Daud A, et al. ESMO 2017:1224PD

Analysis of response and survival in patients with ipilimumab-refractory melanoma treated with pembrolizumab in KEYNOTE-002


Checkpoint inhibitor treatment results in durable responses and deepening of responses over time.1–3 In the randomized phase II KEYNOTE-002 study, pembrolizumab significantly improved progression-free survival (PFS) compared with chemotherapy in patients with ipilimumab-refractory melanoma.3 Pembrolizumab also demonstrated durable responses and a manageable safety profile.3 An exploratory post hoc analysis of these results was presented at the ESMO 2017 Congress, which assessed the evolution of response and survival by best overall response in the patients from KEYNOTE-002 treated with pembrolizumab.4

Study design

  • Patients with ipilimumab-refractory melanoma were randomized to receive pembrolizumab 2 mg/kg or 10 mg/kg (n = 361) or investigator’s choice of one of five chemotherapy regimens (n = 179).
  • Patients were treated until disease progression or unacceptable toxicity.
    • Patients with disease progression in the chemotherapy arm were allowed to cross over to the pembrolizumab arm.
  • In the post hoc analysis, response was assessed at Week 12, every six weeks until Week 48, and then every 12 weeks thereafter.
    • Response was assessed by investigator review using Response in Evaluation Criteria in Solid Tumors version 1.1.
    • Responses were confirmed by subsequent scan and were based on best overall response with confirmation.
  • Survival was assessed every 12 weeks during follow-up.
  • Given that there was no difference in efficacy between the doses, pembrolizumab arms were combined for analyses.
  • Outcomes included PFS, overall survival (OS), and duration of response (DOR).

Key findings

Baseline characteristics and disposition

  • As of February 3, 2017, the median follow-up was 42.7 months (range: 38.7–49.9) for all pembrolizumab-treated patients.
  • Among all pembrolizumab-treated patients (all-treated population), median age was 61 years (range: 15–89).
    • The majority of patients were male (59%), had stage M1c disease (82%), had normal lactate dehydrogenase levels (51%), and had more than one prior line of therapy (73%).
    • Median tumour size was 94.5 mm (range: 10–560).
  • Baseline characteristics in the subsets of patients who achieved a complete response (CR), partial response (PR), or stable disease (SD) were similar to the all-treated population.
  • At the time of data cutoff, 22 patients (6%) in the all-treated population were still receiving pembrolizumab and nine patients were on treatment hold for observation.
    • Patients discontinued treatment for the following reasons: progressive disease (57%), adverse events (19%), patient withdrawal (11%), physician decision (6%), and other (1%).


  • Of the patients treated with pembrolizumab, 187 had a best overall response of CR, PR, or SD.
  • Median DOR was not reached in the all-treated population.
    • Median time to response was 2.9 months (range: 1.9–27.9).
  • Nine patients with CR (31%), 28 patients with PR (40%), and 63 patients with SD (72%) had subsequent progression.
    • In these patients, median DOR was:
      • For CR: 17.1 months (range: 5.5–36.1);
      • For PR: 7.7 months (range: 2.0–31.8); and
      • For SD: 5.8 months (range: 2.7–25.3).
  • Time and duration of response to pembrolizumab in the CR, PR, and SD populations are summarized in Table 1.
  • PFS and OS of the all-treated, CR, PR, and SD populations are summarized in Figures 1 and 2.

Table 1. Time to and duration of responses to pembrolizumab

Figure 1. PFS in all pembrolizumab-treated patients and in those with a best response of CR, PR, or SD

Figure 2. OS in all pembrolizumab-treated patients and in those with a best response of CR, PR, or SD


  • No new safety signals were observed with long-term follow-up.

Key conclusions

  • Responses to pembrolizumab were durable and associated with prolonged OS in patients with ipilimumab-refractory melanoma.
  • Even in these heavily pretreated patients, best response evolved over time with late conversions from SD to PR/CR and from PR to CR observed.

References: 1. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013;369(2):134–44. 2. Hamid O, Robert C, Ribas A, et al. Randomized comparison of two doses of the anti-PD-1 monoclonal antibody MK-3475 for ipilimumab-refractory (IPI-R) and IPI-naïve (IPI-N) melanoma (MEL). J Clin Oncol 2014;32(Suppl): abstr 3000. 3. Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol 2015;16(8):908–18. 4. Daud A, Puzanov I, Dummer R, et al. Analysis of response and survival in patients (pts) with ipilimumab (ipi)-refractory melanoma treated with pembrolizumab (pembro) in KEYNOTE-002. ESMO Annual Congress Abstracts 2017:1224PD.