April 28, 2025
4 min learn
Key takeaways:
- Including perioperative pembrolizumab to plain of care considerably improved EFS for sufferers with superior HNSCC.
- Regimens with a number of immunotherapies are seemingly the subsequent step.
The addition of neoadjuvant and adjuvant pembrolizumab to plain of care considerably improved outcomes for sure sufferers with superior head and neck squamous cell carcinoma, in line with outcomes of a randomized section 3 research.
Findings from the KEYNOTE-689 trial, introduced at American Affiliation for Most cancers Analysis Annual Assembly, confirmed people with stage III or IVA resected, domestically superior illness who obtained pembrolizumab (Keytruda, Merck) had no less than a 27% enchancment in EFS.
Ravindra Uppaluri
“I consider these information help this routine as a brand new commonplace of take care of these sufferers,” Ravindra Uppaluri, MD, PhD, director of head and neck surgical oncology at Brigham and Girls’s Hospital and Dana-Farber Most cancers Institute and affiliate professor of otolaryngology at Harvard Medical Faculty, advised Healio.
“It’s actually thrilling,” he added. “It’s a brand new frontier for our sufferers. These sufferers are actually tough to deal with, and it is a actually thrilling subsequent section for sufferers with head and neck most cancers.”
Therapy panorama has been ‘static’
Sufferers identified with stage III or IV domestically superior HNSCC have traditionally been handled with upfront surgical procedure or radiation, Uppaluri mentioned.
Sufferers who underwent surgical procedure and who didn’t have constructive margins or tumors that prolonged past the lymph nodes additionally obtained adjuvant radiation. Those that had high-risk options obtained chemoradiation.
“This paradigm has been in place for almost 2 many years,” Uppaluri mentioned. “There have been research accomplished in 2004 that supported this strategy, and it’s been type of static since that point.”
Immune checkpoint inhibitors had beforehand been investigated in HNSCC together with chemoradiation.
“Disappointingly, when immune checkpoint inhibitors have been mixed with chemoradiation, all these research have been unfavourable,” Uppaluri mentioned.
Uppaluri and colleagues investigated whether or not immunotherapy earlier than and after surgical procedure may enhance outcomes amongst 714 sufferers with stage III or IVA resectable, domestically superior HNSCC within the open-label KEYNOTE-689 trial. They randomly assigned sufferers 1:1 to perioperative pembrolizumab and commonplace of care (n = 363) or commonplace of care alone (n = 351).
Normal of care included surgical procedure and postoperative radiotherapy. Sufferers with high-risk options additionally obtained chemotherapy.
Researchers grouped sufferers based mostly on mixed constructive scores (CPS), a measure of PD-L1 expression.
The investigational arm obtained two cycles of neoadjuvant pembrolizumab, three cycles of concurrent (with postoperative chemoradiotherapy) pembrolizumab and 12 cycles of adjuvant pembrolizumab (200 mg IV) each 3 weeks.
Postoperative radiotherapy dosage and fractions different based mostly on sufferers’ danger ranges.
EFS served as the first endpoint. Main pathological response (mPR) and OS served as secondary endpoints.
‘We have been thrilled’
At median follow-up of 38.3 months (vary, 9-66.5), sufferers within the investigational arm had considerably improved EFS in contrast with the usual of care arm (median EFS, 51.8 months vs. 30.4 months; HR = 0.73; 95% CI, 0.58-0.92).
Sufferers who obtained pembrolizumab who had a CPS rating of no less than 10 derived the best profit (median EFS, 59.7 months vs. 26.9 months; HR = 0.66; 95% CI, 0.49-0.88).
Sufferers within the investigational arm additionally had considerably improved mPR charges (mPR distinction: 9.3%; 95% CI, 6.7%-12.8%).
The distinction in mPR charges elevated for sufferers with a CPS rating of 10 or larger (mPR distinction: 13.7%; 95% CI, 9.7%-18.7%).
“We have been thrilled,” Uppaluri mentioned. “Remedies for these sufferers have been restricted to surgical procedure and radiation with out and with chemotherapy for 20-some years. We actually hit a wall by way of the place we have been in bettering outcomes. Seeing these outcomes was actually fairly dramatic.”
Grade 3 or larger treatment-related opposed occasions occurred in 44.6% of sufferers who obtained pembrolizumab and 42.9% who obtained commonplace of care.
Immune-mediated opposed occasions occurred in 43.2% of sufferers who obtained pembrolizumab, the commonest being hypothyroidism (24.7%).
The investigational arm had 4 deaths and the usual of care arm had one.
‘The subsequent frontier’
The researchers proceed to guage sufferers from KEYNOTE-689 and plan an extra evaluation of OS subsequent 12 months.
“From what we’ve seen already, the OS curves are separating favoring pembrolizumab with commonplace of care however we’ll have to attend and see,” Uppaluri mentioned.
Future research will examine when pembrolizumab is appearing on the most cancers.
“It’s attainable that each the neoadjuvant and adjuvant parts are essential, however I feel future research — and that is going to take effort and time from the entire group — will attempt to study the contribution of parts” Uppaluri mentioned.
Neoadjuvant regimens together with a number of immunotherapies have been explored, as nicely.
Healio beforehand reported on a research that confirmed neoadjuvant doublets — nivolumab (Opdivo, Bristol Myers Squibb) plus relatlimab (Opdualag, Bristol Myers Squibb), in addition to nivolumab plus ipilimumab (Yervoy, Bristol Myers Squibb) — each produced larger numerical pathologic response charges than nivolumab monotherapy.
“That’s actually the subsequent frontier,” Uppaluri mentioned. “Can we add extra immunotherapies to get higher than we’re proper now? The findings from that research are encouraging. There have been information already within the literature about some doublets and potential for improved pathologic responses.”
Immunotherapy with bispecific antibodies, different focused brokers and chemotherapy may give sufferers totally different choices, too.
“I’m actually enthusiastic about this as a result of I feel that with these information now being on the market, what we’ll see is the concept that presumably a small subset of sufferers, perhaps a much bigger subset, could finally keep away from surgical procedure,” Uppaluri mentioned. “It might be that some sufferers reply so nicely that every one they want is this sort of remedy, and that may be, clearly, an enormous game-changer.”
For extra info:
Ravindra Uppaluri, MD, PhD, could be reached at ruppaluri@companions.org.
Sources/Disclosures
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Uppaluri R, et al. Summary CT001. Introduced at: American Affiliation for Most cancers Analysis Annual Assembly; April 25-30, 2025; Chicago.
Disclosures:
Merck funded the research. Uppaluri reviews analysis funding from Daiichi Sankyo and Merck Sharp & Dohme LLC, and consulting charges from Daiichi Sankyo, Merck and Regeneron. Please see the research for all different authors’ related monetary disclosures.
