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Lancet Oncol. 2016 Jul;17(7):943-955. doi: 10.1016/S1470-2045(16)30126-7. Epub 2016 Jun 4.

Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial.

Author information

1
New York University Langone Medical Center, New York, NY, USA; H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
2
H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
3
Massachusetts General Hospital, Boston, MA, USA.
4
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
5
University of Virginia School of Medicine, Charlottesville, VA, USA.
6
Indiana University Simon Cancer Center, Indianapolis, IN, USA.
7
University of Pennsylvania, Philadelphia, PA, USA.
8
Lehigh Valley Health Network, Allentown, PA, USA.
9
Indiana University Simon Cancer Center, Indianapolis, IN, USA; University of Michigan, Ann Arbor, MI, USA.
10
Beth Israel Deaconess Medical Center, Boston, MA, USA.
11
Bristol-Myers Squibb, Princeton, NJ, USA.
12
Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu.

Erratum in

Abstract

BACKGROUND:

Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy.

METHODS:

We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3-5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov, number NCT01783938, and is ongoing but no longer enrolling patients.

FINDINGS:

Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3-5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 [50%; 95% CI 37·6-62·4] of 68 patients) and in the ipilimumab followed by nivolumab group (30 [43%; 31·1-55·3] of 70 patients). The most common treatment-related grade 3-4 adverse events during the whole study period were colitis (ten [15%]) in the nivolumab followed by ipilimumab group vs 14 [20%] in the reverse sequence group), increased lipase (ten [15%] vs 12 [17%]), and diarrhoea (eight [12%] vs five [7%]). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 [41%; 95% CI 29·4-53·8] vs 14 [20%; 11·4-31·3]). Progression was reported in 26 (38%; 95% CI 26·7-50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0-72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7-50·8) and 42 (60%; 47·6-71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8-25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7-not reached), whereas over a median follow-up of 14·7 months (IQR 5·6-23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2-26·5; HR 0·48 [95% CI 0·29-0·80]). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64-85 vs 54%; 42-65).

INTERPRETATION:

Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events.

FUNDING:

Bristol-Myers Squibb.

PMID:
27269740
PMCID:
PMC5474305
DOI:
10.1016/S1470-2045(16)30126-7
[Indexed for MEDLINE]
Free PMC Article

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