I am a medical oncologist and I’ve been focused on skin cancers for the majority of my career and a major part of my research efforts has been on immunotherapy drugs. I’ve been working on research in Merkel cell carcinoma, which is a rare but very aggressive skin cancer, three times more lethal than melanoma and I’ve been working on it for the last 15 years or so.

Could you outline the methodology?

So the trial that we’re going to talk about today is called the ADAM trial, ADAM stands for adjuvant avelumab in Merkel. So in Merkel cell carcinoma, as I said, it’s a very aggressive skin cancer and in stage III Merkel where the cancer has spread to the lymph nodes, we know that patients have a very high risk of the cancer coming back. The rate of recurrence for stage III is close to 40-60%, depending on whether patients have stage IIIa or IIIb. Prior to immunotherapy drugs becoming available, these patients also had a very high risk of mortality with 25-50% risk of dying from Merkel cell. So since then we have had a lot of improvement in stage IV Merkel cell with a lot of PD-1 and anti-PD-L1 agents becoming available. Unfortunately we still don’t have good data on the use of these agents in earlier stages to prevent the cancer from coming back. So the ADAM trial is trying to shed more light on that important question of using immunotherapy proactively to prevent the cancer from coming back.

What did you find?

In the ADAM trial we had 100 patients total with stage III Merkel cell and it was a randomised trial, placebo controlled, double-blinded. It was conducted across nine major academic centres throughout the US. 100 patients were randomised in a 1:1 ratio to either avelumab or matched placebo.

The key results that we found, first of all, safety-wise there were no new safety signals. We now know pretty much from all the clinical trials of immunotherapy and skin cancers and other cancers, the safety profile of avelumab was very consistent with what we have seen in other trials. Around 15% of patients had grade 3 or higher adverse events and around 8% of patients actually discontinued, which is very consistent with what we have seen in other trials.

In terms of efficacy, the primary endpoint of our trial was relapse free survival and what we found out was that the avelumab arm had a numerically improved relapse free survival with a hazard ratio of 0.55 when we adjusted for age. One thing I forgot to mention, that the avelumab arm, even though it was a randomised trial, it’s a relatively small randomised trial and there were some prognostic variables which were distributed differently between the two arms. An important one was age – the avelumab arm on average was five years older as compared to the placebo arm, so that’s why we adjusted for age and other prognostic variables and this was pre-specified. So the age adjusted hazard ratio was 0.55 with a p-value of 0.07.

Even though the results may not be considered statistically significant, according to the p-value threshold, we feel that the hazard ratio is quite impressive and is clinically very meaningful. One thing we realised, because the avelumab arm was older we noticed that a lot of patients in the avelumab arm had events which were related to non-Merkel cell carcinoma deaths. Since relapse free survival is a composite endpoint of relapse and survival, we accounted for those non-MCC deaths by doing an exploratory analysis on just the probability of relapse. When we look for that the hazard ratio for relapse in that avelumab versus placebo arm was 0.47, suggesting a clinically meaningful reduction in the risk of relapse.

So we are very impressed by the effectiveness of avelumab in reducing the risk of relapse. But then the question comes does that translate into a disease specific survival advantage. So when we look at MCC-specific survival one heartening thing that we found out in the trial was both the avelumab and placebo arms are actually doing very well in the long term. So people who relapsed more so in the placebo arm were effectively salvaged using immunotherapy and in the overall cohort of 100 patients only 8% disease specific mortality was seen, which compares so well compared to what we had seen historically, the numbers I mentioned were 25-50%.

So our results suggest that we can use immunotherapy proactively in this high risk population or if patients want to do surveillance we can follow them very closely and at the sign of first relapse introduce immunotherapy and the chances are that both groups are likely to do reasonably well at the end of their journey.

What impact could these findings have in the clinic?

The biggest impact of these findings is that now we have data from a very clean design trial with avelumab versus placebo where both the groups were treated equally. Now we have data that we did not have before and I believe that is going to inform our discussions in the clinic. There may not be a right or wrong answer for all patients but I think we have data that we can now discuss and tailor our recommendations to the unique goals of each patient in our clinic.