As reported in the Journal of Clinical Oncology by Robert and colleagues, a high proportion of patients with metastatic melanoma achieving complete response on pembrolizumab (Keytruda) in the phase Ib KEYNOTE-001 trial maintained complete response for prolonged durations after treatment discontinuation.
The current analysis included 105 (16.0%) patients who achieved a complete response among the 655 patients with ipilimumab (Yervoy)-naive or ipilimumab-treated advanced/metastatic melanoma who received one of three pembrolizumab dose regimens (2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks) in the trial. Eligible patients who received pembrolizumab for ≥ 6 months and at least two doses beyond confirmed complete response could discontinue therapy.
In the trial, response was centrally assessed every 12 weeks using RECIST version 1.1. For the current analysis, complete response was defined on investigator assessment using immune-related response criteria.
Prolonged Complete Responses
At data cutoff, with a median follow-up of 43 months, 92 (87.6%) of the 105 patients had a complete response, with a median follow-up of 30 months from first complete response. The median duration of treatment in these patients was 24 months (range = 1–53 months).
Fourteen patients (13.3%) continued to receive treatment for a median of ≥ 40 months; treatment was discontinued in 91 patients (86.7%), including 67 (63.8%) who were followed by observation without additional anticancer therapy. Among these 67 patients, median time to overall response was 3 months (range = 0.5–11 months); median time to complete response was 13 months (range = 3–36 months); median duration of treatment was 23 months (range = 8–44 months); and median duration of treatment after complete response was 7 months (range = 0.5–41 months).
As of data cutoff, only 7 of 105 patients with a complete response had confirmed progressive disease—2 while receiving initial pembrolizumab treatment, 4 after stopping pembrolizumab and proceeding to observation, and 1 who was reported as still receiving pembrolizumab. All 7 remained alive.
Among all 105 patients who had a complete response, estimated 24-month disease-free survival rate from time of complete response was 90.9% (95% confidence interval [CI] = 82.5%–95.4%). Among the 67 patients who discontinued pembrolizumab after complete response for observation, estimated 24-month disease-free survival from treatment discontinuation was 89.9%. Among all 89 patients who discontinued pembrolizumab after complete response for reasons other than progressive disease, estimated 24-month disease-free survival from treatment discontinuation was 85.8%.
Potential Factors in Response
On univariate analysis among 459 patients with baseline data on tumor programmed cell death ligand 1 (PD-L1) status and tumor size, complete response occurred in 42.7% of those with smaller (1–5 cm) PD-L1–positive tumors (≥ 1% staining in tumor cells and mononuclear inflammatory cells). Patients with larger tumors (5–90 cm) had a lower complete response rate (< 10%), except for those with tumors measuring 5 to 10 cm with positive PD-L1 expression, who had a complete response rate of 20.5%; this rate was similar to the rate of 20.7% among those with smaller tumors (1–5 cm) who were PD-L1–negative.
The investigators concluded: “Patients with metastatic melanoma can have durable complete remission after discontinuation of pembrolizumab, and the low incidence of relapse after median follow-up of approximately 2 years from discontinuation provides hope for a cure for some patients. The mechanisms underlying durable [complete response] require further investigation.”
The study was supported by Merck & Co.
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