CheckMate-067

Incomplete

Hodi FS, et al. "Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial". Lancet Oncology. 2018. 19(11):1480-1492.
PubMed • Full text

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Clinical Question

Among patients with previously untreated metastatic melanoma, what is the efficacy and safety of the anti-PD1 antibody nivolumab alone or nivolumab combined with the anti-CTLA4 antibody ipilimumab, compared to ipilimumab alone?

Bottom Line

Nivolumab monotherapy or the combination therapy nivolumab and ipilimumab improves progression-free survival and overall survival significantly compared to ipilimumab monotherapy.

Major Points

Metastatic melanoma had a very poor prognosis until the first decade of this century. Around 2011, with the approval of the first targeted therapies and the first antibodies that block checkpoints in the immune system, this situation changed. Ipilimumab, an anti-CTLA-4 antibody, was the first immunotherapy associated with an improved overall survival. Of the population that was treated with ipilimumab, approximately 20% of them had long-term survival.

Another form of checkpoint inhibition, with an antibody called 'anti–programmed death 1 (PD-1)', showed even more efficacy. Two anti-PD1 treatments, pembrolizumab and nivolumab, were approved by the FDA in 2014 as a second line treatment for treating metastatic melanoma. These two anti-PD1 agents showed objective response rates between 30 and 40% for these patients. Moreover, the majority of these responses were seen as durable.

A phase 2 trial that compared the combination of nivolumab and ipilimumab with ipilimumab monotherapy (only BRAF negative melanoma included) showed objective responses of around 60% in the combination group (11% with the ipilimumab monotherapy). Complete responses were even seen in 22% of the patients in the combination group (0% in the ipilimumab group). These impressive numbers were not without cost. Serious treatment-related adverse events (grade 3 or 4) were seen in 54% of the patients in the combination group.

This phase 3 trial, CheckMate-067, was conducted to confirm and extend the findings of the phase 2 trial and to evaluate both safety and efficacy of the monotherapy nivolumab or the combination therapy nivolumab and ipilimumab, compared to ipilimumab monotherapy.

Design

• Multicenter, double-blind, randomized, controlled trial
• N=945
  • Combination nivolumab and ipilimumab (n=314)
  • Nivolumab monotherapy (n=316)
  • Ipilimumab monotherapy (n=315)
• Randomization was stratified to:
  • PD-L1 status (positive vs. negative or indeterminate)
  • BRAF mutation status (V600 mutation–positive or wild-type)
  • AJCC 7th edition metastasis stage (M0, M1a, or M1b vs. M1c).
• Setting: 137 centers in Australia, Europe, Israel, New Zealand, and North America
• Enrollment: June 2013, March 2014
• Mean follow-up: X years
• Analysis: (Intention-to-treat)
• Primary outcome: progression-free survival (PFS) and overall survival (OS)

Population

Inclusion Criteria

• Unresectable stage III or stage IV cutaneous melanoma
• Untreated patients
• Age ≥18 years
• Measurable disease by CT or MRI scan per RECIST 1.1 criteria
• ECOG performance status of 0-1
• For biomarker analysis: tumor tissue from an unresectable or metastatic site

Exclusion Criteria

• ECOG performance status ≥2
• Active brain metastases
• Uveal melanoma
• Autoimmune disease

Baseline Characteristics

• Demographics:
  • mean age: 60 years
  • female: 35.4%
• ECOG performance status:
  • 0 (73.2%)
  • 1 (26.6%)
  • 2 (0.1%)
  • not reported (0.1%)
• Disease extent:
  • M1c (58.0%)
  • M0, M1a or M1b (42.0%)
• LDH:
  • ≤ULN (62.3%)
  • >ULN (36.1%)
  • ≤2 x ULN (87.4%)
  • >2 x ULN (11.0%)
  • unknown (1.6%)
• Brain metastases: no (96.4%)
• PD-L1 status: positive (23.6%)
• BRAF status: positive (31.5%), wildtype (68.5%)

Interventions

• Randomized (1:1:1) to:
  • nivo + ipi
  • nivo + ipi placebo (nivo mono)
  • nivo placebo + ipi (ipi mono)

(all treatments administered intravenuously)


• Treatment arms and dose scheme:
  • Nivo + ipi: 1 mg of nivolumab per kg (bodyweight) every 3 weeks plus 3 mg of ipilimumab per kg every 3 weeks and total of 4 doses, followed by 3 mg of nivolumab per kg, every 2 weeks for the third cycle and beyond
  • Nivo mono: 3 mg of nivolumab per kg, every 2 weeks (plus ipilimumab-matched placebo)
  • Ipi mono: 3 mg of ipilimumab per kg, every 3 weeks with total of 4 doses (plus nivolumab-matched placebo)
• Treatment continued until either:
  • Disease progression (per RECIST 1.1)
  • Unacceptable toxic adverse events
  • Withdrawal of consent

Outcomes

Comparisons are between nivo + ipi vs. nivo mono vs. ipi mono if not mentioned clearly.

Primary Outcomes

Progression-free survival

Median PFS nivo + ipi group was 11.5 months

Median PFS nivo mono group was 6.9 months

Median PFS ipi mono group was 2.9 months

Significant improvement in PFS between nivo + ipi vs. ipi (HR for death or progression = 0.42; 99.5% CI, 0.31 to 0.57; P<0.001)

Significant improvement in PFS between nivo vs. ipi (HR = 0.57; 99.5% CI, 0.43 to 0.76; P<0.001)

Non significant improvement in PFS between nivo + ipi vs. nivo (HR = 0.74; 95% CI, 0.60 to 0.92)

Overall survival (Wolchock et al. 2017)

At a minimum follow-up period of 36 months:

Median OS nivo + ipi group was not reached

Median OS nivo mono group was 37.6 months

Median OS ipi mono group was 19.9 months

Significant improvement in OS between nivo + ipi vs. ipi (HR for death = 0.55; P<0.001)

Significant improvement in OS between nivo vs. ipi (HR = 0.65; P<0.001)

Overall survival rate at 3 years for nivo + ipi group was 58%

Overall survival rate at 3 years for nivo mono group was 52%

Overall survival rate at 3 years for ipi mono group was 34%

Secondary Outcomes

Objective Response Rate (ORR)

ORR nivo + ipi group was 57.6%

ORR nivo mono group was 43.8%

ORR ipio mono group was 19.0%

Progression-Free Survival based on PD-L1 expression level

• PD-L1 positive:

PFS nivo + ipi group 14.0 months

PFS nivo mono group 14.0 months

PFS ipi mono group 3.9 months

• PD-L1 negative:

PFS nivo + ipi group 5.3 months

PFS nivo mono group 11.2 months

PFS ipi mono group 2.8 months

Overall Survival based on PD-L1 expression level

• PD-L1 positive:

Overall survival rate at 3 years for nivo + ipi group was 65%

Overall survival rate at 3 years for nivo mono group was 61%

• PD-L1 negative:

Overall survival rate at 3 years for nivo + ipi group was 56%

Overall survival rate at 3 years for nivo mono group was 50%

Mean change from baseline in EORTC, Quality of Life Questionnaire (EORTC QLQ-C30) for Global Health Status, Social Functioning, Cognitive Functioning, Role Functioning and Physical Functioning

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Adverse Events

• Adverse events of any grade that were treatment related:
  • 95.5% in the nivo + ipi group
  • 82.1% in the nivo group
  • 86.2% in the ipi group
• Common adverse events in the nivo + ipi group:
  • Diarrhea (44.1%)
  • Rash (40.3%)
  • Fatigue (35.1%)
  • Pruritus (33.2%)
  • Nausea (25.9%)
• Common adverse events in the nivo group:
  • Fatigue (34.2%)
  • Rash (25.9%)
  • Pruritus (18.8%)
• Common adverse events in the ipi group:
  • Pruritus (35.4%)
  • Diarrhea (33.1%)
  • Rash (32.8%)
  • Fatigue (28.0%)
• Discontinuation due to treatment-related adverse events of any grade:
  • 36.4% in the nivo + ipi group
  • 14.8% in the ipi group
  • 7.7% in the nivo group

Criticisms

• At start of this phase 3 trial it was already known that ipilimumab was inferior to nivolumab
• While clearly demonstrating superiority over ipilimumab, this trial fails to compare the efficacy of the combi nivolumab and ipilimumab head-to-head against nivolumab monotherapy

Funding

Funded by Bristol-Myers Squibb, producers of both nivolumab and ipilimumab.