Dr Nihanthy D Sreenath

Consultant & Head, Unit II - Department of Medical Oncology,

Saroj Gupta Cancer Centre & Research Institute,Kolkata - India

Dr Akhil Santhosh

Consultant Medical Oncologist,

MVR Cancer Centre, Kozhikode

Perioperative immunotherapy in head and neck squamous cell carcinoma (HNSCC) has returned to center stage following the presentation of KEYNOTE-689. By integrating neoadjuvant and adjuvant pembrolizumab with definitive surgery and postoperative radiotherapy (± chemotherapy), the study signals a potential paradigm shift in curative-intent treatment.
However, as with many “practice-changing” developments in oncology, important questions remain.

Learning From Prior Negative Trials

Curative-intent immune checkpoint blockade (ICB) in HNSCC has previously yielded disappointing results:

• KEYNOTE-412 narrowly missed statistical significance for event-free survival when pembrolizumab was added concurrently to chemoradiotherapy (HR 0.83).
• JAVELIN HN100 demonstrated worse progression-free survival with avelumab plus CRT (HR 1.21), raising concerns about potential biological antagonism between ICB and intensive CRT, possibly related to lymphodepletion.
• IMvoke010, evaluating adjuvant atezolizumab after surgery and CRT, failed to improve outcomes, suggesting that delayed immune activation may miss the optimal window for antigen priming.

Against this backdrop, KEYNOTE-689’s perioperative sequencing appears biologically rational. Yet its apparent success may reflect trial design as much as therapeutic strategy.

Timing Is Everything - But Which Timing?

KEYNOTE-689 combined neoadjuvant immune priming with prolonged adjuvant pembrolizumab, making it difficult to determine which component drove benefit.

A central unanswered question persists:
Is the observed benefit due to early immune priming, postoperative consolidation, or cumulative exposure?

This distinction has practical implications. In resource-constrained settings, abbreviated perioperative dosing could be substantially more feasible than prolonged adjuvant therapy. Experience from lung cancer—where short-course neoadjuvant nivolumab has produced durable benefit—highlights the importance of defining the minimum effective exposure.

Methodological Considerations

Several aspects of trial design merit scrutiny:

• No crossover to immunotherapy was allowed in the control arm, despite established survival benefit of PD-1 blockade in recurrent/metastatic HNSCC. This may overestimate the perioperative advantage.
• Approximately 10% of control-arm patients did not receive assigned adjuvant therapy, yet were retained in intention-to-treat analyses. The absence of detailed reporting regarding progression, toxicity, or withdrawal introduces potential analytic bias.

Such considerations are critical when interpreting event-driven endpoints in curative-intent trials.

The HPV Question

HPV-positive oropharyngeal cancer represents a biologically distinct and prognostically favorable subset of HNSCC. Yet efficacy outcomes for this subgroup were not reported.
The underrepresentation and underreporting of HPV-associated disease remains a recurring limitation across perioperative and definitive-intent trials. Without stratified outcomes, risk-adapted and biology-driven treatment refinement remains constrained.

Where Is Quality of Life?

Perhaps most notably, health-related quality-of-life (HRQoL) data were not reported.
A triphasic approach—neoadjuvant immunotherapy, surgery, postoperative radiotherapy ± chemotherapy, and prolonged ICB—imposes significant physical and psychosocial burden. In a disease where speech, swallowing, and functional preservation define survivorship, patient-reported outcomes are essential to contextualize survival gains.

Measured Optimism

KEYNOTE-689 represents a meaningful advance in the evolution of perioperative immunotherapy for resectable HNSCC. Nevertheless, its findings must be interpreted in light of:

• Prior negative curative-intent ICB trials
• Unresolved questions regarding optimal sequencing and duration
• Incomplete subgroup reporting
• Absence of patient-reported outcomes

For now, cautious optimism—rather than immediate wholesale adoption—appears prudent. Peer-reviewed publication, longer follow-up, and clarity regarding how much immunotherapy is enough will determine whether KEYNOTE-689 reshapes standard care or remains a compelling proof of concept.