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Bending the Curve Trial by Trial
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CheckMate 648

Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma

Phase 3N = 970NCT03143153

Population
Previously untreated, unresectable advanced, recurrent or metastatic oesophageal squamous-cell carcinoma
Design
Open-label phase 3 trial; 970 patients randomised 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints OS and PFS by blinded independent central review, tested hierarchically first in patients with tumour-cell PD-L1 expression of 1% or more, then in all randomised patients. The reported analysis had a minimum follow-up of 13 months.
Primary endpoint
OS, PFS
Arms
  • Nivolumab plus chemotherapy (experimental): Nivolumab plus chemotherapy
  • Nivolumab plus ipilimumab (experimental): Nivolumab plus ipilimumab
  • Chemotherapy (control): Chemotherapy alone
People
Doki Y
OSHR 0.54Δ median OS+6.3 monthsOSHR 0.74Δ median OS+2.5 monthsOSHR 0.64Δ median OS+4.6 months
Show the numbers
Results reported for CheckMate 648
EndpointAnalysisNivolumab plus chemotherapy / Nivolumab plus ipilimumabChemotherapyEffect
OSTumour-cell PD-L1 expression of 1% or moreprimaryDoki 2022median 15.4 monthsmedian 9.1 monthsHR 0.54P<0.001The abstract reports the hazard ratio with a 99.5% confidence interval of 0.37 to 0.80 (hierarchical testing), so no ci95 is entered. Minimum follow-up 13 months.
OSAll randomised patients (nivolumab plus chemotherapy vs chemotherapy)primaryDoki 2022median 13.2 monthsmedian 10.7 monthsHR 0.74P=0.002Hazard ratio 99.1% CI 0.58 to 0.96. Grade 3 or 4 treatment-related adverse events: 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, 36% with chemotherapy alone.
OSTumour-cell PD-L1 expression of 1% or moreprimaryDoki 2022median 13.7 monthsmedian 9.1 monthsHR 0.64P=0.001Hazard ratio 98.6% CI 0.46 to 0.90.
OSAll randomised patients (nivolumab plus ipilimumab vs chemotherapy)primaryDoki 2022median 12.7 monthsmedian 10.7 monthsHR 0.78P=0.01Hazard ratio 98.2% CI 0.62 to 0.98.
PFSTumour-cell PD-L1 expression of 1% or more (nivolumab plus chemotherapy vs chemotherapy)primaryDoki 2022——HR 0.65P=0.002Hazard ratio 98.5% CI 0.46 to 0.92; the abstract gives no median PFS. The abstract states that nivolumab plus ipilimumab did not show a significant PFS benefit over chemotherapy in this PD-L1 group.
Results reported for CheckMate 648
EndpointAnalysisNivolumab plus chemotherapy / Nivolumab plus ipilimumabChemotherapyEffect
OSTumour-cell PD-L1 expression of 1% or moreprimaryDoki 2022median 15.4 monthsmedian 9.1 monthsHR 0.54P<0.001The abstract reports the hazard ratio with a 99.5% confidence interval of 0.37 to 0.80 (hierarchical testing), so no ci95 is entered. Minimum follow-up 13 months.
OSAll randomised patients (nivolumab plus chemotherapy vs chemotherapy)primaryDoki 2022median 13.2 monthsmedian 10.7 monthsHR 0.74P=0.002Hazard ratio 99.1% CI 0.58 to 0.96. Grade 3 or 4 treatment-related adverse events: 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, 36% with chemotherapy alone.
OSTumour-cell PD-L1 expression of 1% or moreprimaryDoki 2022median 13.7 monthsmedian 9.1 monthsHR 0.64P=0.001Hazard ratio 98.6% CI 0.46 to 0.90.
OSAll randomised patients (nivolumab plus ipilimumab vs chemotherapy)primaryDoki 2022median 12.7 monthsmedian 10.7 monthsHR 0.78P=0.01Hazard ratio 98.2% CI 0.62 to 0.98.
PFSTumour-cell PD-L1 expression of 1% or more (nivolumab plus chemotherapy vs chemotherapy)primaryDoki 2022——HR 0.65P=0.002Hazard ratio 98.5% CI 0.46 to 0.92; the abstract gives no median PFS. The abstract states that nivolumab plus ipilimumab did not show a significant PFS benefit over chemotherapy in this PD-L1 group.
Illustrative — modelled from reported values, not trial data. OS, primary.
0%25%50%75%100%0102030Months (modelled)
  • Nivolumab plus chemotherapy (experimental)
  • Chemotherapy (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsNivolumab plus chemotherapyChemotherapy
0100.0%100.0%
1063.8%46.7%
1942.5%23.5%
2927.1%11.0%
3917.3%5.1%
Illustrative — modelled from reported values, not trial data. OS, primary.
0%25%50%75%100%051015202530Months (modelled)
  • Nivolumab plus chemotherapy (experimental)
  • Chemotherapy (control)

Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.

Data table (modelled values)
MonthsNivolumab plus chemotherapyChemotherapy
0100.0%100.0%
865.7%59.6%
1741.0%33.2%
2526.9%19.8%
3317.7%11.8%
Primary publication: Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022;386(5):449-462. PubMedDOI

Appears in

Sources

  1. Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma. N Engl J Med. 2022;386(5):449-462.

    PubMedDOI