Josh Friedman , 2025-04-28 15:30:00
April 28, 2025
4 min read
Key takeaways:
- Adding perioperative pembrolizumab to standard of care significantly improved EFS for patients with advanced HNSCC.
- Regimens with multiple immunotherapies are likely the next step.
The addition of neoadjuvant and adjuvant pembrolizumab to standard of care significantly improved outcomes for certain patients with advanced head and neck squamous cell carcinoma, according to results of a randomized phase 3 study.
Findings from the KEYNOTE-689 trial, presented at American Association for Cancer Research Annual Meeting, showed individuals with stage III or IVA resected, locally advanced disease who received pembrolizumab (Keytruda, Merck) had at least a 27% improvement in EFS.
Ravindra Uppaluri
“I believe these data support this regimen as a new standard of care for these patients,” Ravindra Uppaluri, MD, PhD, director of head and neck surgical oncology at Brigham and Women’s Hospital and Dana-Farber Cancer Institute and associate professor of otolaryngology at Harvard Medical School, told Healio.
“It’s really exciting,” he added. “It’s a new frontier for our patients. These patients are really difficult to treat, and this is a really exciting next phase for patients with head and neck cancer.”
Treatment landscape has been ‘static’
Patients diagnosed with stage III or IV locally advanced HNSCC have historically been treated with upfront surgery or radiation, Uppaluri said.
Patients who underwent surgery and who did not have positive margins or tumors that extended beyond the lymph nodes also received adjuvant radiation. Those who had high-risk features received chemoradiation.
“This paradigm has been in place for nearly 2 decades,” Uppaluri said. “There were studies done in 2004 that supported this approach, and it’s been sort of static since that time.”
Immune checkpoint inhibitors had previously been investigated in HNSCC along with chemoradiation.
“Disappointingly, when immune checkpoint inhibitors have been combined with chemoradiation, all these studies have been negative,” Uppaluri said.
Uppaluri and colleagues investigated whether immunotherapy before and after surgery could improve outcomes among 714 patients with stage III or IVA resectable, locally advanced HNSCC in the open-label KEYNOTE-689 trial. They randomly assigned patients 1:1 to perioperative pembrolizumab and standard of care (n = 363) or standard of care alone (n = 351).
Standard of care included surgery and postoperative radiotherapy. Patients with high-risk features also received chemotherapy.
Researchers grouped patients based on combined positive scores (CPS), a measure of PD-L1 expression.
The investigational arm received two cycles of neoadjuvant pembrolizumab, three cycles of concurrent (with postoperative chemoradiotherapy) pembrolizumab and 12 cycles of adjuvant pembrolizumab (200 mg IV) every 3 weeks.
Postoperative radiotherapy dosage and fractions varied based on patients’ risk levels.
EFS served as the primary endpoint. Major pathological response (mPR) and OS served as secondary endpoints.
‘We were thrilled’
At median follow-up of 38.3 months (range, 9-66.5), patients in the investigational arm had significantly improved EFS compared with the standard of care arm (median EFS, 51.8 months vs. 30.4 months; HR = 0.73; 95% CI, 0.58-0.92).
Patients who received pembrolizumab who had a CPS score of at least 10 derived the greatest benefit (median EFS, 59.7 months vs. 26.9 months; HR = 0.66; 95% CI, 0.49-0.88).
Patients in the investigational arm also had significantly improved mPR rates (mPR difference: 9.3%; 95% CI, 6.7%-12.8%).
The difference in mPR rates increased for patients with a CPS score of 10 or higher (mPR difference: 13.7%; 95% CI, 9.7%-18.7%).
“We were thrilled,” Uppaluri said. “Treatments for these patients have been limited to surgery and radiation without and with chemotherapy for 20-some years. We really hit a wall in terms of where we were in improving outcomes. Seeing these results was really quite dramatic.”
Grade 3 or higher treatment-related adverse events occurred in 44.6% of patients who received pembrolizumab and 42.9% who received standard of care.
Immune-mediated adverse events occurred in 43.2% of patients who received pembrolizumab, the most common being hypothyroidism (24.7%).
The investigational arm had four deaths and the standard of care arm had one.
‘The next frontier’
The researchers continue to evaluate patients from KEYNOTE-689 and plan an additional analysis of OS next year.
“From what we’ve seen already, the OS curves are separating favoring pembrolizumab with standard of care but we’ll have to wait and see,” Uppaluri said.
Future studies will investigate when pembrolizumab is acting on the cancer.
“It’s possible that both the neoadjuvant and adjuvant components are important, but I think future studies — and this is going to take time and effort from the whole community — will try to examine the contribution of components” Uppaluri said.
Neoadjuvant regimens including multiple immunotherapies have been explored, as well.
Healio previously reported on a study that showed neoadjuvant doublets — nivolumab (Opdivo, Bristol Myers Squibb) plus relatlimab (Opdualag, Bristol Myers Squibb), as well as nivolumab plus ipilimumab (Yervoy, Bristol Myers Squibb) — both produced higher numerical pathologic response rates than nivolumab monotherapy.
“That’s really the next frontier,” Uppaluri said. “Can we add additional immunotherapies to get better than we are right now? The findings from that study are encouraging. There have been data already in the literature about some doublets and potential for improved pathologic responses.”
Immunotherapy with bispecific antibodies, other targeted agents and chemotherapy could give patients different options, too.
“I’m really excited about this because I think that with these data now being out there, what we’ll see is the idea that possibly a small subset of patients, maybe a bigger subset, may ultimately avoid surgery,” Uppaluri said. “It could be that some patients respond so well that all they need is this kind of therapy, and that would be, obviously, a huge game-changer.”
For more information:
Ravindra Uppaluri, MD, PhD, can be reached at ruppaluri@partners.org.
Sources/Disclosures
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Uppaluri R, et al. Abstract CT001. Presented at: American Association for Cancer Research Annual Meeting; April 25-30, 2025; Chicago.
Disclosures:
Merck funded the study. Uppaluri reports research funding from Daiichi Sankyo and Merck Sharp & Dohme LLC, and consulting fees from Daiichi Sankyo, Merck and Regeneron. Please see the study for all other authors’ relevant financial disclosures.
