As reported in the Journal of Clinical Oncology by Caroline Robert, MD, PhD, of Institut Gustave Roussy, Villejuif, France, and colleagues, a high proportion of patients with metastatic melanoma achieving a complete response on pembrolizumab (Keytruda) in the phase Ib KEYNOTE-001 trial maintained their complete response for prolonged durations after treatment discontinuation.¹ 

The current analysis included 105 patients (16.0%) who achieved a complete response among the 655 patients with ipilimumab (Yervoy)-naive or -treated advanced/metastatic melanoma who received 1 of 3 pembrolizumab regimens (2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks) in the KEYNOTE-001 trial. Eligible patients who received pembrolizumab for ≥ 6 months and at least two doses beyond a confirmed complete response could discontinue therapy. 

In the trial, response was centrally assessed every 12 weeks using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. For the current analysis, a 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 of the 105 patients (87.6%) were still in complete response, with a median follow-up of 30 months from the first complete response; median duration of treatment in these patients was 24 months (range = 1–53 months). A total of 14 patients (13.3%) continued to receive treatment for a median of ≥ 40 months. 

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.

— Caroline Robert, MD, PhD and colleagues

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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, the median time to overall response was 3 months (range = 0.5–11 months), the median time to complete response was 13 months (range = 3–36 months), the median duration of treatment was 23 months (range = 8–44 months), and the 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, the estimated 24-month disease-free survival rate from the 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, the 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, the 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 was seen 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 cm) had a lower complete response rate (< 10%), except for those with tumors measuring 5 to 10 cm and 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.” ■

DISCLOSURE: The study was supported by Merck & Co. For full disclosures of the study authors, visit jco.ascopubs.org. 

REFERENCE

1. Robert C, Ribas A, Hamid O, et al: Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J Clin Oncol. December 28, 2017 (early release online).