Neoadjuvant Nivolumab and Relatlimab in Merkel Cell Carcinoma

Proportion of patients with a pathological complete response, as determined on the week 6 surgical specimen using the guidelines published by the International Neoadjuvant Melanoma Consortium: Complete pathological response (pCR) = 0% viable tumour cells in the surgical specimen

Proportion of patients with each non-pCR response category, as determined on the week 6 surgical specimen using the guidelines published by the International Neoadjuvant Melanoma Consortium:

• Near complete pathological response - (near pCR) - >0% - ≤10% viable tumour
• Partial pathological response (pPR) - >10 - ≤50% viable tumour
• Non pathological response (pNR) - >50% viable tumour

The treatment related adverse events (AE) as described in CTCAE version 5.0, from the initiation of study treatment up to 135 days after the last dose of study treatment

The proportion of patients within each response category, as assessed using RECIST version 1.1, comparing week 6 to baseline CT and MRI.

Objective response rate= CR and PR

The proportion of patients within each response category, as assessed using PERCIST (standardised uptake value [SUV]) comparing week 6 to baseline PET.

Metabolic response rate = CMR and PMR.

The proportion of patients alive and disease free from the time of surgery

• The proportion of patients alive and with RECIST-defined progression of disease from the date of consent to the first radiographical evidence of local, regional or distant progression.
• Disease progression which leads to unresectable MCC.

The proportion of patients with EFS defined as from the time of first dose of study treatment to the earliest of:

• Disease progression to unresectable stage III or stage IV disease)
• Recurrence of MCC
• Treatment-related death
• Disease related death

The proportion of patients alive at years 1, 2, 5 and 10, and to actual date of death (in months), from the initiation of study treatment.

• Changes in patient rated quality of life scores using QLQ-C30 and EQ-5D-5L from date of consent to 6 -12 weekly intervals until the end of year 1.
• The correlation of patient-rated quality of life scores with adverse events.

• Proportion of patients receiving full neoadjuvant drug treatment per schedule and number of treatments missed.
• Proportion of patients undergoing planned surgery at week 6.
• Reasons for incomplete study treatment e.g. adverse event, withdrawn consent, , disease progression, patient lost to follow-up.

• Proportion of patients with and without polyomavirus in tumour tissue at baseline.
• Correlate Merkel cell polyomavirus viral positivity (MCPyV+) in stage I-III MCC with pathological response.

• Morphological assessment H&E, including viable MCC cells, Ki67, TILs density, % fibrosis, % necrosis, compared with paired baseline measures.
• Tumour PD-L1 expression status (+ve status = ≥1% tumour cells positive staining using Dako 28-8 PD-L1 IHC assay).
• Characterisation of immune profile in tumour microenvironment using multiplex immunohistochemistry and Imaging mass cytometry.
• RNA sequencing - gene expression profile including potential to perform single cell analysis on dissection specimen from tumour dissociates (single cell RNA seq).
• Characterisation of peripheral immune profile through Cytometry by time of flight.
• DNA sequencing to determine tumour mutational burden and key somatic mutations.
• Response to treatment using circulating tumour DNA in peripheral blood using droplet digital PCR to quantify tumour DNA (copies/ml plasma) of known mutation in MCC tissue.

• Correlation of bacterial diversity and abundance with treatment response and incidence of treatment-related toxicities
• Correlation of self-reported dietary habits (including use of oral probiotics) at baseline and impact on bacterial diversity in the gut
• The use of antibiotics and/or steroids during neoadjuvant treatment and the impact on intestinal bacterial diversity and abundance

Proportion of patients with concordance in pathological response, RECIST response and metabolic response (PERCIST)

Proportion of patients with CR, PR, SD and PD as measured with both response criteria

Comparison of primary and secondary efficacy outcomes to those reported in the Checkmate 358 trial