Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA.
Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
ESMO Open. 2023 Aug;8(4):101584. doi: 10.1016/j.esmoop.2023.101584. Epub 2023 Jun 26.
Combinations of avelumab [anti-programmed death-ligand 1 (anti-PD-L1)] or talazoparib [poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor] with binimetinib (MEK inhibitor) were expected to result in additive or synergistic antitumor activity relative to each drug administered alone. Here, we report phase Ib results from JAVELIN PARP MEKi, which investigated avelumab or talazoparib combined with binimetinib in metastatic pancreatic ductal adenocarcinoma (mPDAC).
Patients with mPDAC that had progressed with prior treatment received avelumab 800 mg every 2 weeks plus binimetinib 45 mg or 30 mg two times daily (continuous), or talazoparib 0.75 mg daily plus binimetinib 45 mg or 30 mg two times daily (7 days on/7 days off). The primary endpoint was dose-limiting toxicity (DLT).
A total of 22 patients received avelumab plus binimetinib 45 mg (n = 12) or 30 mg (n = 10). Among DLT-evaluable patients, DLT occurred in five of 11 patients (45.5%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in three of 10 patients (30.0%) at the 30-mg dose. Among patients treated at the 45-mg dose, one (8.3%) had a best overall response of partial response. Thirteen patients received talazoparib plus binimetinib 45 mg (n = 6) or 30 mg (n = 7). Among DLT-evaluable patients, DLT occurred in two of five patients (40.0%) at the 45-mg dose, necessitating de-escalation to 30 mg; DLT occurred in two of six patients (33.3%) at the 30-mg dose. No objective responses were observed.
Combinations of avelumab or talazoparib plus binimetinib resulted in higher-than-expected DLT rates. However, most DLTs were single occurrences, and the overall safety profiles were generally consistent with those reported for the single agents.
ClinicalTrials.govNCT03637491; https://clinicaltrials.gov/ct2/show/NCT03637491.
avelumab[抗程序性死亡配体 1（anti-PD-L1）]或 talazoparib[多聚（腺苷二磷酸核糖）聚合酶（PARP）抑制剂]与 binimetinib（MEK 抑制剂）联合使用有望产生比单独使用每种药物更具加性或协同性的抗肿瘤活性。在此，我们报告了 JAVELIN PARP MEKi 的 Ib 期结果，该研究评估了转移性胰腺导管腺癌（mPDAC）中avelumab 或 talazoparib 联合 binimetinib 的疗效。
先前接受过治疗的 mPDAC 患者接受avelumab 800mg，每 2 周一次，加用 binimetinib 45mg 或每日两次 30mg（连续），或 talazoparib 0.75mg 每日一次，加用 binimetinib 45mg 或每日两次 30mg（7 天 ON/7 天 OFF）。主要终点是剂量限制毒性（DLT）。
共有 22 例患者接受了avelumab 加 binimetinib 45mg（n=12）或 30mg（n=10）治疗。在可评估 DLT 的患者中，45mg 剂量组的 11 例患者中有 5 例（45.5%）发生 DLT，需要降低剂量至 30mg；30mg 剂量组的 10 例患者中有 3 例（30.0%）发生 DLT。在接受 45mg 剂量的患者中，1 例（8.3%）患者的总体最佳反应为部分缓解。13 例患者接受 talazoparib 加 binimetinib 45mg（n=6）或 30mg（n=7）治疗。在可评估 DLT 的患者中，45mg 剂量组的 5 例患者中有 2 例（40.0%）发生 DLT，需要降低剂量至 30mg；30mg 剂量组的 6 例患者中有 2 例（33.3%）发生 DLT。未观察到客观缓解。
avelumab 或 talazoparib 加 binimetinib 的联合使用导致 DLT 发生率高于预期。然而，大多数 DLT 是单一事件，总体安全性与单一药物报告的安全性一致。
ClinicalTrials.govNCT03637491；https://clinicaltrials.gov/ct2/show/NCT03637491。
