Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, Maryland, USA.
The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University, Baltimore, Maryland, USA.
J Immunother Cancer. 2020 Sep;8(2). doi: 10.1136/jitc-2020-001282.
We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab.
Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint.
While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor co-mutations.
Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.
我们首次开展了可切除非小细胞肺癌（NSCLC）的新辅助 PD-1 阻断治疗试验，发现纳武利尤单抗单药治疗具有安全性和可行性，且病理性缓解率令人鼓舞。在此结果基础上，以及纳武利尤单抗联合伊匹单抗（抗 CTLA-4）治疗晚期 NSCLC 的有前景数据，我们扩大了研究范围，纳入了新辅助纳武利尤单抗联合伊匹单抗治疗的研究臂。
纳入组织学确诊、未经治疗的可切除 IB 期（≥4cm）-III A 期（美国癌症联合委员会肿瘤淋巴结转移分期系统第七版）、治疗初治 NSCLC 患者，接受纳武利尤单抗 3mg/kg 静脉注射联合伊匹单抗 1mg/kg 静脉注射，每 6 周一次，在计划切除前 6 周进行。纳武利尤单抗 3mg/kg 于术前约 4 周和 2 周时再次给药。主要终点是安全性和可行性，计划入组 15 例患者。病理性缓解是关键次要终点。
尽管按照方案治疗方案是可行的，但由于毒性作用，在 15 例患者入组 9 例后，研究者一致决定提前终止该研究臂。所有患者均接受了每一次计划的治疗剂量，且适合进行计划手术；然而，6 例患者（67%）发生了治疗相关不良事件（TRAEs），3 例患者（33%）发生了≥3 级 TRAEs。3 例患者（33%）因活检证实肿瘤进展而无法进行确定性手术。在接受手术的 6 例患者中，3 例患者存活且无疾病，2 例患者复发且正在接受全身治疗，1 例患者术后因急性呼吸窘迫综合征死亡。2 例接受手术的患者有肿瘤完全病理缓解（pCR），自手术以来超过 24 个月仍无疾病。病理性缓解与治疗前肿瘤 PD-L1 表达相关，但与肿瘤突变负担无关。在 9 例患者中有 5 例（59%）发现肿瘤共突变，其中 2 例因肿瘤进展而无法手术的患者存在肿瘤共突变。
尽管治疗是可行的，但由于毒性作用，研究者一致决定提前终止该研究臂。鉴于此，虽然达到 pCR 的患者的长期无疾病生存状态令人鼓舞，但在可切除 NSCLC 患者中进一步探索新辅助纳武利尤单抗联合伊匹单抗仍需要确定可预测反应的生物标志物。
