Phase IB Study of Osimertinib in Combination with Navitoclax in EGFR-mutant NSCLC Following Resistance to Initial EGFR Therapy (ETCTN 9903).
Phase IB Study of Osimertinib in Combination with Navitoclax in EGFR-mutant NSCLC Following Resistance to Initial EGFR Therapy (ETCTN 9903).
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DOI：
10.1158/1078-0432.ccr-20-4084
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发表时间：
2021-03-15
期刊：
影响因子：
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通讯作者：
Oxnard GR
中科院分区：
文献类型：
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作者：
Bertino EM;Gentzler RD;Clifford S;Kolesar J;Muzikansky A;Haura EB;Piotrowska Z;Camidge DR;Stinchcombe TE;Hann C;Malhotra J;Villaruz LC;Paweletz CP;Lau CL;Sholl L;Takebe N;Moscow JA;Shapiro GI;Jänne PA;Oxnard GR
奥希替尼是EGFR突变型NSCLC的有效治疗方法，但耐药性总是会出现。Navitoclax是一种BCL-2/BCL-xL的口服抑制剂，在EGFR突变型NSCLC的临床前模型中与奥希替尼表现出协同作用。在恶性血液病中，BCL-2家族抑制剂联合治疗可有效增加细胞凋亡并降低耐药性。这项单臂IB期研究评价了奥希替尼和navitoclax的安全性、耐受性和可行性，包括在T790 M+患者中以推荐的II期剂量（RP 2D）进行剂量扩展。符合条件的患者患有既往TKI暴露的晚期EGFR突变型NSCLC。计划5个剂量水平（DL），奥希替尼40 - 80 mg PO每日一次，navitoclax 150 - 325 mg PO每日一次。共入组了27例患者（18例剂量递增，9例扩展）：中位年龄65岁，67%为女性，48%为外显子19 del和37%为L 858 R，中位既往接受过1线治疗。最常见的不良事件是淋巴细胞减少症（37%）、疲乏（22%）、恶心（22%）和血小板减少症（37%）。在剂量递增中未观察到DLT;选择奥希替尼80 mg、navitoclax 150 mg作为RP 2D。大多数患者（78%）在3个周期内接受了>95%的计划剂量。在扩展队列中，客观缓解率（ORR）为100%，中位无进展生存期（PFS）为16.8个月。通过早发性血小板减少症证明了navitoclax的促凋亡作用。在RP 2D下，navitoclax和奥希替尼口服联合治疗安全可行，具有临床疗效。早期血小板减少症很常见，支持navitoclax的靶向作用。需要进一步研究BCL-2/BCL-xL抑制以增强奥希替尼活性。
Osimertinib is an effective therapy in EGFR mutant NSCLC, but resistance invariably develops. Navitoclax is an oral inhibitor of BCL-2/BCL-xL that has exhibited synergy with osimertinib in preclinical models of EGFR-mutant NSCLC. In hematologic malignancies, BCL-2 family inhibitors in combination therapy effectively increase cellular apoptosis and decrease drug resistance. This single arm phase IB study evaluated safety, tolerability and feasibility of osimertinib and navitoclax, including dose expansion in T790M+ patients at the recommended phase 2 dose (RP2D). Eligible pts had advanced EGFR-mutant NSCLC with prior TKI exposure. Five dose levels (DL) were planned with osimertinib from 40 – 80 mg PO daily and navitoclax from 150 – 325 mg PO daily. A total of 27 pts were enrolled (18 dose escalation, 9 expansion): median age 65, 67% female, 48% exon 19 del and 37% L858R, median 1 prior line of therapy. The most common adverse events were lymphopenia (37%), fatigue (22%), nausea (22%), and thrombocytopenia (37%). No DLTs were seen in dose escalation; osimertinib 80 mg, navitoclax 150 mg was chosen as the RP2D. Most patients (78%) received >95% of planned doses through 3 cycles. In expansion cohort, objective response rate (ORR) was 100% and median progression-free survival (PFS) was 16.8 months. A pro-apoptotic effect from navitoclax was demonstrated by early-onset thrombocytopenia. Oral combination therapy with navitoclax and osimertinib was safe and feasible at RP2D with clinical efficacy. Early thrombocytopenia was common, supporting an target engagement by navitoclax. Further study of BCL-2/BCL-xL inhibition to enhance osimertinib activity is warranted.