Department of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands.
Maastricht University Medical Centre, Department of Clinical Pharmacy and Toxicology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, Netherlands.
Br J Cancer. 2020 Apr;122(8):1166-1174. doi: 10.1038/s41416-020-0776-z. Epub 2020 Mar 9.
Mutations in KRAS result in a constitutively activated MAPK pathway. In KRAS-mutant tumours existing treatment options, e.g. MEK inhibition, have limited efficacy due to resistance through feedback activation of epidermal growth factor receptors (HER).
In this Phase 1 study, the pan-HER inhibitor dacomitinib was combined with the MEK1/2 inhibitor PD-0325901 in patients with KRAS-mutant colorectal, pancreatic and non-small-cell lung cancer (NSCLC). Patients received escalating oral doses of once daily dacomitinib and twice daily PD-0325901 to determine the recommended Phase 2 dose (RP2D). (Clinicaltrials.gov: NCT02039336).
Eight out of 41 evaluable patients (27 colorectal cancer, 11 NSCLC and 3 pancreatic cancer) among 8 dose levels experienced dose-limiting toxicities. The RP2D with continuous dacomitinib dosing was 15 mg of dacomitinib plus 6 mg of PD-0325901 (21 days on/7 days off), but major toxicity, including rash (85%), diarrhoea (88%) and nausea (63%), precluded long-term treatment. Therefore, other intermittent schedules were explored, which only slightly improved toxicity. Tumour regression was seen in eight patients with the longest treatment duration (median 102 days) in NSCLC.
Although preliminary signs of antitumour activity in NSCLC were seen, we do not recommend further exploration of this combination in KRAS-mutant patients due to its negative safety profile.
KRAS 突变导致 MAPK 通路持续激活。在 KRAS 突变肿瘤中，现有的治疗选择，如 MEK 抑制，由于通过表皮生长因子受体（HER）的反馈激活而产生耐药性，疗效有限。
在这项 1 期研究中，pan-HER 抑制剂达克替尼与 MEK1/2 抑制剂 PD-0325901 联合用于治疗 KRAS 突变的结直肠癌、胰腺癌和非小细胞肺癌（NSCLC）患者。患者接受每日一次达克替尼和每日两次 PD-0325901 的递增口服剂量，以确定推荐的 2 期剂量（RP2D）。（Clinicaltrials.gov：NCT02039336）。
在 8 个剂量水平的 41 名可评估患者中（27 名结直肠癌，11 名 NSCLC 和 3 名胰腺癌）有 8 名患者出现剂量限制毒性。连续达克替尼给药的 RP2D 为 15mg 达克替尼加 6mg PD-0325901（21 天/7 天停药），但主要毒性包括皮疹（85%）、腹泻（88%）和恶心（63%），导致无法长期治疗。因此，探索了其他间歇性方案，但仅略微改善了毒性。在 NSCLC 中，最长治疗时间（中位数为 102 天）的 8 名患者中观察到肿瘤消退。
尽管在 NSCLC 中看到了初步的抗肿瘤活性迹象，但由于其不良安全状况，我们不建议在 KRAS 突变患者中进一步探索这种联合用药。
