Neoadjuvant and Adjuvant Pembrolizumab (Pembro) Plus Standard of Care (SOC) in Resectable Locally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC): Postoperative Risk Subgroup Analysis of KEYNOTE-689

Abstract

Purpose/Objective(s)

The addition of neoadjuvant and adjuvant (starting concurrently with postoperative radiotherapy [PORT] ± cisplatin) pembro to SOC significantly improved event-free survival (EFS) vs SOC alone for participants (pts) with resectable LA HNSCC in the randomized phase 3 KEYNOTE-689 study (NCT03765918). We present a subgroup analysis by postoperative pathological features.

Materials/Methods

Pts had resectable SCC of the oral cavity/larynx/hypopharynx (stage III/IVA) or oropharynx (stage III/IVA p16− or stage III T4 N0-2 p16+) and were randomized 1:1 to pembro 200 mg Q3W (2 cycles neoadjuvant, 3 cycles adjuvant concurrent with PORT, 12 cycles beyond PORT) + SOC vs SOC (surgery + PORT [60 Gy in 30 fractions for low risk or 66 Gy in 33 fractions for high risk] ± 3 cycles cisplatin 100 mg/m² Q3W [high risk only]). Postoperative pathological features by blinded independent pathologist review were based on the presence (high risk) or absence (low risk) of positive margins (<1 mm) or extranodal extension. EFS by blinded independent central review with pembro + SOC vs SOC by risk subgroups was a prespecified exploratory analysis. Formal statistical testing was not planned. As of 25 July 2024, the median follow-up for all pts was 38.3 mo (range, 9.0–66.5).

Results

Among 363 pts randomized to pembro + SOC and 351 to SOC: 321 (88.4%) and 308 (87.7%) completed surgery; 118 (32.5%) and 156 (44.4%) had presence of high-risk features, and 196 (54.0%) and 148 (42.2%) did not. 274 pts in the pembro + SOC group and 275 in the SOC group received PORT, of whom 107 and 139 pts also received concurrent cisplatin (median 3 cycles in both groups). Median (range) total PORT dose was 60.0 Gy (2.0–70.0) in the pembro + SOC group and 66.0 Gy (6.0–72.0) in the SOC group. In the high-risk subgroup, median EFS was 41.1 vs 19.5 mo, respectively (HR 0.73, 95% CI 0.52–1.05). The 3-year EFS was 52.0% vs 40.7%. Grade ≥3 TRAEs occurred in 52.1% vs 53.9% of pts. Any-cause AEs led to discontinuation of PORT in 3 pts in the pembro + SOC group and 1 pt in the SOC group. In the low-risk subgroup, median EFS was not reached vs 51.5 mo (HR 0.74, 95% CI 0.51–1.08). The 3-year EFS was 67.7% vs 58.8%. Grade ≥3 TRAEs occurred in 42.9% vs 30.4% of pts. Any-cause AEs led to discontinuation of PORT in 4 pts in the pembro + SOC group and 3 pts in the SOC group.

Conclusion

Efficacy results for pts with either presence or absence of high-risk pathological features after surgery demonstrated downgrading of pathological features with the addition of neoadjuvant and adjuvant pembro to SOC, consistent with the primary analysis of KEYNOTE-689. In the pembro + SOC group, fewer pts had high-risk pathological features and more pts received a lower radiation dose and no cisplatin. The safety profile of pembro + PORT ± cisplatin was in line with expectations.