CheckMate 651
Nivolumab plus ipilimumab versus EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck
Phase 3N = 947NCT02741570
- Population
- Recurrent or metastatic squamous cell carcinoma of the head and neck, no prior systemic therapy in the recurrent or metastatic setting
- Design
- Randomised (1:1), open-label phase 3 trial in patients without prior systemic therapy for recurrent or metastatic squamous cell carcinoma of the head and neck of the oral cavity, oropharynx, hypopharynx or larynx. Nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, versus EXTREME (cetuximab with cisplatin or carboplatin and fluorouracil for up to six cycles, then cetuximab maintenance). Stratified by PD-L1 expression, p16 status and prior chemotherapy for locally advanced disease. Primary endpoints were overall survival in all randomly assigned patients and in the PD-L1 combined positive score (CPS) 20 or more population.
- Primary endpoint
- OS
- Arms
- Nivolumab plus ipilimumab (experimental, n = 472): Nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks
- EXTREME regimen (control, n = 475): Cetuximab plus cisplatin or carboplatin plus fluorouracil (up to six cycles), then cetuximab maintenance
- People
- Haddad RI, senior author Argiris A
OSHR 0.95Δ median OS+0.4 monthsOSHR 0.78Δ median OS+3 monthsOSHR 0.82 (95% CI 0.69–0.97)Δ median OS+2.5 months
Show the numbers
| Endpoint | Analysis | Nivolumab plus ipilimumab | EXTREME regimen | Effect |
|---|---|---|---|---|
| OSAll randomly assigned patients | finalHaddad 2023 | median 13.9 months | median 13.5 months | HR 0.95P=0.4951Primary endpoint; not met (the paper tested the two primary OS endpoints in parallel at an overall two-sided alpha of 0.025). Hazard ratio interval is 97.9% CI 0.80 to 1.13, not a 95% CI. |
| OSPD-L1 CPS 20 or more | finalHaddad 2023 | median 17.6 months | median 14.6 months | HR 0.78P=0.0469Primary endpoint; not met: the paper reports P = .0469 against an overall two-sided alpha of 0.025 (O'Brien-Fleming spending), and the abstract states the primary endpoints were not met. The paper also notes fewer CPS 20 or more patients (363) than the 372 events needed to keep planned power. Hazard ratio interval is 97.51% CI 0.59 to 1.03, not a 95% CI. |
| OSPD-L1 CPS 1 or more | finalHaddad 2023 | median 15.7 months | median 13.2 months | HR 0.82 (95% CI 0.69–0.97)Secondary endpoint, descriptive only: under the testing hierarchy, OS in CPS 1 or more was to be analysed descriptively because OS in CPS 20 or more was not statistically significant. |
| PFSPD-L1 CPS 20 or more | finalHaddad 2023 | median 5.4 months | median 7 months | Secondary endpoint; medians only. |
| ORRPD-L1 CPS 20 or more | finalHaddad 2023 | 34.1% | 36% | Secondary endpoint. Median duration of response in the same population was 32.6 versus 7.0 months (abstract). |
| Endpoint | Analysis | Nivolumab plus ipilimumab | EXTREME regimen | Effect |
|---|---|---|---|---|
| OSAll randomly assigned patients | finalHaddad 2023 | median 13.9 months | median 13.5 months | HR 0.95P=0.4951Primary endpoint; not met (the paper tested the two primary OS endpoints in parallel at an overall two-sided alpha of 0.025). Hazard ratio interval is 97.9% CI 0.80 to 1.13, not a 95% CI. |
| OSPD-L1 CPS 20 or more | finalHaddad 2023 | median 17.6 months | median 14.6 months | HR 0.78P=0.0469Primary endpoint; not met: the paper reports P = .0469 against an overall two-sided alpha of 0.025 (O'Brien-Fleming spending), and the abstract states the primary endpoints were not met. The paper also notes fewer CPS 20 or more patients (363) than the 372 events needed to keep planned power. Hazard ratio interval is 97.51% CI 0.59 to 1.03, not a 95% CI. |
| OSPD-L1 CPS 1 or more | finalHaddad 2023 | median 15.7 months | median 13.2 months | HR 0.82 (95% CI 0.69–0.97)Secondary endpoint, descriptive only: under the testing hierarchy, OS in CPS 1 or more was to be analysed descriptively because OS in CPS 20 or more was not statistically significant. |
| PFSPD-L1 CPS 20 or more | finalHaddad 2023 | median 5.4 months | median 7 months | Secondary endpoint; medians only. |
| ORRPD-L1 CPS 20 or more | finalHaddad 2023 | 34.1% | 36% | Secondary endpoint. Median duration of response in the same population was 32.6 versus 7.0 months (abstract). |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 0.82 | 0.69–0.97 |
- Nivolumab plus ipilimumab (experimental)
- EXTREME regimen (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Nivolumab plus ipilimumab | EXTREME regimen |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 9 | 63.8% | 63.0% |
| 17 | 42.8% | 41.8% |
| 26 | 27.3% | 26.3% |
| 35 | 17.5% | 16.6% |
- Nivolumab plus ipilimumab (experimental)
- EXTREME regimen (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Nivolumab plus ipilimumab | EXTREME regimen |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 11 | 64.8% | 59.3% |
| 22 | 42.0% | 35.2% |
| 33 | 27.3% | 20.9% |
| 44 | 17.7% | 12.4% |
Appears in
Sources
Haddad RI, Harrington K, Tahara M, Ferris RL, Gillison M, Fayette J, et al. Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651. J Clin Oncol. 2023;41(12):2166-2180.