Improved survival seen with pembrolizumab + CRT in locally advanced head-and-neck SCC

First-line pembrolizumab plus chemoradiotherapy shows favourable trend to improved EFS in locally advanced head and neck squamous cell carcinoma.

Less than 50% of patients remain free of disease at 3 years

Standard-of-care for patients with unresected locally advanced head-and-neck squamous cell carcinoma (LA-HNSCC) is concurrent chemoradiotherapy (CRT) with high-dose cisplatin1. However, less than 50% of patients remain free of disease at 3 years and the 5-year overall survival (OS) rate is about 50%2. Recently, pembrolizumab (with or without chemotherapy) was shown to improve survival in patients with recurrent or metastatic HNSCC3. The randomised, double-blind, phase 3 KEYNOTE-412 study (NCT03040999) investigated the efficacy and safety of pembrolizumab plus CRT versus placebo plus CRT in patients with LA-HNSCC. Dr Jean-Pascal Machiels (Cliniques Universitaires Saint-Luc, Belgium) presented the first results4.

In KEYNOTE-412, 804 patients with newly diagnosed, treatment-naïve LA-HNSCC were 1:1 randomised to receive pembrolizumab (200 mg every 3 weeks) plus CRT (70 Gy/35F plus cisplatin 100 mg/m2 every 3 weeks) or placebo plus CRT. A pembrolizumab or placebo priming dose was given 1 week before CRT, followed by 2 doses during CRT and 14 doses of maintenance therapy after CRT, for a total of 17 doses. The primary endpoint was EFS (efficacy boundary, one-sided P=0.0242). OS and safety/tolerability were secondary endpoints.

Pembrolizumab plus CRT: A favourable trend towards improved EFS

After a median follow-up of 47.7 months, median EFS for participants treated with pembrolizumab plus CRT was not reached versus 46.6 months for participants treated with placebo plus CRT (HR 0.83; P=0.0429), so the primary endpoint was not met. EFS rates at 24 months were 63.2% versus 56.2%, respectively; EFS rates at 36 months were 57.4% versus 52.1%, respectively. Median OS was also not significantly different between both study arms (HR 0.90). The difference in median EFS between the arms was somewhat more pronounced in patients with PD-L1 CPS ≥1 (n=685; HR 0.80) and in patients with PD-L1 CPS ≥20 (n=291; HR 0.73). No new safety signals were observed. 

Based on these results, Dr Machiels concluded that “pembrolizumab plus CRT is associated with a favourable trend toward improved EFS versus placebo in patients with LA-HNSCC. PD-L1 expression may be an informative biomarker. However, LA-HNSCC remains a challenging disease to treat.”

  1. Machiels J-P, et al. Ann Oncol. 2020;31:1462–1475.
  2. Braakhuis BJM, et al. Ann Oncol. 29012;23 Suppl 10:x173–7.
  3. Burtness B, et al. Lancet 2019;394:1915–1928.
  4. Machiels J-P, et al. Primary results of the phase III KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). Abstract LBA5, ESMO Congress 2022, Paris, France, 09–13 September.