Adjuvant avelumab (Bavencio) numerically improved relapse-free survival (RFS) vs placebo, without reaching statistical significance, in patients with high-risk stage III Merkel cell carcinoma (MCC) in the phase 3 ADAM trial (NCT03271372); similarly high survival across both treatment arms suggests some patients can be safely managed with close monitoring and treatment at relapse, according to Shailender Bhatia, MD.¹
“Probably one of the most important findings is MCC-specific survival. Both the placebo and avelumab arms had good survival rates, suggesting patients on the placebo arm who [relapsed] were effectively salvaged using subsequent immunotherapy,” Bhatia said in an exclusive interview with OncLive®.2 “These data are now going to inform the discussions we're having in the clinic, and we can individualize the risk-benefit preferences of each patient using these data to guide whether to [pursue] adjuvant therapy.”
Data from this randomized, double-blind, placebo-controlled trial of 100 patients with high-risk stage III MCC presented at the 2026 ASCO Annual Meeting (ASCO 2026) showed that 1-year relapse-free survival (RFS) was 87.2% (95% CI, 73.8%-94.1%) with avelumab vs 59.6% (95% CI, 46.1%-71.5%) with placebo; this corresponded to a stratified, age-adjusted hazard ratio (HR) of 0.55 (95% CI, 0.28-1.06; P = .075) for RFS failure.1 An exploratory analysis of relapse alone showed a stratified, age-adjusted HR of 0.47 (95% CI, 0.24-0.95), with a 1-year absolute risk reduction of 27.6%. MCC-specific survival was 92% across the full cohort. Distant metastasis-free survival also numerically favored avelumab, with a stratified, age-adjusted HR of 0.89 (95% CI, 0.41-1.94).
In the interview, Bhatia unpacked the trial design, spotlighted efficacy and safety findings, and explained how the results are shaping adjuvant therapy discussions for Merkel cell carcinoma. Bhatia is director of the Melanoma and Renal Cancer Team and holds the Lyn and Daniel Lerner Endowed Chair for Merkel Cell Carcinoma at Fred Hutch and is a professor in the Division of Hematology and Oncology at the University of Washington School of Medicine.
OncLive: What was the rationale for studying adjuvant avelumab in Merkel cell carcinoma?
Bhatia: ADAM is a [phase 3,] investigator-initiated trial, which we led in collaboration with 9 other major academic centers. ADAM stands for Adjuvant Avelumab in Merkel [cell carcinoma], and the [trial enrolled] high-risk patients with stage III MCC. Patients with stage III MCC are further subdivided into two groups: stage IIIA and stage IIIB. [Those with stage IIIA] disease have lymph node metastases detected either using sentinel lymph nodes, or an unknown primary [with] clinically detected lymph nodes. [Those with] stage IIIB [disease] have clinically detected lymph node metastases with a known primary, and they seem to have an even higher risk of recurrence.
What were the study design and key objectives evaluated in the ADAM trial?
In terms of the design, we designed it as a rigorous trial with phase 3 statistics. It's a randomized, double-blinded, placebo-controlled trial. We randomized 100 patients total, in a 1:1 ratio, to either avelumab or placebo. For the avelumab treatment, we used a dose de-escalation schema, where patients got avelumab every 15 days for the first 4 months, then the frequency was reduced to every 30 days for the next 4 months. Following the first 8 months, where we thought the risk of recurrence was highest, we further de-escalated to every 4 months to time the infusions with the timing of the scans. [We then] followed patients every 4 months with scans for the first 2 years, every 6 months for the next 3 years, and after that we've left it to investigator discretion. The primary end point of the trial is RFS, although we looked at a lot of secondary end points, including overall survival [OS], distant [metastasis]-free survival [DMFS], and safety end points as well.
ADAM Trial in Merkel Cell Carcinoma: Key Highlights
- Adjuvant avelumab numerically improved 1-year RFS vs placebo (87.2% vs 59.6%; stratified, age-adjusted HR, 0.55; 95% CI, 0.28-1.06; P = .075) in patients with high-risk stage III Merkel cell carcinoma.
- In exploratory analysis, avelumab reduced the risk of relapse alone by nearly half (stratified, age-adjusted HR, 0.47; 95% CI, 0.24-0.95), with a 28% absolute risk reduction at 1 year.
- MCC-specific survival was 92% across the full cohort, suggesting patients who relapsed on placebo were effectively salvaged with subsequent immunotherapy.
Is there a “sweet spot” for the duration of adjuvant immunotherapy across cancer types?
In skin cancers, most trials of adjuvant therapy have used 1 year of immune checkpoint blockade. To be honest, we don't know what the sweet spot is. We think that the majority of the benefit from adjuvant therapy comes in the first few months when the risk of recurrence is highest, but we don't know how long we need to keep treating to maintain that initial benefit. It's an open question for the field, and unless we do dedicated trials, which are focused on the duration of therapy, we are probably not going to have a definitive answer on that.
What were the key findings from the ADAM trial presented at ASCO 2026, and what stood out most?
For the ADAM trial, first of all, this major academic collaboration was done without a CRO or a cooperative group. The first message is that investigator-initiated research of the highest rigor can be accomplished with relatively limited resources, and I credit our amazing team at the University of Washington, and also our academic collaborators who have come together to answer an important question in the field.
In terms of the main results, I'll first talk about safety. We did not see any new safety signal that we haven't seen previously with immune checkpoint inhibitors in the adjuvant setting. The toxicity of avelumab was pretty much as we would expect, with close to a 15% rate of treatment-related grade 3 or higher [treatment-related] adverse effects [TRAEs], and around 7% to 8% of patients discontinuing treatment due to [a TRAE].
In terms of the efficacy end points, our primary end point was [RFS]. There was a clear impact of avelumab on the biology of recurrences [compared with] the placebo group, as we had expected. This was a high-risk setting, and there was around a 40% rate of relapse in the placebo group. Most of those relapses happened in the first year. In the avelumab group, there was a clear separation of the two curves: after the first year, only 12% of patients had relapsed in the avelumab group, as compared to 40% in the placebo group, which suggests an absolute risk reduction of 28%, impressive for any adjuvant trial. What we also noticed is in the avelumab arm there were some late recurrences happening; we had some recurrences in the second year and the third year, but then after that, the curve seemed to stabilize.
One thing that affected the primary end point to some degree is that the avelumab arm was, on average, 5 years older as compared to the placebo arm. That probably accounted for some non–cancer-related deaths happening, and as you know, RFS is a composite end point of relapse as well as survival. Those non-MCC deaths seem to bring down the RFS curve somewhat in the avelumab arm. Despite that, our [HR] was an impressive 0.55 with a P value of .07, which does not quite meet the level of statistical significance, but we feel that the results are going to be meaningful in the clinic.
We also did an exploratory analysis of relapse only, and that suggests an [HR] of 0.47, and around a 50% reduction in the risk of relapse over a patient's journey. We also looked at other secondary end points like distant [metastasis]-free survival, which also seems to be favoring the avelumab arm, although the numbers, as you would expect, are lower as compared to the overall relapse.
