Final analysis of the investigator-initiated randomized study of anti–PD-L1 durvalumab (durva) with radiation versus chemoradiation (CRT) for intermediate-risk HPV-positive (HPV+) locally advanced oropharyngeal squamous cell carcinoma (LA-OPSCC): Canadian Cancer Trials Group (CCTG) HN.9 (EORTC 1740-HNCG).

Abstract

6017 Background: Primary immunotherapy (IO) with radiotherapy remains an investigational approach in HPV+ LA-OPSCC. The CCTG-led international phase II, randomized, non-comparative, HN.9 (NCT03410615) trial evaluated the efficacy of the of durva+RT as a chemo-sparing approach in patients (pts) with intermediate-risk, HPV+, LA-OPSCC. Methods: Pts with newly diagnosed, PDL1-unselected, pathologically proven, treatment-naïve HPV+ LA-OPSCC (UICC/AJCC 8th Edition T1-2N1 or T3N0-1 smokers [≥10 pack years] or T1-3 N2 with any smoking history) eligible for definitive CRT were randomized (1:2) to Arm A (CRT: 70Gy/35F + cisplatin 100 mg/m2 Q3W on days 1,22,43 of RT) vs Arm B (durva IV 1500 mg, days -7, 22 of RT, followed by adjuvant durva for 6 doses). Primary objective was 3-year EFS in Arm B (efficacy if one-sided 90% CI lower bound [LB] >83%). Secondary objectives: QoL (MDADI, FACT-HN at baseline, end of RT, 3,6,12,24 and 36 mo), OS, safety, distant metastasis-free survival (DMFS) and locoregional control (LRC). Safety was assessed per CTCAE v5. The trial closed early based on emerging external efficacy data of IO in HN LA setting, enrolling 129 pts overall (80 of the planned 120 in Arm B) with approximately 80% power retained for the primary analysis. Results: 129 pts were randomized across 21 Canadian and European sites. Baseline characteristics were well balanced between arms. At the data cutoff (Sep 19, 2025), median follow-up time was 55.7 mo. In both arms, all pts received the planned RT schedule. In Arm A, the median number of cisplatin cycles was 2 (21% received <200m/m 2 and 79%≥ 200 mg/m 2 ). In arm B, all pts (100%) received durva concurrent to RT. 126 pts were eligible for efficacy analysis. The estimated 3-year EFS in Arm B was 80% (one-sided 90% CI: LB 73%); the prespecified efficacy criterion (LB >83%) was not met. The 3-year EFS in Arm A was 89%. The estimated 3-year OS rates were 92% in both arms. At 3 years, LRC were 97 and 91% in Arms A and B respectively. DMFS was 89% in Arm A and 86% in Arm B. Grade ≥ 3 adverse events any time during trial were similar between Arm B (69%) and Arm A (63%). QoL completion was 96% at baseline and 80%+ throughout; acute worsening during RT followed by gradual recovery (slower in arm B during adjuvant durva), with longer-term persistence of isolated issues (hearing loss, dry mouth) was similar to published experience for drug+RT regimens. Conclusions: Durva+RT did not improve 3-year EFS in the overall patient population of intermediate-risk HPV+ OPSCC. No new safety signal was observed. Specific toxicities varied by arm, but overall QoL experience, including swallowing, was similar between arms and with prior trials. Subgroup analysis, blood, tissue and microbiome-based correlates are ongoing. Clinical trial information: NCT03410615 .