Perioperative Pembrolizumab Meets EFS End Point in Newly Diagnosed, Resected Stage III/IVA HNSCC

Neoadjuvant pembrolizumab (Keytruda), followed by adjuvant pembrolizumab plus radiotherapy with or without cisplatin, and maintenance pembrolizumab, produced a significant improvement in event-free survival (EFS) vs adjuvant radiotherapy with or without cisplatin in patients with newly diagnosed, resected stage III or IVA, locally advanced head and neck squamous cell carcinoma (HNSCC), according to topline results from the phase 3 KEYNOTE-689 trial (NCT03765918).¹

The EFS results were deemed statistically significant and clinically meaningful at the prespecified first interim analysis conducted by an independent data monitoring committee, rendering it the first phase 3 trial to show such an improvement with anti–PD-1 therapy in an intention-to-treat (ITT) population with earlier stages of HNSCC, according to a news release from Merck. A statistically significant improvement in the secondary end point of major pathological response (mPR) was also seen in the pembrolizumab arm. The safety profile of pembrolizumab was similar to that seen in prior trials, and no new signals occurred.

A trend toward improvement in overall survival (OS)—another secondary end point—appeared to favor treatment with pembrolizumab. However, the results did not reach statistical significance in patients with a PD-L1 combined positive score (CPS) of 10 or greater at the time of the analysis. Formal testing in the CPS 1 or greater and ITT populations was not performed because of the trial’s statistical testing hierarchy. OS will also be evaluated at the next interim analysis.

Findings from the trial will be presented at an upcoming medical conference and will be submitted to regulatory agencies for further review.

“These results are substantial, as KEYNOTE-689 marks the first positive trial in two decades for patients with resected, locally advanced HNSCC,” Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, stated in a news release. “These statistically significant and clinically meaningful findings have the potential to be practice-changing and continue to highlight the promising role of [pembrolizumab] for certain patients with earlier stages of disease.”

Pembrolizumab is currently indicated for use in combination with platinum and fluorouracil as frontline treatment in patients with metastatic or unresectable, recurrent HNSCC; first-line monotherapy for patients with metastatic or with unresectable, recurrent HNSCC with a PD-L1 CPS of 1 or greater; and monotherapy for patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.²

In 2 prior phase 2 trials (NCT02296684; NCT02641093) neoadjuvant pembrolizumab demonstrated evidence of efficacy and pathological response at the time of surgery in patients with high-risk, resectable, locally advanced HNSCC.³

The randomized, open-label, active-controlled KEYNOTE-689 trial was designed to evaluate pembrolizumab as neoadjuvant therapy followed by pembrolizumab in combination with standard radiotherapy, with or without cisplatin, as adjuvant treatment and continued as maintenance therapy in patients with newly diagnosed, resected stage III or IVA, locally advanced HNSCC.¹

To be eligible for enrollment patients needed to have histologically confirmed, resectable, nonmetastatic squamous cell carcinoma. Only patients with either a stage III, T4, N0-2, M0, human papillomavirus (HPV)–positive oropharyngeal primary; stage III or IVA HPV-negative oropharyngeal cancer; or stage III or IVA larynx/hypopharynx/oral cavity primaries will be allowed to enroll.⁴

Patients were required to be eligible for primary surgery according to the investigator and in accordance with local practice; have evaluable tumor burden assessed by CT scan or MRI based on RECIST 1.1 criteria; provide newly obtained core or excisional biopsy of a tumor lesion not previously irradiated; and have HPV status results for oropharyngeal cancer defined as p16. An ECOG performance status of 0 or 1 within 10 days of randomization was also required.⁴

The primary end point was EFS, and secondary endpoints included OS, mPR, pathological complete response, and safety. All efficacy end points will be evaluated according to PD-L1 CPS status.¹

Approximately 704 patients were randomly assigned 1:1 to the investigational and control arms. In the investigational arm patients received 200 mg of intravenous (IV) pembrolizumab as neoadjuvant therapy every 3 weeks (Q3W) for 2 cycles, followed by 200 mg of IV pembrolizumab Q3W for 15 cycles plus standard radiotherapy in the adjuvant setting. Patients who were considered high risk also received 100 mg/m² of IV cisplatin Q3W for 3 cycles in the adjuvant setting.

In the control arm, patients received only surgery and adjuvant radiotherapy with or without cisplatin based on risk status.

References

1. Merck’s Keytruda (pembrolizumab) met primary endpoint of event-free survival (EFS) as perioperative treatment regimen in patients with resected, locally advanced head and neck squamous cell carcinoma. News release. Merck. October 8, 2024. Accessed October 8, 2024. https://www.merck.com/news/mercks-keytruda-pembrolizumab-met-primary-endpoint-of-event-free-survival-efs-as-perioperative-treatment-regimen-in-patients-with-resected-locally-advanced-head-and-neck-squamous-c/
2. Keytruda. Prescribing information. Merck; 2021. Accessed October 8, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf
3. Uppaluri R, Lee NY, Westra W, et al. KEYNOTE-689: Phase 3 study of adjuvant and neoadjuvant pembrolizumab combined with standard of care (SOC) in patients with resectable, locally advanced head and neck squamous cell carcinoma. J Clin Oncol. 2019;37(suppl 15):TPS6090. doi:10.1200/JCO.2019.37.15_suppl.TPS609
4. Study of pembrolizumab given prior to surgery and in combination with radiotherapy given post-surgery for advanced head and neck squamous cell carcinoma (MK-3475-689). ClinicalTrials.gov. Updated April 16, 2024. Accessed October 8, 2024. https://clinicaltrials.gov/study/NCT03765918