背景:Zandelisib是一种选择性的PI3Kδ抑制剂,每天一次(QD)口服60mg,持续2个周期(反应诱导),然后在随后的28天周期的第1-7天间歇给药(ID)进行维持,同时可能使调节性T细胞恢复降低持续PI3Kδ抑制所见免疫不良事件(irAE)的风险。在37例R/RFL患者的zandelisib的Ib期研究中,总有效率(ORR)为87%(78%单药;利妥昔单抗为95%),只有8%的停产是由于irAE(PagelICML2021)。
目标:来自TIDAL的完全注册FL人群的顶线结果,一项评估Zandelisib在R/R惰性淋巴瘤中的全球II期研究(NCT03768505)。
方法:年龄≥18岁,FLI-IIIA级,≥2次既往治疗后的进行性疾病,并且没有先前的PI3K抑制剂。需要同意。FL样本量(计划):120例患者。主要疗效人群(PEP):前91名患者接受治疗。
方法:Zandelisib60mgQD2个周期,其次是ID在周期3+。
方法:IRC评估的ORR(卢加诺标准)经过至少6个月的随访。
结果:91例PEPFL患者(共121例):中位数3种先前疗法(范围,2-8),21(23%)之前的干细胞移植,42(46%)最后一次治疗难治,31(34%)肿瘤≥5cm,51(56%)POD24。ORR为70.3%(64/91;95%CI:59.8%,79.5%),完全缓解(CR)率为35.2%(32/91;95%CI:25.4%,45.9%)。早期发生反应:87.5%(56/91)发生在周期2结束时,75%(24/91)的CR发生在周期4结束时。对于准确的反应持续时间(DOR)估计,数据仍然不成熟。中位随访9.4个月(范围,0.8-24)对于所有121名患者,12(9.9%)因任何治疗相关的AE而停药。特别关注的3级AE(AESI)包括腹泻(6/121;5%),结肠炎(2/121;1.7%),皮疹(4/121;3.3%),口腔炎(3/121;2.5%),AST和ALT升高和非感染性肺炎(各1/121;0.8%)。大多数3级AESI(15[83%])发生在每日给药期间(周期1-3)。
结论:Zandelisib关于ID导致严重预处理的FL患者的ORR和CR率高,并且与3级AESI的低发生率和由于治疗相关的AE而中断相关。
BACKGROUND: Zandelisib is a selective PI3Kδ inhibitor administered orally at 60 mg once daily (QD) for 2 cycles (response induction), then intermittent dosing (ID) on days 1-7 of subsequent 28-day cycles for maintenance, while potentially enabling regulatory T-cell recovery to reduce risk of immune adverse events (irAEs) seen with continuous PI3Kδ inhibition. In a phase Ib study of zandelisib in 37 R/R FL patients, the overall response rate (ORR) was 87% (78% single agent; 95% with rituximab), with only 8% discontinuations due to irAEs (Pagel ICML 2021).
OBJECTIVE: Topline results from the fully enrolled FL population from
TIDAL, a global phase II study evaluating zandelisib in R/R indolent lymphomas (NCT03768505).
METHODS: Age ≥18y with FL Grade I-IIIA, progressive disease after ≥2 prior therapies, and no prior PI3K inhibitor. Consent required. FL sample size (planned): 120 patients. Primary efficacy population (PEP): first 91 patients treated.
METHODS: Zandelisib 60 mg QD for 2 cycles, followed by ID during cycle 3+.
METHODS: IRC-assessed ORR (Lugano criteria) after a minimum 6-month follow-up.
RESULTS: 91 FL patients in PEP (of 121 enrolled): median 3 prior therapies (range, 2-8), 21 (23%) prior stem cell transplant, 42 (46%) refractory to last therapy, 31 (34%) tumors ≥5 cm, 51 (56%) POD24. ORR was 70.3% (64/91; 95% CI: 59.8%, 79.5%) and complete response (CR) rate was 35.2% (32/91; 95% CI: 25.4%, 45.9%). Responses occurred early: 87.5% (56/91) occurred at end of Cycle 2, 75% (24/91) of CRs at end of Cycle 4. Data still immature for accurate duration of response (DOR) estimation. With median follow-up of 9.4 months (range, 0.8-24) for all 121 patients, 12 (9.9%) discontinued due to any treatment-related AE. Grade 3 AEs of special interest (AESI) included diarrhea (6/121; 5%), colitis (2/121; 1.7%), rash (4/121; 3.3%), stomatitis (3/121; 2.5%), and AST and ALT elevation and non-infectious pneumonitis (1/121 each; 0.8%). Most Grade 3 AESIs (15 [83%]) occurred during daily dosing (cycles 1-3).
CONCLUSIONS: Zandelisib on ID led to high ORR and CR rates in heavily pretreated FL patients and was associated with a low rate of grade 3 AESI and discontinuations due to treatment-related AEs.