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Adding first-line pembrolizumab to CRT in locally advanced HNSCC does not significantly prolong survival or event-free survival

Presented By
Prof. Jean-Pascal Machiels, Cliniques Universitaires Saint-Luc, Belgium
ESMO 2022
Phase 3, KEYNOTE-412

The primary endpoint of a study comparing first-line pembrolizumab plus chemoradiotherapy (CRT) to CRT alone failed to meet its primary endpoint (even though there was a strong trend for improvement of event-free survival =EFS) in patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC), the first results of the phase 3 KEYNOTE-412 trial suggested.

Standard-of-care for patients with unresected LA-HNSCC is concurrent chemoradiotherapy (CRT) with high-dose cisplatin [1]. However, less than 50% of patients remain free of disease after 3 years and the 5-year overall survival (OS) rate is about 50% [2]. Pembrolizumab (with or without chemotherapy) was recently shown to improve survival in patients with recurrent or metastatic HNSCC [3]. The phase 3 KEYNOTE-412 trial (NCT03040999) investigated the efficacy of pembrolizumab plus CRT versus placebo plus CRT in patients with LA-HNSCC. Prof. Jean-Pascal Machiels (Cliniques Universitaires Saint-Luc, Belgium) presented the first results [4].

In the KEYNOTE-412 trial, 804 patients with newly diagnosed, treatment-naïve LA-HNSCC were randomised 1:1 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.

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, CI 0,68-1,03). Hence, the primary endpoint was not met (see Figure).

EFS rates at 24 months were 63.2% versus 56.2% and 57.4% vs 52.1% at 36 months for pembrolizumab plus CRT and placebo plus CRT participants, respectively. Median OS was also not significantly different between the 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 patients with PD-L1 CPS ≥20 (n=291; HR 0.73). No new safety signals were observed.

Based on these results, Prof. Machiels concluded that “pembrolizumab plus CRT is associated with a favourable trend towards 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(11):1462–1475.
  2. Braakhuis BJM, et al. Ann Oncol. 2012;23 Suppl 10:x173–7.
  3. Burtness B, et al. Lancet. 2019;394(10212):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, 09–13 September, Paris, France.


Figure: Event-free survival per treatment arm in the intention-to-treat population [4].

Pembro, pembrolizumab. CRT, chemoradiotherapy. EFS, event-free survival. NR, normal range.

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