Summary of 15th Annual MMIG Meeting

July 20, 2021

This year’s 15th annual MMIG meeting was the first MMIG meeting to take place over Zoom and had a record setting number of attendees (104)!

Speakers/Topics:
1. Introduction of Polish MCC collaborators
Monika Dudzisz-Śledź and Piotr Rutkowski (Maria Sklodowska-Curie National Research Institute of Oncology)
2. Molecular characterization of classical and variant MCC cell lines
Jürgen Becker (University of Duisburg-Essen)
3. Repurposing Disulfiram for the treatment of MCC
Natasha Hill (National Institutes of Health)
4. Immunotherapy responders after treatment discontinuation: A potentially concerning recurrence rate?
Yassi Moshiri (University of Washington)
5. Circulating tumor DNA as a biomarker for MCC tumor burden
Lisa Zaba (Stanford University)
6. MDM2 Inhibitor [KRT-232] Therapy in p53 WT MCC Patients Refractory to PD-1/L1 Immunotherapy: preliminary results and observations
Michael Wong (MD Anderson Cancer Center)
7. Brainstorming session for the 2nd International MCC Symposium
Paul Nghiem (University of Washington)

1. Introduction of Polish MCC collaborators
Monika Dudzisz-Śledź and Piotr Rutkowski (Maria Sklodowska-Curie National Research Institute of Oncology)

Multi-center collaboration (Warsaw, Wroclaw, Gliwice & Cracov, Poland)

Retrospective study on locally advanced and metastatic/ unresectable MCC
- Locally Advanced (n=161)
  - Perioperative radiotherapy improves treatment outcomes and reduces disease progression but does not impact overall survival
  - Male gender, nodal involvement at diagnosis, the absence of SLNB in patients without clinical metastasis in lymph nodes were associated with lower disease specific survival and overall survival
- Metastatic/ Unresectable MCC (N=36)
  - Prognosis of these patients is poor and avelumab in the 2nd line allows achieving better results, which are similar to clinical trial results
- Plan to submit study findings to a journal

2. Molecular characterization of classical and variant MCC cell lines
Jürgen Becker (University of Duisburg-Essen)

Variant MCC (vMCC) cell lines: grow adherently and lack neuroendocrine markers such as chromogranin A¹
Classical MCC (cMCC) cell lines: have neuroendocrine growth pattern and grow in suspension as loose or compact spheroids¹
Clustering of mRNA & miRNA expression and DNA methylation suggest that vMCCs have closer gene signatures to SCC, when compared to cMCCs
Despite similarities between vMCCs and SCCs they still exhibit clear differences:
- Canonical Head & Neck SCC marker, miR-205, is not expressed in vMCCs
- In contrast to SCCs, vMCCs have a low expression of E-cadherin
CMCCs and vMCCs may represent two distinct states or different forms of neoplastic transformation; specifically, hypermethylation of the neuroendocrine genes HES6 and INSM1, and intermediate expression of ISL1 and CHGA suggest that vMCCs may be locked in an incomplete neuroendocrine transformation process.

3. Repurposing Disulfiram for the treatment of MCC
Natasha Hill (National Institutes of Health)

National Center for Advancing Translational Sciences (NCATS) High-throughput Drug Screen
- Disulfiram selectively reduces MCC cell viability
  - Disulfiram: binds and inhibits aldehyde dehydrogenase (anti-MCC activity likely due to off-target effects)
- Copper (Cu) increases disulfiram potency in MCC
  - Combination is cytostatic and cytotoxic
  - Disulfiram and copper do not induce apoptosis
- Potential mechanism for disulfiram + Cu anticancer activity:
  - Synergizes with etoposide (VP16) in MCC
  - Induce autophagy and immunogenic cell death
- Small clinical trial with disulfiram / Cu plus avelumab
  - Disulfiram 500 mg PO daily (patients must abstain from alcohol use)
    - If not tolerated, dose reduce in 125 mg increments.
  - 2 mg of Copper as Copper Gluconate daily with meal (OTC supplement)
  - Disulfiram / Cu plus VP16 possible PO combination for patients who fail immunotherapy or can’t reach infusion center.

4. Immunotherapy responders after treatment discontinuation: A potentially concerning recurrence rate?
Yassi Moshiri (University of Washington)

Frequent MCC recurrences post-immunotherapy (IMTX) discontinuation
Study aims to assess MCC recurrence risk after discontinuation of IMTX in a Seattle based cohort (N=183)
Overall response rate of 60% is comparable to prior first-line IMTX clinical trials (of note, this cohort includes immune-suppressed pts, that were not included in trials)
Continuing IMTX is associated with lower risk of MCC recurrence
Those with complete responses tended to have fewer recurrences after d/c of immuno-tx compared to patients with progressive disease
Risk of MCC recurrence after IMTX discontinuation is greater than for melanoma

5. Circulating tumor DNA as a biomarker for MCC tumor burden
Lisa Zaba (Stanford University)

No clinically available blood test that provides recurrence monitoring data for all patients regardless of Merkel polyomavirus serologic status
Study aimed to see if circulating tumor DNA (ctDNA) can be used as a biomarker to detect MCC recurrences (n=25)
ctDNA tracking can be useful for MCC pts regardless of tumor viral status
- Currently looking at correlation between tumor size and level of ctDNA
6 sites are now or will soon open for multi-center study
Contact Lisa Zaba ([email protected]) if you would like to utilize the ctDNA test for your MCC patients

6. MDM2 Inhibitor [KRT-232] Therapy in p53 WT MCC Patients Refractory to PD-1/L1 Immunotherapy: preliminary results and observations
Michael Wong (MD Anderson Cancer Center)

1st clinical proof-of-concept for inhibiting the MDM2 pathway in p53(wt) MCC.
Safety and efficacy data continue to inform KRT-232 dose and schedule optimization.
Opportunity exists to explore combination approaches of KRT-232 and anti-PD-1/L1 agents.
Preliminary evidence suggests encouraging benefit in a subset of patients.
New combination arm with avelumab has been added for patients with p53 (wild type) metastatic MCC who are anti-PD-1/L1 treatment-naïve.

7. Brainstorm session on 2nd International MCC Symposium
Paul Nghiem (University of Washington)

Seattle MCC team will host; likely in a warmer climate (during winter)
Aiming for first or second quarter of 2022 for a two-day event
Survey was sent out to MMIG members, but if you did not fill it out there is still time to do so! https://forms.gle/xAGDXvcEyu4Hf9zG8

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.

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