Results of the PI3Kδ inhibitor ME-401 alone or with rituximab in relapsed/refractory (R/R) follicular lymphoma (FL).
Results of the PI3Kδ inhibitor ME-401 alone or with rituximab in relapsed/refractory (R/R) follicular lymphoma (FL).
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PI3Kδ 抑制剂 ME-401 单独使用或联合利妥昔单抗治疗复发/难治性 (R/R) 滤泡性淋巴瘤 (FL) 的结果。
DOI：
10.1200/jco.2019.37.15_suppl.7512
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发表时间：
2019
影响因子：
45.3
通讯作者：
J. Pagel
中科院分区：
文献类型：
--
作者：
A. Zelenetz;D. Jagadeesh;N. Reddy;A. Stathis;H. Salman;A. Asch;V. Kenkre;H. Jhangiani;A. Iasonos;J. Soumerai;Judith Llorin;J. Pagel
7512背景：ME-401是一种强效和选择性口服PI 3 k δ抑制剂，正在R/R B细胞恶性肿瘤患者（患者）中进行的Ib期研究（NCT 02914938）中进行评价。70例患者接受治疗;方法：ECOG ≤2、既往未接受过PI 3 K治疗且在接受过≥1次既往治疗后出现疾病进展（POD）的患者最初入选剂量递增期（60-180 mg），然后入选60 mg扩展队列，作为单药治疗或与利妥昔单抗联合治疗。ME-401最初按每日连续时间表（CS）给药，直至POD或不可接受的毒性。然后在2个周期（n = 18）或≥3个周期（n = 9）的CS治疗后评价28天周期第1-7天的间歇性方案（IS）。CS毒性通过转换为IS进行管理。IS上的POD由CS交换机管理。结果：48名FL患者接受ME-401单独治疗（n = 39）或与利妥昔单抗联合治疗（n = 9）。中位年龄64.5岁（范围38-81），中位既往治疗2次（范围1-10），30例既往治疗≥3次，25例为POD 24。28例患者仍在接受治疗，中位随访时间为9.3个月（范围0.5-22.5），20例患者停药：9例POD，4例不良事件（AE），4例撤回知情同意书，3例接受干细胞移植。迟发性（>第2周期）3级免疫相关AE（irAE），主要是腹泻/结肠炎和皮疹，CS组9/30例（30%）报告，2个周期后转为IS组2/18例（11%）报告，irAE在转换后15天和18天观察到。4名患有3级irAE的患者有药物假期，然后在IS上恢复皮质类固醇ME-401，没有AE复发。随访疾病评估的34/43例患者（79%）的客观缓解率：ME-401单药治疗79%（包括26%的形态学/代谢CR），ME-401+利妥昔单抗治疗78%，POD 24治疗91%，≥ 3线治疗75%。24/27例（89%）IS患者继续治疗，20例IS患者和4例因IS患者的POD而转为CS，3例患者在转为CS后因持续POD而停药。结论：ME-401在R/R FL中实现了高持久应答率。IS似乎降低了irAE的发生率并维持应答。IS上的POD可以通过恢复到CS来挽救。一项评价ME-401 IS或CS给药的随机化研究正在招募R/R FL患者，因irAE转换为IS，如果IS接受POD，则转换为CS。临床试验信息：NCT 02914938。[表：见正文]
7512 Background: ME-401, a potent and selective oral PI3kδ inhibitor, is being evaluated in a Phase 1b study in patients (pts) with R/R B-cell malignancies (NCT02914938). 70 pts were treated; we report here results in FL. Methods: Pts with ECOG ≤2, no prior PI3K therapy and progression of disease (POD) after ≥1 prior therapy were initially enrolled in a dose escalation phase (60-180 mg) then in 60 mg expansion cohorts as monotherapy or in combination with rituximab. ME-401 was given initially on a daily continuous schedule (CS) until POD or unacceptable toxicity. An intermittent schedule (IS) on days 1-7 of a 28-day cycle was then evaluated after 2 cycles (n = 18) or ≥3 cycles (n = 9) of CS. Toxicity on CS managed by switch to IS. POD on IS managed by switch to CS. Results: 48 FL pts received ME-401 alone (n = 39) or with rituximab (n = 9). Median age 64.5 yrs. (range 38-81), median prior therapies 2 (range 1-10), 30 had ≥3 prior therapies and 25 were POD24. 28 pts remain on therapy with median follow-up of 9.3 months (range 0.5-22.5) and 20 discontinued: 9 POD, 4 adverse events (AEs), 4 withdrew consent, and 3 for stem cell transplant. Delayed (> Cycle 2) grade 3 immune related AEs (irAEs), primarily diarrhea/colitis and rash, reported in 9/30 (30%) on CS and 2/18 (11%) switched to IS after 2 cycles, with irAEs noted 15 and 18 days after switch. 4 pts with grade 3 irAEs had a drug holiday and corticosteroids then resumed ME-401 on IS without AE recurrence. Objective responses in 34/43 pts (79%) with follow-up disease assessment: 79% with ME-401 alone (including 26% morphologic/metabolic CR), 78% with ME-401 plus rituximab, 91% in POD24, and 75% in ≥3rd line therapy. 24/27 (89%) IS pts continue therapy, 20 on IS and 4 who switched to CS due to POD on IS, and 3 pts discontinued due to persistent POD after switch to CS. Conclusions: ME-401 achieves a high rate of durable responses in R/R FL. IS appears to reduce the incidence of irAEs and maintains responses. POD on IS can be salvaged by reverting to CS. A randomized study to evaluate ME-401 given by IS or CS is enrolling pts with R/R FL, with switch to IS for irAEs and switch to CS if POD on IS. Clinical trial information: NCT02914938. [Table: see text]