Five-year data from a phase Ib study represent the longest follow-up of a single-agent neoadjuvant PD1 treatment to date and confirm the efficacy of neoadjuvant/adjuvant single-agent PD1 blockade in the highest risk subset of patients with resectable cutaneous melanoma. Pathologic response to treatment remains prognostic, as patients with ≤10% viable tumour remaining had a 5-year overall survival (OS) of 100%. Patients with ≤10% viable tumour who had a recurrence do so after 3 years of follow-up and have salvageable recurrences.
Findings from the longest follow-up of a neoadjuvant study in patients with resectable stage III/IV cutaneous melanoma are published by Dr. Tara C. Mitchell of the Department of Medicine, Hospital of the University of Pennsylvania and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania in Philadelphia, PA, US, and colleagues on 4 July 2023 in the Annals of Oncology.
The authors wrote in the background that neoadjuvant targeted and immunotherapies for patients with resectable stage III/IV cutaneous melanoma has gained interest in recent years with a few key phase I-II study results demonstrating high clinical and pathological response rates, disease-free survival (DFS), and OS. Recently, a large, randomised SWOG S1801 study has demonstrated improved event-free survival (including events of disease progression prior to surgery, disease recurrence, and death) in patients treated with neoadjuvant compared to adjuvant PD1 blockade, with practice changing clinical implications.
While these outcomes have been promising, the data have been limited by a relatively short follow-up, with a median follow-up time of 14.7 months in SWOG S1801. Additionally, most other studies investigating neoadjuvant immunotherapy report 2-year DFS and OS with longer term results remaining uncharacterised.
This phase Ib study evaluated a single dose of neoadjuvant pembrolizumab in addition to one year of adjuvant pembrolizumab for patients with resectable stage III/IV cutaneous melanoma. The investigators found a 2-year DFS of 100% in patients who had a major pathologic response (MPR, ≤10% viable tumour) to the neoadjuvant treatment. The latest article published in the Annals of Oncology reports long-term recurrence and survival outcomes for patients treated in this study.
A total, 30 patients with resectable stage III/IV cutaneous melanoma received one dose of 200 mg intravenous neoadjuvant pembrolizumab 3 weeks prior to surgical resection, followed by one year of adjuvant pembrolizumab. The primary outcomes were 5-year OS, 5-year recurrence-free survival, and recurrence patterns.
At 5 years of follow-up (median 61.9 months), no deaths occurred in patients with MPR (<10% viable tumour) or complete pathological response (pCR, no viable tumour), compared to a 5-year OS of 72.8% for the remainder of the cohort (p = 0.12). Two of 8 patients with a pCR or MPR recurred. Of the patients with >10% viable tumour remaining, 8 of 22 patients (36%) recurred. Additionally, median time to recurrence was 3.9 years for patients with ≤10% viable tumour and 0.6 years for patients with >10% viable tumour (p = 0.044).
The authors concluded that pathological response to neoadjuvant immunotherapy remains an important prognostic factor with respect to OS. Long-term follow-up demonstrates that patients with MPR can develop recurrences, which tend to occur later. Additionally, these recurrences appear to be responsive to subsequent treatment, with none resulting in death with over 5 years of median follow-up in the study. These results demonstrate the long-term efficacy of single-agent neoadjuvant/adjuvant PD1 blockade in patients with a pCR and the importance of long-term follow-up for these patients.
Further research is needed to define the role of limiting surgery or individualising adjuvant treatment based on response to neoadjuvant therapy.
The study was funded by Merck.
Reference
Sharon CE, Tortorello GN, Ma KL, et al. Long-term outcomes to neoadjuvant pembrolizumab based on pathological response for patients with resectable stage III/IV cutaneous melanoma. Annals of Oncology; Published online 4 July 2023. DOI: https://doi.org/10.1016/j.annonc.2023.06.006
