Amol Akhade: KEYNOTE-689 – A Turning Point in Resectable HNSCC – Or a Cautious Step Forward?
Amol Akhade, Consultant Medical Oncologist at Suyog Cancer Clinics, shared a post on LinkedIn:
“KEYNOTE-689: A Turning Point in Resectable HNSCC — Or a Cautious Step Forward?
The NEJM publication of the phase 3 KEYNOTE-689 trial marks the first positive perioperative immunotherapy study in locally advanced, resectable head and neck squamous cell carcinoma (HNSCC).
Study Design
Patients received 2 cycles neoadjuvant + 15 cycles adjuvant pembrolizumab, alongside surgery and standard adjuvant RT/CRT, vs standard care alone.
Key Efficacy Results:
- Event-Free Survival (EFS) CPS ≥10: 59.8% vs 45.9% (HR 0.66, p=0.004) CPS ≥1: 58.2% vs 44.9% (HR 0.70, p=0.003) All patients: 57.6% vs 46.4% (HR 0.73, p=0.008)
- Pathologic response:
Major pathologic response (MPR): 9.4% Pathologic CR: 3.0%
Grade ≥3 TRAEs: 44.6% (vs 42.9%)
Immune-related AEs ≥Grade 3: 10.0% (vs 0.6%)
But the OS Story Is Not So Clear…
Although 3-year OS appears better in the pembrolizumab arm:
CPS ≥10: 68.2% vs 59.2% (HR 0.72, p=0.04) CPS ≥1: 69.0% vs 60.2% (HR 0.72)
All: 68.4% vs 61.1% (HR 0.76)
These results did not cross the interim alpha boundary — meaning OS benefit is not statistically significant at this time.
Crossover and Transparency Gaps
A major concern:
- Crossover to pembrolizumab was not allowed
- Post-progression treatment data not reported
In the post–KEYNOTE-048 era, access to PD-1 inhibitors is standard. Without knowing whether control arm patients received ICI at recurrence, we risk overinterpreting the OS signal.
Clinical trials in 2025 must disclose this critical context.
Subgroup Forest Plot Findings: Who Really Benefits?
KEYNOTE-689’s subgroup analysis revealed:
More benefit in:
- <65 years (HR 0.55) Male patients (HR ~0.60)
- Oral cavity primaries (HR 0.59)
- Former smokers (HR 0.51) PD-L1 CPS ≥10 tumors (across geographies)
Less clear benefit in:
- CPS <1 (small subgroup) Females and older adults (≥65 yrs) Hypopharyngeal tumors (wide CI, no signal)
These nuances matter when applying trial results to real-world practice.
Takeaways:
- KEYNOTE-689 sets the stage for immunotherapy in curative-intent HNSCC.
- But the trial has critical limitations: no crossover, OS immaturity, and lack of salvage therapy data.
- Subgroup data show heterogeneous benefit — not all patients may gain equally.”
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