Pembrolizumab for Advanced Melanoma: Key Points from A Randomized, Open-Label, Stage II Clinical Trial
Author: Caden Carver, BS Published: September 9, 2023
Melanoma is the most-deadly form of skin cancer. The severity and prognosis of disease depends on multiple factors, with Breslow depth largely considered the most prognostic. Other prognostic factors include TNM staging classification, presence of ulceration, perineural involvement, and others. In broad terms, melanoma involving the lymph nodes can be classified as Stage III, and melanoma with distant metastasis can be classified as Stage IV. These advanced lesions are commonly surgically excised, and treatment with additional immunotherapy can improve outcomes.
In March 2023, a study entitled Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma by Patel et al was published in the New England Journal of Medicine. The primary goal of the study was to investigate the efficacy of pembrolizumab for treating stage III or IV melanoma when used as neoadjuvant and adjuvant therapy compared to adjuvant therapy alone.
Researchers in the study conducted a randomized, open-label, phase II clinical trial. They enrolled 313 adult patients with confirmed stage III or IV melanoma. Patients who had previously received immunotherapy for melanoma, and those with active autoimmune disease, uveal melanoma, or brain metastasis were not included in the study. Participants were randomly assigned to either a neoadjuvant-adjuvant group or adjuvant only group, using the stratification factors of stage IIIB, IIIC, IIID, IV, and lactate dehydrogenase (LDH) level. 154 patients received three doses of 200 mg IV pembrolizumab prior to surgical resection, followed by 15 doses after resection, as part of the neoadjuvant-adjuvant group. 159 patients received 18 doses of pembrolizumab following surgical resection, as part of the adjuvant-only group.
Primary outcomes of the study were event free survival and overall survival, analyzed up to three years after randomization. Presence of recurrence was based on imaging, PE, and lesion biopsy. Adverse events were scored using the NCI Common Terminology Criteria for Adverse Events (NCICTCAE). Across all patients in the study, 105 total adverse events occurred. Thirty-eight occurred in patients in the neoadjuvant-adjuvant group, and 67 occurred in the adjuvant only group. Event free survival at two years was 72% (95% CI 64-80) in the neoadjuvant-adjuvant group, compared to 49% (95% CI 41-59) in the adjuvant group (p=0.004). Across all participants, 36 deaths occurred, 14 of which occurred in the neoadjuvant-adjuvant group and 22 of which occurred in the adjuvant only group. Disease recurrence occurred in nine (5.8%) patients receiving neoadjuvant-adjuvant pembrolizumab, compared to 41 (25.9%) patients receiving adjuvant-only pembrolizumab. Severe (grade 3 or 4 by NCICTCAE) adverse events occurred in 12% of patients in the neoadjuvant-adjuvant group, compared to 14% of patients in the adjuvant-only group. Researchers reported no deaths that were directly attributed to pembrolizumab, and discovered no new adverse effects of pembrolizumab.
Limitations to the study were limited sample sizes for some subsets of melanoma, limiting the generalizability of the results for all types of melanoma. The follow-up period of the study was relatively limited, pointing to a need for long-term analysis of the effects of checkpoint inhibitor therapy.
Key takeaways from this study are that the addition of neoadjuvant pembrolizumab to surgical resection improves patient outcomes in Stage III or IV melanoma. This study demonstrates that optimal timing of immune checkpoint inhibition therapy has the potential to improve overall and event free survival in advanced melanoma.
This article is a summary of : Patel SP, Othus M, Chen Y, et al. Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med. 2023;388(9):813-823. doi:10.1056/NEJMoa2211437
