Early Phase 3 trials like JAVELIN adding immunotherapy to chemoradiation failed to improve outcomes. However, subgroup analyses consistently showed a potential benefit in PD-L1 high-expressing patients, a crucial lesson that informed the design of subsequent, more successful studies.
While neoadjuvant pembrolizumab (KEYNOTE-689) is now standard of care for resectable head and neck cancer, it carries a critical risk. During the pre-surgical treatment window, some patients may experience disease progression or toxicity that makes them ineligible for their planned curative surgery.
Pursuing non-surgical larynx preservation for advanced disease carries a high functional cost. Even in successful cases at top centers, nearly half the patients end up with a permanent tracheostomy, and a quarter suffer from chronic aspiration, undermining the primary goal of maintaining quality of life.
A 10-year update of the landmark RTOG 9111 trial revealed a paradox: the concurrent chemoradiation arm achieved the highest rate of larynx preservation but had the lowest overall survival. This was due to a higher rate of non-cancer-related deaths, highlighting the severe long-term toxicities of this intensive approach.
The HN009 trial challenged the standard high-dose cisplatin regimen for head and neck cancer. While weekly cisplatin reduced expected hearing and kidney toxicity, it unexpectedly caused more bone marrow toxicity. The overall "toxicity score" showed no difference between arms for HPV-positive patients, halting the trial's progression.
The practice-changing KEYNOTE-689 trial was open-label, meaning patients knew their treatment. This could introduce bias; patients on the standard care arm may have dropped out ("bailed"), while those on the pembrolizumab arm might have progressed, artificially making the rates of patients reaching surgery appear similar.