCN) guidelines support the use of checkpoint inhibitors as preferred agents for disseminated Merkel cell cancer and, what has been published, this recommendation is well-founded and a remarkable advance for patients with this disease,” Olszanski told Cancer Network.


Immunotherapy in Merkel Cell Carcinoma

Merkel Cell Cancer | Johns Hopkins Medicine

By Caroline Helwick
July 25, 2018

At the 2018 ASCO Annual Meeting, investigators presented long-term follow-up data for immunotherapy in patients with Merkel cell carcinoma and new data for its use in the neoadjuvant setting. The results drew high interest from attendees and a number of questions were raised following the presentation.

Merkel cell carcinoma is a rare, aggressive, and often fatal skin cancer that is associated with the Merkel cell polyomavirus in ~80% of patients. The other 20% of patients harbor a heavy ultraviolet-induced mutation load. Until recently, chemotherapy was the only treatment option for unresectable disease.

Paul Nghiem, MD, PhD

As pointed out by an expert in the area, Paul Nghiem, MD, PhD, “Merkel cell typically responds to cytotoxic chemotherapy, but responses are frustratingly nondurable….

This cancer will be fatal in 33% to 46% of patients within the first 5 years of diagnosis—at least it was so, in the era before we had more effective therapies.” The effective therapies are antibodies targeting the inhibitory programmed cell death protein 1 (PD-1) receptor or its ligand (PD-L1).

A prognosis that was once dire has become more hopeful, at least for patients who respond to immunotherapy.

These are truly striking data indicating that immunotherapy is a preferred way to treat this cancer, compared with chemotherapy.

— Paul Nghiem, MD, PhD

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“In 2018, happily the field has been thrown on its head in terms of early management of advanced disease,” said Dr. Nghiem, George F. Odland Endowed Chair in Dermatology at the University of Washington, Seattle.

The National Comprehensive Cancer Network (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) still list clinical trials as the preferred first treatment option, but now avelumab (Bavencio), pembrolizumab (Keytruda), and nivolumab (Opdivo) are listed ahead of chemotherapy.

In 2017, avelumab became the first drug ever approved by the U.S. Food and Drug Administration for Merkel cell carcinoma. Pembrolizumab and nivolumab have shown similar efficacy in metastatic disease, and their approval in this setting is pending. Updates of these studies were presented at the ASCO meeting, as were new data for neoadjuvant nivolumab in resectable disease.

Neoadjuvant Nivolumab

“Neoadjuvant nivolumab resulted in high response rates after just two doses.

Median progression-free and overall survival have not been reached,” reported Suzanne Topalian, MD, Director of the Melanoma Program, at Johns Hopkins Medicine, and Associate Director of the Johns Hopkins Bloomberg~Kimmel Institute for Cancer Immunotherapy, Baltimore.

1 “Nivolumab induced radiographic responses in 40% and major pathologic responses in 65% of evaluable patients. In some patients, this avoided the need for more extensive surgery,” she added.

Suzanne Topalian, MD

The results came from the international phase I/II CheckMate 358 trial that included a cohort of patients with resectable stages IIA to IV Merkel cell carcinoma. Patients with stage IIA Merkel cell cancer have a ~50% risk of mortality within 5 years, according to Dr. Topalian.

Patients received nivolumab every 2 weeks (on days 1 and 15) for 2 doses and underwent surgery about 2 weeks later. Nine patients also received postoperative radiation therapy. Patients could resume nivolumab if they developed progressive disease within 1 year, as one of the patients did.

The analysis was 29 patients who received at least 1 dose of nivolumab; 27 went on to surgery about 4 weeks later. The median follow-up was 67 weeks, with some patients followed for about 2 years. No new safety signals were seen with the drug in the neoadjuvant setting, and only 2 patients had a grade 3 or 4 adverse event.

Now the question is whether these changes will translate into prolonged survival.

— Suzanne Topalian, MD

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Radiographic regression by computed tomography was noted for 40% of 25 evaluable patients, in whom target lesions were reduced by more than 30%, she reported. Dr. Topalian added that radiographic response underestimated the impact of nivolumab in this short treatment interval; a better reflection was pathologic tumor response.

In 17 tumors evaluated by central pathologic review, the researchers documented a 47% rate of pathologic complete response by traditional criteria and an 18% major pathologic response rate, defined as up to 10% viable tumor cells remaining. These preliminary data yielded a total major pathologic response rate of 65% by central review, she reported.

Some of the responses were “striking,” added Dr. Topalian. One patient had a distended cheek and underlying 9-cm tumor. After a pathologic complete response and postoperative radiotherapy, she has no evidence of disease at 19 months.

Another patient with a major pathologic response in bulky axillary lymph node metastases had 47 axillary nodes resected, only 2 of which contained microscopic tumor.

Without any postoperative therapy, the patient appears to be disease-free at 18 months.

“Median progression-free survival for the 27 patients undergoing surgery has not been reached.

Among 15 patients who had either a pathologic complete response or a major pathologic response by central or site investigator review, none has relapsed after surgery with a median follow-up of 12 months,” she said. “Now the question is whether these changes will translate into prolonged survival.”

Update on JAVELIN Merkel 200: ‘Striking Survival’

Dr. Nghiem presented an update on the international phase II JAVELIN Merkel 200 registration trial of avelumab in metastatic disease, calling the survival rates “striking,” as more than one-third of chemotherapy–refractory patients were still alive at 2 years.2

Patients who had previously been treated with at least one line of chemotherapy for metastatic disease received avelumab at 10 mg/kg once every 2 weeks. In the updated analysis, 88 patients were followed for a median of 29.2 months.

The confirmed overall response rate in the second-line setting or beyond was 33%, with 11.4% being complete responses. For the 29 responders, the median duration of response has not been reached. Of the 10 patients achieving complete responses, 7 are ongoing, and 67% of responders are expected to still be responding at 2 years.

Studies of anti–PD-1/PD-L1 agents in the first-line setting have demonstrated even higher response rates, essentially double those achieved with chemotherapy. This indicates Merkel cell carcinoma is a highly immunosensitive malignancy, he said.

Durable responses led to stable rates of progression-free survival: 29% at 12 months and 26% at 24 months. Median progression-free survival, however, was 3 months, due to early disease progression (