Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2023 Apr 14;29(8):1423-1428. doi: 10.1158/1078-0432.CCR-22-3484.
Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance.
We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation.
Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%-88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%-58%).
We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.
表皮生长因子受体（EGFR）突变型肺癌患者对奥希替尼的原发和获得性耐药仍然是重大挑战。获得性 EGFR 改变，如 EGFR T790M 或 C797S，介导对 EGFR 酪氨酸激酶抑制剂（TKI）的耐药性，而双重 EGFR TKI 联合治疗可能预防或逆转针对靶标的耐药性。
我们进行了两项前瞻性的 I/II 期试验，评估奥希替尼联合达可替尼治疗针对原发性和获得性耐药的针对靶标的耐药性。在初始治疗研究中，患者接受达可替尼联合奥希替尼作为初始治疗。在获得性耐药试验中，对单独使用奥希替尼进展且有获得性 EGFR 第二部位突变证据的 EGFR 突变型肺癌患者给予达可替尼联合或不联合奥希替尼。
93%（任何级别）的患者出现皮肤毒性，72%（任何级别）的患者出现腹泻。作为初始治疗，联合治疗的总体反应率为 73%[95%置信区间（CI），50%-88%]。在任何患者进展时均未观察到 EGFR 获得性二级改变。在获得性耐药环境中，总体反应率为 14%（95%CI，1%-58%）。
我们在针对 EGFR 的一线治疗中观察到双重 EGFR 抑制没有获得性二级 EGFR 改变，但该方案与更大的毒性相关。在出现第二部位获得性 EGFR 改变后，联合治疗对逆转获得性耐药无效。我们的研究强调需要制定更好的策略来解决 EGFR 突变型肺癌患者针对靶标的耐药性。
