KEYNOTE-048: pembrolizumab, alone or with chemotherapy, as first treatment for recurrent or metastatic head and neck cancer
Pembrolizumab, either alone in PD-L1-positive tumours or combined with chemotherapy, helped patients with recurrent or metastatic head and neck squamous cell cancer live longer than the previous cetuximab-based standard.
Open-label phase 3 trial of 882 patients with untreated recurrent or metastatic head and neck squamous cell carcinoma randomised to pembrolizumab alone, pembrolizumab plus platinum and fluorouracil, or the EXTREME regimen (cetuximab plus platinum and fluorouracil). Primary endpoints were OS and PFS in PD-L1 CPS 20 or more, CPS 1 or more, and all patients.
Pembrolizumab alone improved OS in CPS 20 or more (14.9 vs 10.7 months, HR 0.61) and CPS 1 or more (12.3 vs 10.3 months, HR 0.78) and was non-inferior overall. Pembrolizumab plus chemotherapy improved OS in all patients (13.0 vs 10.7 months, HR 0.77). It replaced EXTREME as the first-line standard and made PD-L1 CPS testing routine in head and neck cancer.
- Pembrolizumab alone vs EXTREME, CPS 20 or more: median OS 14.9 vs 10.7 months, HR 0.61 (95% CI 0.45-0.83).
- Pembrolizumab alone vs EXTREME, CPS 1 or more: median OS 12.3 vs 10.3 months, HR 0.78.
- Pembrolizumab plus chemotherapy vs EXTREME, all patients: median OS 13.0 vs 10.7 months, HR 0.77 (95% CI 0.63-0.93).
- Response rates were lower with pembrolizumab alone (17% vs 36% in CPS 20 or more) but responses lasted far longer (median 22.6 vs 4.5 months).
- Grade 3 or higher all-cause adverse events 55% (pembrolizumab alone), 85% (pembrolizumab plus chemotherapy) and 83% (EXTREME).
Patients with head and neck squamous cell cancer that has recurred or spread should be treated first with pembrolizumab: alone if their tumour is strongly PD-L1 positive and they can wait for a slower response, or with chemotherapy if the tumour is bulky or PD-L1 low. Cetuximab-based chemotherapy is no longer the default. Long-term follow-up shows a small but real group of patients alive at four to five years, which was almost unheard of before.
- Open-label with a complex multi-comparison design; PFS was not improved in any comparison.
- Pembrolizumab alone has a lower response rate and early progression can occur, so patients with rapidly symptomatic disease may need chemotherapy added.
- CPS below 1 (about 15% of patients) derived no clear benefit from either pembrolizumab arm.
- EXTREME is now an outdated comparator; the optimal strategy for HPV-positive versus HPV-negative disease was not defined.
Pages like this
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- TrialKEYNOTE-048
Shares Combined positive score (CPS), No one can predict who responds to immunotherapy, PD-1, Pembrolizumab.