Papadimitrakopoulou Vassiliki, Lee J Jack, Wistuba Ignacio I, Tsao Anne S, Fossella Frank V, Kalhor Neda, Gupta Sanjay, Byers Lauren Averett, Izzo Julie G, Gettinger Scott N, Goldberg Sarah B, Tang Ximing, Miller Vincent A, Skoulidis Ferdinandos, Gibbons Don L, Shen Li, Wei Caimiao, Diao Lixia, Peng S Andrew, Wang Jing, Tam Alda L, Coombes Kevin R, Koo Ja Seok, Mauro David J, Rubin Eric H, Heymach John V, Hong Waun Ki, Herbst Roy S
Vassiliki Papadimitrakopoulou, J. Jack Lee, Ignacio I. Wistuba, Anne S. Tsao, Frank V. Fossella, Neda Kalhor, Sanjay Gupta, Lauren Averett Byers, Julie G. Izzo, Ximing Tang, Ferdinandos Skoulidis, Don L. Gibbons, Li Shen, Caimiao Wei, Lixia Diao, S. Andrew Peng, Jing Wang, Alda L. Tam, John V. Heymach, and Waun Ki Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; Scott N. Gettinger, Sarah B. Goldberg, Ja Seok Koo, and Roy S. Herbst, Yale University, New Haven, CT; Vincent A. Miller, Foundation Medicine, Cambridge, MA; Kevin R. Coombes, Ohio State University College of Medicine, Columbus, OH; and David J. Mauro and Eric H. Rubin, Merck, North Wales, PA.
J Clin Oncol. 2016 Oct 20;34(30):3638-3647. doi: 10.1200/JCO.2015.66.0084.
By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers.
Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling-targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers.
Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02).
Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.
通过应用肺癌消除靶向治疗生物标志物整合方法（BATTLE）试验所确立的非小细胞肺癌（NSCLC）实时活检、基于生物标志物的适应性随机研究原则，我们开展了BATTLE-2（BATTLE-2项目：先前接受过治疗的晚期非小细胞肺癌患者的生物标志物整合靶向治疗研究），这是一项伞状研究，旨在评估针对KRAS突变癌症的靶向治疗效果。
对接受过一种以上先前治疗仍难治的晚期NSCLC患者（排除敏感的EGFR突变和ALK基因融合），按KRAS状态分层，随机分为四组：（1）厄洛替尼，（2）厄洛替尼加MK-2206，（3）MK-2206加AZD6244，或（4）索拉非尼。进行肿瘤基因表达谱靶向的下一代测序以评估预测性和预后生物标志物。
200例患者，27%患有KRAS突变（KRAS mut+）肿瘤，被适应性随机分配至厄洛替尼组（n = 22）、厄洛替尼加MK-2206组（n = 42）、MK-2206加AZD6244组（n = 75）或索拉非尼组（n = 61）。总共186例患者可评估，8周疾病控制率（DCR）这一主要终点为48%（第1组，32%；第2组，50%；第3组，53%；第4组，46%）。对于KRAS mut+患者，DCR分别为20%、25%、62%和44%，而对于KRAS野生型患者，第1、2、3和4组的DCR分别为36%、57%、49%和47%。无进展生存期的中位数为2.0个月，不受KRAS状态影响，KRAS mut+患者中第1组为1.8个月，第2组与第3组和第4组相比为2.5个月（P = 0.04）。总生存期的中位数为6.5个月，KRAS野生型患者中第1组和第2组与第3组和第4组相比分别为9.0个月和5.1个月（P = 0.03）。间充质肿瘤的总生存期中位数为7.5个月，而上皮性肿瘤为5个月（P = 0.02）。
尽管对于KRAS mut+患者，不含厄洛替尼的治疗方案改善了无进展生存期，且间充质肿瘤的预后有所改善，但仍需要更好的生物标志物驱动的治疗策略。
