Highlights
- •Improvement in overall survival with pembrolizumab versus chemotherapy in advanced melanoma not significant.
- •Significant progression-free survival benefit, durable response and lower high-grade treatment-related adverse events.
- •Together, data support pembrolizumab as a standard-of-care for advanced melanoma.
Abstract
Aim
To evaluate the protocol-specified final analysis of overall survival (OS) in the
KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced
melanoma.
Methods
In this randomised, phase II study, eligible patients had advanced melanoma with documented
progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAFV600 mutant-positive. Patients were randomised to pembrolizumab 2 mg/kg or 10 mg/kg every
3 weeks or investigator-choice chemotherapy. Crossover to pembrolizumab was allowed
following progression on chemotherapy. The protocol-specified final OS was performed
in the intent-to-treat population. Survival was positive if p < 0.01 in one pembrolizumab arm.
Results
A total of 180 patients were randomised to pembrolizumab 2 mg/kg, 181 to pembrolizumab
10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1–35.5),
368 patients died and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2 mg/kg
(hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67–1.10, p = 0.117) and 10 mg/kg (0.74, 0.57–0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy;
median OS was 13.4 (95% CI 11.0–16.4) and 14.7 (95% CI 11.3–19.5), respectively, versus
11.0 months (95% CI 8.9–13.8), with limited improvement after censoring for crossover.
Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective
response rate and duration of response improved with pembrolizumab versus chemotherapy,
regardless of dose. Grade III–V treatment-related adverse events occurred in 24 (13.5%),
30 (16.8%) and 45 (26.3%) patients, respectively.
Conclusion
Improvement in OS with pembrolizumab was not statistically significant at either dose
versus chemotherapy.
Keywords
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References
- Targeting oncogenic drivers and the immune system in melanoma.J Clin Oncol. 2013; 31: 499-506
- Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723
- Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N Engl J Med. 2011; 364: 2517-2526
- Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib.N Engl J Med. 2012; 366: 707-714
- Enhancement of antitumor immunity by CTLA-4 blockade.Science. 1996; 271: 1734-1736
- Clinical experience with ipilimumab 3 mg/kg: real-world efficacy and safety data from an expanded access programme cohort.J Transl Med. 2014; 12: 116
- Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.N Engl J Med. 2013; 369: 134-144
- Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial.Lancet. 2014; 384: 1109-1117
- Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.J Clin Oncol. 2014; 32: 1020-1030
- Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013; 369: 122-133
- Nivolumab in previously untreated melanoma without BRAF mutation.N Engl J Med. 2015; 372: 320-330
- Pembrolizumab versus ipilimumab in advanced melanoma.N Engl J Med. 2015; 372: 2521-2532
- Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial.Lancet Oncol. 2015; 16: 908-918
- Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2015; 16: 375-384
- Overall survival in patients with advanced melanoma who received nivolumab versus Investigator's choice chemotherapy in CheckMate 037: a randomized, controlled, open-label phase III trial.J Clin Oncol. 2017; 35 (JCO2016718023)
- Sharper Bonferroni procedure for multiple tests of significance.Biometrika. 1988; 75: 800-802
- 3-Year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.in: ASCO annual meeting; 2016; Chicago, IL. 2016
- Association of pembrolizumab with tumor response and survival among patients with advanced melanoma.JAMA. 2016; 315: 1600-1609
Article info
Publication history
Published online: September 26, 2017
Accepted:
July 18,
2017
Received:
July 12,
2017
Footnotes
☆These data have been presented in part at the ESMO annual congress, Copenhagen, Denmark, October 7–11, 2016.
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
