Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer Discov. 2019 Mar;9(3):384-395. doi: 10.1158/2159-8290.CD-18-0839. Epub 2018 Nov 28.
fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner ( < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, = 0/20) with (the most common upstream partner for fusion-positive NSCLC), and 67% (95% CI, 30%-93%, = 6/9) with non- partners. The median duration of response in all fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although is the most common fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non--containing cancers. Novel approaches to targeting -containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed..
融合是包括非小细胞肺癌（NSCLC）在内的各种肿瘤的致癌驱动因素。在一项 I/ Ib 期试验中，研究了多激酶 RET 抑制剂 RXDX-105 的安全性和抗肿瘤活性。确定了每日口服 275mg 的推荐 II 期剂量。最常见的与治疗相关的不良事件是疲劳（25%）、腹泻（24%）、低磷血症（18%）、斑丘疹（18%）和非斑丘疹（17%）。在 RET 抑制剂初治的融合阳性 NSCLC 患者的 Ib 期队列中，客观缓解率（ORR）为 19%（95%CI，8%-38%， = 6/31）。有趣的是，ORR 因基因融合伙伴而异（<0.001，Fisher 精确检验）：0%（95%CI，0%-17%， = 0/20）与 （融合阳性 NSCLC 最常见的上游伙伴），67%（95%CI，30%-93%， = 6/9）与非伙伴。所有融合阳性 NSCLC 中反应的中位持续时间未达到（范围，5 至 18+个月）。意义：尽管 是 NSCLC 中最常见的融合，但 RXDX-105 的 RET 抑制仅在非- 包含的癌症中产生反应。需要针对包含 - 的肿瘤的新方法，同时需要更深入地了解导致观察到的差异化反应的生物学。
