Naporafenib in Combination With Rineterkib or Tremetinib for KRAS- or BRAF-Mutant Non-Small Cell Lung Cancer

According to a first-in-human phase 1b study, naporafenib in combination with rineterkib among patients with KRAS-/BRAF-mutant non-small cell lung cancer (NSCLC), and naporafenib in combination with trametinib among patients with KRAS-/BRAF-mutant NSCLC and melanoma, both demonstrated acceptable safety profiles. Naporafenib is a pan-RAF tyrosine kinase inhibitor (TKI). Rineterkib is an ERK1/2 inhibitor and trametinib is a MEK1/2 inhibitor.

In this first-in-human phase 1b study, there were 216 patients treated with either a combination of naporafenib (50 mg to 350 mg daily or 300 to 600 twice daily) and rineterkib (100 to 300 mg daily) or naporafenib (200 mg or 400 mg twice daily) and trametinib (0.5 mg or 1 mg daily, or 1 mg daily for 2 weeks on and 2 weeks off). Patients enrolled for the naporafenib-rineterkib combination had KRAS-/BRAF-mutant NSCLC (n = 101) and those enrolled for naporafenib-trametinib had KRAS-/BRAF-mutant and NRAS-mutant melanoma (NSCLC, n = 79; melanoma, n = 36). The primary objective was identification of the recommended dose for expansion (RDE), as well as safety and tolerability. Secondary objectives included antitumor activity.

A total of 10 out of 62 patients experienced dose-limiting toxicities. The RDE for naporafenib-rineterkib was found to be 400 mg twice daily of naporafenib and 200 mg daily of rineterkib. The RDE for naporafenib-trametinib was found to be 200 mg twice daily of naporafenib plus 1 mg daily of trametinib, and 400 mg naporafenib twice daily plus 0.5 mg trametinib daily.

The most common grade ≥3 treatment-related adverse event was increased lipase for naporafenib-rineterkib and rash for naporafenib-trametinib. Among patients with NSCLC, there were 3 patients with a partial response treated with naporafenib-rineterkib and 2 patients with a partial response treated with naporafenib-trametinib. The on-treatment median reduction of DUSP6 mRNA levels from baseline was 45.5% for naporafenib-rineterkib and 76.1% for naporafenib-trametinib.

Study authors concluded that “both naporafenib combinations had acceptable toxicity profiles” and that “antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect.”

Source:

Planchard D, Wolf J, Solomon B, et al. A phase 1b study of the combination of naporafenib with rineterkib or trametinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer. Lung Cancer. Published online September 27, 2024. doi: 10.1016/j.lungcan.2024.107964