18th Annual Multicenter Merkel Interest Group (MMIG) Meeting

The MCC Multi-center Merkel Interest Group hosted the 18th Annual Multi-center Merkel Interest Group meeting on Friday, March 8th, 2024 from 5-7 p.m. PST.  This event ran concurrently with the 2024 AAD Annual Meeting from March 8-12, 2024, in San Diego, CA.

Summary of 18th Annual MMIG Meeting 

Friday, March 8th, 2024 

San Diego, CA & Virtual event  

Prepared by: 

Rian Alam, Kate Biese, Macy Gilmour, Krista Lachance, Ankita Menon, & Paul Nghiem  

Announcements 

1. If you would like to view the meeting recording, please contact Kate directly ([email protected]) 
2. Please contact Paul Nghiem ([email protected]) or Kate Biese ([email protected]) if you would like to present at next year’s meeting or if you have any feedback to improve future meetings 

MMIG Meeting Agenda (times in PST)  

Meeting notes: 

      1. Merkel Cell Carcinoma – From DeepMerkel to Crystal Clear  

Tom Andrew, MD (Newcastle University, Newcastle-Upon-Tyne)  

• Staging and predicted prognosis of MCC can be complicated
  • Need for streamlined staging method 
• 2 cohorts- 1 from UK, 1 from SEER-17
  • Data from 2010-2020 
• Performed Kaplan-Meier analyses to look at factors that could influence survival 
  • Age, sex, primary tumor location, marital status 
• Found that a Cox Proportional Hazard had a superior concordance/prediction score (0.71) than AJCC staging only (0.66) 
  • Increasing variables within the model led to better prediction 
• Development of ‘DeepMerkel’ Model 
  • Combined two AI models to better predict prognosis and survival 
    • ‘Deep Learning’- used to tweak variables 
    • ‘XGBoost’ reduces distance between predicted and observed patient outcomes 
• DeepMerkel survival predication closely matched actual cohort data (C-index 0.93) 
  • More accurate then AJCC (C-index 0.69)
  • Not only predicts if a pt will die in next 10 years, but when 
• SHAP (a game theory approach) used to summarize DeepMerkel output 
  • Ranked the influence of the top 20 clinicopathological and treatment features on disease specific survival 
• Next steps: 
  • Use DeepMerkel to develop informed treatment plans for patients 

      2. Why are Patients with XMEN Disease Getting Early Onset Merkel Cell Carcinoma?  

Jennifer Strong, BS (Brownell Lab, NIH/NIAMS)  

• MCC incidence: 1 in 100 million for people under 30 
• Identified 3 MCC pts under 30 who presented w/ XMEN Disease
  • Rare primary immunodeficiency
  • Loss-of-fxn of MAGT1 gene
    • Gene important in function of cytotoxic T cells 
    • Leads to impaired immune response 
• All 3 XMEN MCC patients shared similarities 
  • Advanced MCC  
  • Virus-positive tumors  
  • Dx w/ MCC 3 decades before immunocompromised MCC median age 
  • Today, all 3 are alive and disease free (typical immunocompromised 5-yr survival <40%) 
• Found that healthy XMEN pts had increased MCPyV burden across every single tested skin site in contrast to non-XMEN pts 
  • Increased MCPyV detection compared to other polyomaviruses 
  • Suggests that MAGT1 mutation increases MCPyV susceptibility selectively 
• One pt developed myelodysplastic syndrome likely from chemo received 13 yrs previously; not typically seen w/ XMEN 
  • Received bone marrow transplant from healthy donor 
  • 1 yr later, still had increased MCPyV burden despite now having a wild-type immune system 
  • Suggests virus susceptibility not from immunosuppression but from MAGT1 mutation in the skin 
• Future directions: Does MAGT1 loss of function increase susceptibility to MCPyV infection? 

      3. What’s New in MCC Clinical Trials  

Ariel Finberg, MD & Austin Jabbour, MD (University of Washington) & Vincent Ma, MD (University of Wisconsin – Madison)  

• 37 clinical trials for MCC, 9 MCC only  
• STAMP trial  
  • Adjuvant; surgically treated adjuvant MCC with pembrolizumab  
  • All MCC stages, excluding pathological stages I and IV 
• ADAM trial  
  • Adjuvant avelumab vs placebo in MCC  
  • MCC stage III disease only  
• Checkmate trial 
  • Refractory and first line; injectable TRL9 agonist (CMP-001) + cemiplimab  
  • Not exclusive to MCC; includes numerous cancers 
• Kartos trial  
  • Refractory; navtemadlin (KRT-232) +/- avelumab  
    • Navtemadlin is an oral MDM2 inhibitor  
      • Restores p53 function, helps cancer cells activate apoptosis  
  • MCC virus positive patients only  
• TRICK-MCC trial 
  • Refractory; triple-checkpoint blockade using Anti-TIM3, LAG3, and PD1 
  • Testing the release of multiple different “brakes” on the immune-system 
  • MCC patients only 
• MATRiX trial 
  • Refractory; ATR inhibitor (Tuvusertib) +/- avelumab 
    • ATR inhibitor is administered orally once daily – 2 weeks on 1 week off
  • 23 (tentative) participating sites across US and Canada 
• ASTX277 phase I/II study, opening in Q3 2024 
  • Refractory; ASTX277 + retifanlimab 
    • ASTX727 = decitabine + cedazuridine, oral hypomethylating agent to upregulate HLA genes  
  • Correlatives include ctDNA, DNA methylation, RNA seq 
  • MCC only 

       4. When is it Safe to Discontinue ICI Therapy? Prospective Data in 105 MCC Patients  

Emily Gong, intended BS (University of Washington)  

• IMTX has revolutionized MCC care but limited data on optimal duration  
  • Recent German cohort: frequent progression post discontinuation of IMTX 
    • 60% of patients progressed after stopping IMTX  
  • Australian cohort: responses were not durable after discontinuing  
    • Median progression-free survival: 21 months  
    • Patients without complete response much likelier to progress  
• Cohort:  
  • 166 pts receiving ICI between 7/2012-7/2021  
    • 105 (63%) achieved objective response, 61 with progression/death  
    • Among cohort, 23% risk of progression at 2 years, jumps to 40% at 3 years  
• 14% risk of progression for pts maintaining IMTX at 2 years, 31% for electively discontinuing   
  • Pts may do better staying on immunotherapy!  
• Long-term responders (pts without death/progression at1 year follow-up from IMTX start) may have durable responses w/ elective discontinuation  
  • 4% risk of progression after 2-years for pts who maintain IMTX, 8% for pts who electively discontinue  
• Patients w/ CR tend to do better than PR after discontinuing IMTX  
  • 29% risk of progression after 2-years off-therapy for CR vs 59% for PR   
• MCC patients with a CR who are long-term responders (patients without progression after one year of f/u from IMTX start) may have durable responses to immunotherapy with elective treatment discontinuation 

      5. Challenges of Treating Merkel Cell Carcinoma in Brazil  

Matheus Lobo, MD (Hospital A. C. Camargo, Department of Skin Oncology) 

• Cancer cases have increased 27% in 10 yrs 
• No immunotherapy approval in Public Insurance System 
• Recent cohort of 881 Brazilian MCC patients 
  • 51.2% female, 82.2% >60 yrs old 
  • 50.5% stage III or IV 
• National institute of Cancer Cohort study in Brazil 
  • 65 MCC patients  
  • 44% virus positive cases 
• Performed survey of Brazilian society of surgical oncology members 
  • 80 responses, 82.5% have treated Merkel in past 
  • Just because physicians had access to technologies, does not mean they had access in proper time 
  • >1/4 of surgeons think there’s a shortage of dermatologists in their region 
  • >50% of surgeons think there is delay in starting treatment for Merkel 
  • 60% believe the greatest obstacle to cancer treatment is lack of access to new therapies 
• 22-board certified surgeons had 5 rounds of discussion to help create guidelines for treating Merkel, accounting for the challenges in Brazil 
• Only 1 clinical trial for Merkel in Brazil, but multiple clinical trials for Melanoma at multiple hospitals 
  • Should try to expand Merkel clinical trials in Brazil to provide immunotherapy access 

      6. The Prognostic Value of the AMERK Test: A Dual Institutional Observational Study  

David Miller, MD/PhD (Massachusetts General Hospital & Harvard Medical School)  

• AMERK detects circulating antibodies against common T-Ag of MCPyV 
• Seropositive near diagnosis previously reported to be associated with decreased recurrence 
• Aim of retrospective study was to evaluate association between initial AMERK serostatus and survival 
• 531 patients with 362 pts with AMERK assessed 
  • 261 pts with AMERK at dx 
  • 132 seronegative and 129 seropositive (titer cutoff was 75) 
• Competing risks regression model and Cox proportional hazard model for EFS and OS 
• Results: 
  • Seronegative patients recur at higher rate than seropositive (46% vs 27% respectively) 
  • Seropositive patients have better Event Free Survival [Hazard Ratio (HR) 0.6; 95% CI 0.41-0.87] (controlled for confounding variables such as stage, immunosuppression, ECOG, prior treatment) 
  • Seropositive patients have better overall survival [Hazard Ratio (HR) 0.58; 95% CI 0.35-0.96] 
  • Seropositive patients have better MCC-specific survival [Hazard Ratio (HR) 0.6; 95% CI 0.32-1.1] 
• AMERK high vs AMERK low has no difference in modeled analysis (accounting for external variables) 
• Clear positive association between AMERK titer and clinical stage, primary tumor size, and disease extent 
• Potential effect modification exists between serostatus and disease extent  
• AMERK at baseline is strongly linked to prognosis as well as stage of disease 
• The utility of AMERK for detecting progression will be reported separately.  

       7. mRNA Vaccine Approaches to Target Virus-Associated Merkel Cell Carcinoma  

Jeff Ishizuka, MD/DPhil (Yale School of Medicine)  

• MCC T antigens are immunogenic and are required for tumor persistence in 80% of US MCC cases 
• MCC’s conserved T antigen makes it an ideal target for a vaccine 
• Developed a large T- antigen expressing murine model 
• mRNA vaccine shown to be capable of controlling melanoma tumors 
• Cooperativity between immunotherapy and vaccine 
• Antigen loss occurred as potential mechanism of resistance 
  • Not possible in actual MCC 
• Patient sample results after vaccination:
  • LTA mRNA vaccine increased LTA tetramer specific CD8+ T cells 
  • Preferentially induced IFN-gamma release compared to placebo controls 
  • Increased tumor cell killing 
• Summary: 
  • MCPyV Large T antigen is compelling target for mRNA-based therapeutic vaccination 
  • LTA-vaccine suppresses tumor growth and increases survival in vitro 
  • LTA-vaccine and PD-1 blockade act cooperatively to control tumors in vivo 

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Goals of the Merkel cell carcinoma Multi-center Interest Group (MMIG) – Promote communication and collaborative studies on MCC – Enhance access to patient data and specimens – Expand evidence-based care for MCC  

Homepage for MMIG is available at: https://merkelcell.org/about-us/mmig/ 

MMIG is funded in part by donations from Merkel cell carcinoma patients. Please note that in many cases, these summaries reflect unpublished data and are provided to help MMIG members manage their patients and give an overview of what is being done at different centers for care and research. 

In attendance at the 2024 MMIG Meeting (N=89 total attendees)  

Asterisk* = in-person attendee 

We apologize if we missed your name or affiliation