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Improved survival with pembrolizumab in the first-line treatment of metastatic or recurrent head and neck cancer

KEYNOTE-048 is an open-label, randomized phase III study comparing pembrolizumab or pembrolizumab + chemotherapy to the current standard EXTREME regimen as first-line systemic therapy for patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). First-line pembrolizumab was found to significantly improve the overall survival (OS) compared to EXTREME in patients expressing PD-L1, with a more favourable safety profile. In the overall patient population, pembrolizumab plus chemotherapy significantly improved the survival compared to the EXTREME regimen with a comparable safety profile. This is the first study to show an OS benefit of PD-1 based therapy over the current first-line standard in the treatment of R/M HNSCC patients.

The current standard treatment for R/M HNSCC consists of platinum-based chemotherapy (5-fluorouracil (5-FU) with cisplatin or carboplatin) plus the EGFR inhibitor cetuximab, also known as the EXTREME regimen. Around 35% of patients respond to this treatment, which leads to a median survival of just over 10 months. Immune checkpoint inhibition is already being used in the second-line treatment of R/M HNSCC patients where it was shown to prolong the survival in comparison to chemotherapy. The phase III KEYNOTE-048 study examined whether the anti-PD-1 monoclonal antibody pembrolizumab could also prolong the survival compared to standard treatment in the first-line setting. KEYNOTE-048 enrolled patients with head and neck cancer who had not received prior chemotherapy or biologic therapy for recurrent or metastatic disease. Patients were randomly allocated in a 1:1:1 ratio to standard treatment with EXTREME, pembrolizumab alone (200 mg q3w for up to 35 cycles); or a novel combination of pembrolizumab and platinum-based chemotherapy (pembrolizumab 200 mg + carboplatin AUC 5 or cisplatin 100 mg/m2 + 5-FU 1,000 mg/m2/d for 4 days for a total of 6 cycles, followed by pembrolizumab monotherapy 200 mg q3w for up to 35 cycles in total). During ESMO 2018 results were presented on the comparison of pembrolizumab with EXTREME in patients expressing PD-L1, and on the comparison of the novel immunotherapy-chemotherapy combination with the standard EXREME regimen in all patients, regardless of PD-L1 expression.

The first comparison included 301 patients who were treated with pembrolizumab monotherapy and 300 patients who received the EXTREME treatment. In patients with a PD-L1 combined positive score (CPS) of 20 or more, the OS was shown to be significantly longer with pembrolizumab than with the standard EXTREME treatment (median OS 14.9 vs. 10.7 months; HR[95%CI]: 0.61[0.45-0.83]; p=0.0007). At two years, this translated into a 16% higher OS rate with pembrolizumab than with EXTREME (38% vs. 22%). Although the response rate to pembrolizumab was lower than with the standard treatment (23.3% vs. 36.1%), the responses to immunotherapy were found to be much more durable than what was seen with EXTREME (20.9 vs. 4.5 months). There was no difference in progression-free survival (PFS) between the 2 treatment groups (HR[95%CI]: 0.99[0.75-1.29]). Similar results were obtained when the threshold for PD-L1 positivity was lowered to a CPS of ≥1. In this cohort, the median OS was 12.3 months with pembrolizumab vs. 10.3 months with EXTREME (HR[95%CI]: 0.78[0.64-0.96]; p=0.0086). At 2-years, 30% of patients with a CPS ≥1 who received pembrolizumab monotherapy were still alive as compared to 19% in the EXTREME arm. In this cohort, the overall response rates (ORRs) with pembrolizumab and EXTREME were 19.1% and 34.9%, respectively, but also here the responses proved to be much more durable with pembrolizumab (median duration of response [DoR]: 20.9 vs. 4.5 months). There was no difference in PFS between the two groups (HR[95%CI]: 1.16[0.75-1.29]).

In the second comparison, 281 patients received the novel combination of pembrolizumab and platinum-based chemotherapy and 278 received standard treatment. The OS was significantly prolonged with the combination therapy compared to EXTREME (median OS 13.0 vs. 10.7 months; HR[95%CI]: 0.77[0.63-0.93], p=0.0034). The ORR was comparable with the two treatments in this comparison at 35.6% for pembrolizumab plus chemotherapy and 36.3% with EXTREME standard treatment. There was no difference in PFS between the two treatment arms (HR[95%CI]: 0.92[0.77-1.10]).

Side effects in the three treatment groups were as expected: pembrolizumab alone was less toxic than the standard treatment, while pembrolizumab combined with chemotherapy had a similar toxicity profile as the EXTREME regimen.

In summary, this is the first study to show superior OS over the decade-old standard of care in R/M HNSCC. Pembrolizumab monotherapy has a better safety profile than the current standard of care and prolongs the survival in PD-L1 positive patients. In the total study population, adding pembrolizumab to chemotherapy was associated with a longer survival than the current standard of care without leading to more toxicity. Further biomarker analyses will hopefully guide the choice whether to use pembrolizumab alone or administer it in combination with chemotherapy in individual patients. Several other studies evaluating immune checkpoint inhibition in the first-line treatment of R/M HNSCC are currently ongoing and their results will further elucidate the full potential of immunotherapy in this setting.


Burtness B, Harrington K, Griel R, et al. KEYNOTE-048: Phase III study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Presented at ESMO 2018, Abstract LBA8_PR.

Speaker Barbara Burtness


Barbara Burtness, MD, PhD,
Yale School of Medicine, Yale Cancer Center, New Haven, USA


See: Keyslides

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