KEYNOTE-048
Needs reviewPembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck
Phase 3N = 882NCT02358031
- Population
- Untreated locally incurable recurrent or metastatic head and neck squamous cell carcinoma
- Design
- Randomised, open-label phase 3 study at 200 sites in 37 countries of participants with untreated, locally incurable recurrent or metastatic HNSCC; 882 participants were allocated 1:1:1, stratified by PD-L1 expression, p16 status and performance status. PD-L1 positivity was not required; investigators and participants were masked to the PD-L1 combined positive score (CPS). Primary endpoints were overall survival and progression-free survival in the intention-to-treat population; there were 14 primary hypotheses across the CPS 20 or more, CPS 1 or more and total populations.
- Primary endpoint
- OS, PFS
- Arms
- Pembrolizumab alone (experimental, n = 301): Pembrolizumab alone
- Pembrolizumab with chemotherapy (experimental, n = 281): Pembrolizumab plus a platinum and 5-fluorouracil
- Cetuximab with chemotherapy (control, n = 300): Cetuximab plus a platinum and 5-fluorouracil
- People
- Burtness B, KEYNOTE-048
OSHR 0.77 (95% CI 0.63–0.93)Δ median OS+2.3 monthsOSHR 0.65 (95% CI 0.53–0.80)Δ median OS+3.2 monthsOSHR 0.60 (95% CI 0.45–0.82)Δ median OS+3.7 months
Show the numbers
| Endpoint | Analysis | Pembrolizumab alone / Pembrolizumab with chemotherapy | Cetuximab with chemotherapy | Effect |
|---|---|---|---|---|
| OSTotal population (all randomly allocated participants; PD-L1 positivity not required for entry) | interimBurtness 2019 | median 13 months | median 10.7 months | HR 0.77 (95% CI 0.63–0.93)P=0.0034Second interim analysis. |
| OSPD-L1 CPS 1 or more | finalBurtness 2019 | median 13.6 months | median 10.4 months | HR 0.65 (95% CI 0.53–0.80)P<0.0001Definitive finding obtained at the final analysis for this hypothesis. |
| OSPD-L1 CPS 20 or more | finalBurtness 2019 | median 14.7 months | median 11 months | HR 0.60 (95% CI 0.45–0.82)P=0.0004Definitive finding obtained at the final analysis for this hypothesis. |
| OSPD-L1 CPS 1 or more | interimBurtness 2019 | median 12.3 months | median 10.3 months | HR 0.78 (95% CI 0.64–0.96)P=0.0086Second interim analysis. |
| OSPD-L1 CPS 20 or more | interimBurtness 2019 | median 14.9 months | median 10.7 months | HR 0.61 (95% CI 0.45–0.83)P=0.0007Second interim analysis. |
| OSTotal population (all randomly allocated participants; PD-L1 positivity not required for entry) | interimBurtness 2019 | median 11.6 months | median 10.7 months | HR 0.85 (95% CI 0.71–1.03)Described in the abstract as non-inferior (margin 1.2), not superior; second interim analysis. |
| OSTotal population | long term-updatemedian follow-up 45 monthsHarrington 2023 | — | — | HR 0.71 (95% CI 0.59–0.85)Post hoc long-term efficacy analysis with no multiplicity or alpha adjustment, as stated in the abstract. Medians are not given in the abstract. |
| OSPD-L1 CPS 1 or more | long term-updatemedian follow-up 45 monthsHarrington 2023 | — | — | HR 0.74 (95% CI 0.61–0.89)Post hoc long-term efficacy analysis with no multiplicity or alpha adjustment, as stated in the abstract. |
| OSTotal population | long term-updatemedian follow-up 45 monthsHarrington 2023 | — | — | HR 0.81 (95% CI 0.68–0.97)Described in the abstract as noninferior in the total population; post hoc, no multiplicity or alpha adjustment. |
| Endpoint | Analysis | Pembrolizumab alone / Pembrolizumab with chemotherapy | Cetuximab with chemotherapy | Effect |
|---|---|---|---|---|
| OSTotal population (all randomly allocated participants; PD-L1 positivity not required for entry) | interimBurtness 2019 | median 13 months | median 10.7 months | HR 0.77 (95% CI 0.63–0.93)P=0.0034Second interim analysis. |
| OSPD-L1 CPS 1 or more | finalBurtness 2019 | median 13.6 months | median 10.4 months | HR 0.65 (95% CI 0.53–0.80)P<0.0001Definitive finding obtained at the final analysis for this hypothesis. |
| OSPD-L1 CPS 20 or more | finalBurtness 2019 | median 14.7 months | median 11 months | HR 0.60 (95% CI 0.45–0.82)P=0.0004Definitive finding obtained at the final analysis for this hypothesis. |
| OSPD-L1 CPS 1 or more | interimBurtness 2019 | median 12.3 months | median 10.3 months | HR 0.78 (95% CI 0.64–0.96)P=0.0086Second interim analysis. |
| OSPD-L1 CPS 20 or more | interimBurtness 2019 | median 14.9 months | median 10.7 months | HR 0.61 (95% CI 0.45–0.83)P=0.0007Second interim analysis. |
| OSTotal population (all randomly allocated participants; PD-L1 positivity not required for entry) | interimBurtness 2019 | median 11.6 months | median 10.7 months | HR 0.85 (95% CI 0.71–1.03)Described in the abstract as non-inferior (margin 1.2), not superior; second interim analysis. |
| OSTotal population | long term-updatemedian follow-up 45 monthsHarrington 2023 | — | — | HR 0.71 (95% CI 0.59–0.85)Post hoc long-term efficacy analysis with no multiplicity or alpha adjustment, as stated in the abstract. Medians are not given in the abstract. |
| OSPD-L1 CPS 1 or more | long term-updatemedian follow-up 45 monthsHarrington 2023 | — | — | HR 0.74 (95% CI 0.61–0.89)Post hoc long-term efficacy analysis with no multiplicity or alpha adjustment, as stated in the abstract. |
| OSTotal population | long term-updatemedian follow-up 45 monthsHarrington 2023 | — | — | HR 0.81 (95% CI 0.68–0.97)Described in the abstract as noninferior in the total population; post hoc, no multiplicity or alpha adjustment. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 0.77 | 0.63–0.93 |
| OS | 0.65 | 0.53–0.8 |
| OS | 0.6 | 0.45–0.82 |
| OS | 0.78 | 0.64–0.96 |
| OS | 0.61 | 0.45–0.83 |
| OS | 0.85 | 0.71–1.03 |
| OS | 0.71 | 0.59–0.85 |
| OS | 0.74 | 0.61–0.89 |
| OS | 0.81 | 0.68–0.97 |
- Pembrolizumab with chemotherapy (experimental)
- Cetuximab with chemotherapy (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Pembrolizumab with chemotherapy | Cetuximab with chemotherapy |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 8 | 65.3% | 59.6% |
| 16 | 42.6% | 35.5% |
| 24 | 27.8% | 21.1% |
| 33 | 17.2% | 11.8% |
- Pembrolizumab with chemotherapy (experimental)
- Cetuximab with chemotherapy (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Pembrolizumab with chemotherapy | Cetuximab with chemotherapy |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 9 | 63.2% | 54.9% |
| 17 | 42.0% | 32.2% |
| 26 | 26.6% | 17.7% |
| 34 | 17.7% | 10.4% |
Appears in
Sources
Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-1928.
Harrington KJ, Burtness B, Greil R, Soulières D, Tahara M, de Castro G Jr, et al. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol. 2023;41(4):790-802.