A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer
Ryan J Sullivan1, Antoine Hollebecque2, Keith T Flaherty3
1Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
Abstract:
Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n = 15), nausea (n = 12), dermatitis acneiform (n = 10), decreased appetite (n = 7), and maculopapular rash (n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.
Insights
The phase I trial identified 300 mg twice daily as the recommended dose for LY3009120, a pan-RAF inhibitor. While safe, the drug showed limited efficacy and no observed pharmacodynamic effects in advanced cancer patients.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- ERK signaling pathway mutations are key drivers in many cancers.
- LY3009120 is a pan-RAF and dimer inhibitor with preclinical activity against RAS- and BRAF-mutated cell lines, including BRAF inhibitor-resistant melanoma.
- Targeting RAF-MEK-ERK pathway is a validated strategy in cancer therapy.
Purpose of the Study:
- To determine the recommended phase II dose (RP2D) of LY3009120.
- To evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of LY3009120 in patients with advanced/metastatic cancer.
- To explore potential pharmacodynamic biomarkers of LY3009120 activity.
Main Methods:
- A multicenter, open-label, phase I clinical trial (NCT02014116) with dose escalation (Part A) and dose confirmation (Part B).
- Oral LY3009120 was administered at doses ranging from 50 to 700 mg twice daily in Part A, and 300 mg twice daily in Part B.
- Safety, PK, and efficacy endpoints were assessed in 51 patients with advanced/metastatic cancer.
Main Results:
- The recommended phase II dose (RP2D) was established at 300 mg twice daily.
- Common drug-related adverse events included fatigue, nausea, and dermatitis acneiform.
- Eight patients achieved stable disease as best overall response; no complete or partial responses were observed.
- Plasma exposures at the RP2D exceeded preclinical levels associated with tumor regression, but predicted pharmacodynamic effects were not detected.
Conclusions:
- LY3009120 is generally well-tolerated at 300 mg twice daily, establishing it as the RP2D.
- Despite adequate drug exposure, LY3009120 demonstrated limited clinical efficacy and unconfirmed pharmacodynamic effects in this patient population.
- Further investigation may be needed to optimize targeting of the ERK pathway or identify patient subsets who could benefit.
