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 . However, less than 50% of patients remain free of disease after 3 years and the 5-year overall survival (OS) rate is about 50% . Pembrolizumab (with or without chemotherapy) was recently shown to improve survival in patients with recurrent or metastatic HNSCC . 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 .
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.”
- Machiels J-P, et al. Ann Oncol. 2020;31(11):1462–1475.
- Braakhuis BJM, et al. Ann Oncol. 2012;23 Suppl 10:x173–7.
- Burtness B, et al. Lancet. 2019;394(10212):1915–1928.
- 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 .
Pembro, pembrolizumab. CRT, chemoradiotherapy. EFS, event-free survival. NR, normal range.
Copyright ©2022 Medicom Medical Publishers
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Letter from the Editor »
Table of Contents: ESMO 2022
Letter from the Editor
High pathological responses to neoadjuvant immune checkpoint inhibition in locally advanced dMMR colon cancer
Fruquintinib: a potential new treatment for patients with refractory mCRC
Second-line avelumab is effective in patients with MSI-H/dMMR mCRC
Upper Gastrointestinal Cancer
Deep learning models predict the risk of relapse and the mutational profile in GIST
Addition of pembrolizumab to lenvatinib does not improve OS in advanced HCC
New, highly selective inhibitor of FGFR2 driver alterations and resistance mutations
Chemo-immunotherapy in gastric cancer is more effective when administered in parallel
Tumour infiltrating lymphocytes identify patients with immunogenic triple-negative breast cancer
OS benefit of abemaciclib in HR-positive/HER2-negative advanced breast cancer not (yet) statistically significant
OS benefit of sacituzumab govitecan in pre-treated HR-positive/HER2-negative metastatic breast cancer
A pathway from air pollution to lung cancer in non-smokers identified
Selective KRASG12C inhibitor sotorasib demonstrates superior PFS and ORR compared to docetaxel in previously treated patients with NSCLC
Promising clinical activity of tepotinib plus osimertinib in NSCLC with MET amplification after progression on first-line osimertinib
High pathological responses in borderline resectable NSCLC patients after induction with dual immunotherapy and concurrent chemoradiotherapy
Treatment with tumour-infiltrating lymphocytes for advanced melanoma outperforms ipilimumab
Neoadjuvant pembrolizumab outperforms adjuvant pembrolizumab in resectable stage III–IV melanomas
Survival-benefit of neoadjuvant T-VEC maintained over 5 years of follow-up
Baseline ctDNA predicts survival in resected stage III–IV melanoma
Genitourinary Cancer – Prostate Cancer
Overall survival benefit of abiraterone in mHSPC is maintained for 7 years
Limited benefit of adding long-term ADT to post-operative radiotherapy in prostate cancer
Intensified ADT benefits biochemical progression-free survival in biochemically relapsed prostate cancer
Genitourinary Cancer – Non-Prostate Cancer
Adjuvant nivolumab plus ipilimumab does not improve survival in patients with localised RCC at high risk of relapse after nephrectomy
Triple therapy improves progression-free survival in patients with advanced RCC versus dual therapy
Adjuvant atezolizumab does not improve outcomes for patients with RCC and increased risk of recurrence
OS benefit for advanced ovarian cancer patients treated with maintenance olaparib
Maintenance tegafur-uracil does not improve survival in locally advanced cervical cancer
Head and Neck Cancer
Adding first-line pembrolizumab to CRT in locally advanced HNSCC does not significantly prolong survival or event-free survival
5-FU-free chemotherapy combination as an alternative for first-line treatment of recurrent or metastatic HNSCC
Epstein Barr virus-specific autologous cytotoxic T lymphocytes do not improve survival in nasopharyngeal carcinoma