Abstract：
BACKGROUND: MET tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with nonsmall cell lung cancer (NSCLC) harboring a MET alteration, including MET exon 14 (METex14) skipping mutation, MET amplification, or MET fusion. However, primary or acquired resistance to TKI therapy ultimately develops. In preclinical models, hyperactivation of MAPK signaling was shown to promote resistance to MET TKI; resistance was overcome by co-treatment with a MET inhibitor and a MEK inhibitor. This phase I/Ib study offers a potential combination strategy simultaneously targeting MET (with capmatinib) and MEK signaling (with trametinib) to overcome resistance to MET inhibitor monotherapy in METex14 NSCLC.
METHODS: In the dose escalation phase, a minimum of 6 and maximum of 18 patients will be enrolled using a conventional 3+3 design with the primary endpoint of identifying a recommended phase 2 dose (RP2D) of capmatinib in combination with trametinib. Once the RP2D is identified, patients will continue to enroll in a dose expansion phase to a total of 15 patients. The primary endpoint of the dose expansion phase is to further characterize the safety profile of the combination.
CONCLUSIONS: This phase I/Ib clinical trial will assess the safety and efficacy of combination capmatinib and trametinib in NSCLC patients whose tumors harbor METex14 skipping mutations, MET amplification, or MET fusion and had developed progressive disease on single agent MET inhibitor therapy.
METHODS: In the dose escalation phase, a minimum of 6 and maximum of 18 patients will be enrolled using a conventional 3+3 design with the primary endpoint of identifying a recommended phase 2 dose (RP2D) of capmatinib in combination with trametinib. Once the RP2D is identified, patients will continue to enroll in a dose expansion phase to a total of 15 patients. The primary endpoint of the dose expansion phase is to further characterize the safety profile of the combination.
CONCLUSIONS: This phase I/Ib clinical trial will assess the safety and efficacy of combination capmatinib and trametinib in NSCLC patients whose tumors harbor METex14 skipping mutations, MET amplification, or MET fusion and had developed progressive disease on single agent MET inhibitor therapy.
摘要：
背景：MET酪氨酸激酶抑制剂（TKI）治疗与MET改变的非小细胞肺癌（NSCLC）患者预后改善相关，包括MET外显子14（METex14）跳跃突变，MET扩增,或MET融合。然而,对TKI治疗的原发性或获得性耐药性最终发展。在临床前模型中，MAPK信号的过度激活被证明可以促进对METTKI的抵抗;通过与MET抑制剂和MEK抑制剂共同治疗克服了抵抗.这项I/Ib期研究提供了一种同时靶向MET（与卡马替尼）和MEK信号（与曲美替尼）的潜在组合策略，以克服METex14NSCLC对MET抑制剂单一疗法的耐药性。
方法：在剂量递增阶段，采用常规3+3设计,纳入最少6例,最多18例患者,主要终点为确定卡马替尼联合曲美替尼的推荐2期剂量(RP2D).一旦RP2D被识别,患者将继续纳入剂量扩大阶段,共15名患者.剂量扩展阶段的主要终点是进一步表征组合的安全性。
结论：本I/Ib期临床试验将评估卡马替尼和曲美替尼联合治疗肿瘤携带METex14跳跃突变的NSCLC患者的安全性和有效性，MET扩增,或MET融合，并在单药MET抑制剂治疗中发展为进行性疾病。
方法：在剂量递增阶段，采用常规3+3设计,纳入最少6例,最多18例患者,主要终点为确定卡马替尼联合曲美替尼的推荐2期剂量(RP2D).一旦RP2D被识别,患者将继续纳入剂量扩大阶段,共15名患者.剂量扩展阶段的主要终点是进一步表征组合的安全性。
结论：本I/Ib期临床试验将评估卡马替尼和曲美替尼联合治疗肿瘤携带METex14跳跃突变的NSCLC患者的安全性和有效性，MET扩增,或MET融合，并在单药MET抑制剂治疗中发展为进行性疾病。
