Addition of pembrolizumab to standard care improved event-free survival for patients with HNSCC

Patients with surgically resectable, locally advanced head and neck squamous cell carcinoma (HNSCC) treated with the addition of neoadjuvant and adjuvant pembrolizumab to the standard of care had significant improvements in event-free survival compared to patients treated only with the standard of care according to the first interim analysis of the phase 3 KEYNOTE-689 trial.¹

A significant improvement was seen in all participants independently of tumor expression of the programmed death ligand 1 according to the combined positive score (CPS).

At a median follow-up of 38.3 months, event-free survival was 57.6% for patients who were treated with the addition of neoadjuvant and adjuvant pembrolizumab (with a CPS ≥1) and 46.4% for patients treated with standard therapy alone (surgery and adjuvant radiotherapy with or without concomitant cisplatin). This represents a 27% reduction in the risk of disease progression, recurrence, or death (hazard ratio, 0.73; 95% CI, 0.58–0.92; p = .008). Based on these data, the US Food and Drug Administration approved this regimen for surgically resectable, locally advanced head and neck cancer in patients who have tumors with a CPS ≥1.

A secondary endpoint of the clinical trial was pathological tumor response in the surgically resected tumor and lymph nodes, which was seen at significantly higher rates in the patients receiving neoadjuvant pembrolizumab. Importantly, this led to patients who were treated with pembrolizumab receiving less chemotherapy and radiation.

The phase 3, multicenter, open-label trial included 363 patients (234 with a CPS ≥10 and 347 with a CPS ≥1) who were assigned to the pembrolizumab group and 351 patients (231 with a CPS ≥10 and 335 with a CPS ≥1) who were assigned to the standard therapy alone group. All patients were at least 18 years old and had newly diagnosed nonmetastatic, resectable, locally advanced HNSCC. Patients included those with stage III oropharyngeal p16-positive disease with tumor size T4 and node stage N0–N2; those with stage III or IV oropharyngeal p16-negative disease; and those with laryngeal, hypopharyngeal, or oral cavity disease regardless of the p16 status.

Treatment-related adverse events were similar between the two treatment groups; these included grade 3 or higher adverse events that occurred in patients in the pembrolizumab group (44.6%) and in patients in the standard-of-care group (42.9%). Also similar were the percentages of deaths in the two groups: 1.1% and 0.3%, respectively.

The lead author of the study, Ravindra Uppaluri, MD, PhD, director of head and neck surgical oncology at the Brigham and Women’s Hospital and Dana–Farber Cancer Institute in Boston, Massachusetts, says that the data show that neoadjuvant treatment is safe in these patients without compromising patients’ ability to undergo planned surgery.

“With these results, we now have a new standard of care for these locally advanced head and neck cancer patients, and this represents the first new change in the field for these patients in over 20 years,” he says. “This dramatic shift in how we take care of patients may also lead to less toxicities of our conventional therapies.”

Commenting on the study, Carole Fakhry, MD, MPH, professor of otolaryngology and chief of the Division of Head and Neck Surgery at Johns Hopkins Medicine in Baltimore, Maryland, says that the treatment approach opens the door for novel paradigms of care that may shift therapeutic modalities in the future. “For many patients who may have previously gone straight to surgery, this study shows a benefit in treatment with immunotherapy before surgery and after adjuvant therapy,” she says, adding that she found it interesting that there was a survival benefit without necessarily a tumor response.