背景：研究發現 R/M HNSCC 應用 PD-1/PD-L1 抑製劑療效明確，靶向免疫檢查點 CTLA-4 可能與放射治療有協同作用。本臨床試驗揭示局部晚期頭頸鱗癌(HNSCC)一線誘導治療（化療+PD-L1/CTLA-4 抑製劑的雙免治療）的可行性及後續的免疫放療（RIT）的有效性。
Background: Inhibition of the PD-1/PD-L1 pathway is efficient in recurrent/metastatic HNSCC. Targeting the immune checkpoint CTLA-4 may be synergistic to radiotherapy. This trial studies feasibility and efficacy of combined PD-L1/CTLA-4 blockade concomitant to induction chemotherapy and radiotherapy.
方法：入組患者為第八版 AJCC 分期 III-IVB 期、既往未接受過治療的 HNSCC 患者。治療方案為順鉑（30mg/m2，d1-3）+多西他賽（75mg/m2，d1）+Durvalumab（1500mg，d5）+Tremelimumab（75mg，d5）的單周期方案。再次活檢在 d22~d26 進行，瘤內 CD8+免疫細胞密度至少增加 20%或病理達完全緩解(pCR)的患者入組後續的放射免疫治療(RIT)，RIT 方案是放療劑量 70Gy+3 個周期的雙免（Durvulumab+Tremelimumab，q4w）+8 個周期的 durvulumab(q4w)治療。主要終點為入組 RIT 接受至少 6 個周期免疫藥物且在第 6 周期的可行率≥80%，即劑量限製性毒性 DLT≤20%（因 DLT 以外的其他原因停止治療的患者被排除在外）；若≤65%，則為可行性不可接受。次要終點是無進展生存期(PFS)和總生存期(OS)。
Methods: Patients with previously untreated stage III-IVB (AJCC 8th edition) HNSCC were eligible for this multicenter phase II trial. Treatment consisted of a single cycle of cisplatin 30mg/m² d1-3, docetaxel 75mg/m² d1, durvalumab 1500mg fix dose d5 and tremelimumab 75mg fix dose d5. Patients with at least 20% increase of intratumoral CD8+ immune cell density or pathological complete response (pCR) in the re-biopsy (performed on d22-26) entered radio-immunotherapy (RIT) up to a total dose of 70Gy. Patients received further three cycles of durvalumab/tremelimumab (q4w, two concomitant and one subsequent) followed by eight cycles of durvalumab mono (q4w). Primary endpoint was a feasibility rate of patients entering RIT to receive treatment until at least cycle 6 of immunotherapy of ≥80% (i.e. dose limiting toxicity/DLT ≤20%; exclusion of patients with other reasons than DLT for treatment discontinuation; feasibility unacceptable if ≤65%). The calculated sample size was 57 patients to enter RIT. Main secondary endpoints were progression-free survival (PFS) and overall survival (OS).
結果：2018 年 9 月~2020 年 5 月，共 80 例（1 例排除）入組。入組患者中位年齡 60 歲，33 例(42%)為吸煙者， 43 例(54%)為口咽部腫瘤(p16+占 53%)，44 例(56%)為 IV 期。中位隨訪 12.5 個月，誘導免疫化療後，41 例達 pCR， 31 例瘤內 CD8+免疫細胞增加。60 例入組 RIT，10 例接受 DLT 評估，4 例因其他原因停藥。RIT 隊列在第 6 周期的可行率為 82%，符合 80%的主要終點(95%CI，單側下限:72%)。RIT 隊列 1-y PFS 為 79%(CI 69-90%)，2-y PFS為 73%(CI 61-87%)，1-y OS 為 89%(CI 81-98%)，2-y OS 為 86%(CI 77-97%)。整個隊列研究 1-y PFS 為 75% (CI 65-85%)、2-y PFS 為 68%(CI 58-81%)、1-y OS 為 86% (CI 78-95%)和 2-y OS 為 80% (CI 70-91%)。95%（75 例）的患者發生≥3 級不良事件，主要包括吞咽困難(53%)、白細胞減少(48%)和感染(29%);DLT 主要包括肝炎(10%)。
Results: Between Sep 2018 and Mai 2020, 80 patients were enrolled (one excluded). Median age was 60 years, 33 patients (42%) were current smokers, 43 patients (54%) had oropharyngeal tumors (53% p16 positive), 44 patients (56%) were stage IV. Median follow up was 12.5 months. After induction chemo-immunotherapy 41 patients had pCR and 31 an intratumoral CD8+ immune cell increase. Of 60 patients entering RIT (primary endpoint cohort), 10 received DLT and 4 discontinued for other reasons. The feasibility rate of the RIT cohort until cycle 6 was 82%, meeting the primary endpoint of ≥80% (95% confidence interval (CI), one-sided (lower boundary): 72%). The RIT cohort had a PFS rate at 1 year of 79% (CI 69-90%) and at 2 years of 73% (CI 61-87%) and an OS rate at 1 year of 89% (CI 81-98%) and at 2 years of 86% (CI 77-97%). The entire study cohort had a PFS rate at 1 year of 75% (CI 65-85%) and at 2 years of 68% (CI 58-81%) and an OS rate at 1 year of 86% (CI 78-95%) and at 2 years of 80% (CI 70-91%). Toxicity (treatment-related or un-related) ≥grade 3 appeared in 75 patients (95%) and mainly consisted of dysphagia (53%), leucopenia (48%) and infections (29%). DLT mainly consisted of hepatitis (10%).
結論：該試驗符合主要終點的可行性。誘導治療後選擇 CD8+T 細胞增加的患者行無化療的 RIT 療法具有良好 PFS 獲益。
Conclusions: The trial met the primary endpoint feasibility. CD8+ T cell-based pathological patient selection after induction therapy identifies patients with promising PFS rates after chemotherapy-free RIT.
