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


RESULTS
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).


CONCLUSIONS
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.


BACKGROUND
Bristol-Myers Squibb.
New York University Langone Medical Center, New York, NY, USA; H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Jeffrey S
JS
Weber
H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA.
Geoff
G
Gibney
Massachusetts General Hospital, Boston, MA, USA.
Ryan J
RJ
Sullivan
Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
Jeffrey A
JA
Sosman
University of Virginia School of Medicine, Charlottesville, VA, USA.
Craig L
CL
Slingluff
Massachusetts General Hospital, Boston, MA, USA.
Donald P
DP
Lawrence
Indiana University Simon Cancer Center, Indianapolis, IN, USA.
Theodore F
TF
Logan
University of Pennsylvania, Philadelphia, PA, USA.
Lynn M
LM
Schuchter
Lehigh Valley Health Network, Allentown, PA, USA.
Suresh
S
Nair
Indiana University Simon Cancer Center, Indianapolis, IN, USA; University of Michigan, Ann Arbor, MI, USA.
Leslie
L
Fecher
Beth Israel Deaconess Medical Center, Boston, MA, USA.
Elizabeth I
EI
Buchbinder
Bristol-Myers Squibb, Princeton, NJ, USA.
Elmer
E
Berghorn
Bristol-Myers Squibb, Princeton, NJ, USA.
Mary
M
Ruisi
Bristol-Myers Squibb, Princeton, NJ, USA.
George
G
Kong
Bristol-Myers Squibb, Princeton, NJ, USA.
Joel
J
Jiang
Bristol-Myers Squibb, Princeton, NJ, USA.
Christine
C
Horak
Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu.
F Stephen
FS
Hodi
D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D000077594:Nivolumab; D011379:Prognosis; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate
D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D000077594:Nivolumab