Abstract C188: A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers
Authors: Wang Ding , Patel Manish , Fakih Marwan , Lockhart A. Craig , Olszanski Anthony J. , Patel Rupal , Brown Peter D. , Oliver Jennifer W. , Multani Pratik S. 
Published: May 2016

Background: RXDX-105 is a potent RET, BRAF and EGFR tyrosine kinase inhibitor (TKI) that exhibits high target affinity at low nanomolar concentrations. The RET proto-oncogene encodes a receptor tyrosine kinase for members of the glial cell line-derived neurotrophic factor (GDNF) family of extracellular signaling molecules. RET gain of function alterations are associated with the development of various types of human cancer, including non-small cell lung cancer (NSCLC). BRAF plays a key role in regulating the MEK/ERK signaling pathway, which affects cell division and differentiation. Acquired BRAF mutations can result in constitutive activation of this pathway, thereby fueling cancer growth. RXDX-105 is being developed as an oral therapy for patients with solid tumors that harbor RET or BRAF mutations or gene rearrangements.

Methods: Adult pts with advanced solid tumors were enrolled in a Ph 1 single agent dose escalation study with a standard 3 + 3 design to determine the recommended Ph 2 dose. Oral RXDX-105 was given as a fixed dose on a continuous daily schedule. Tumor response was assessed at baseline and every 8 wks (RECIST v1.1). Treatment-emergent adverse events (AEs) were recorded according to NCI CTC v4.03. Pharmacokinetic (PK) assessment was also a study objective.

Results: To date, 35 pts (17 M and 18 F) received RXDX-105 across 7 dose levels (20 to 275 mg QD). Median age was 60.5 years (range 27-81). The most frequent tumors (pts) were metastatic CRC (13), ovarian cancer (3), NSCLC (3), cholangiocarcinoma (3), and pancreatic cancer (3). Median number of cycles was 2 (range 1 to 23).

34 pts experienced AEs; 6 pts experienced treatment-related G3 AEs, including anemia, hypophosphatemia, fatigue, diarrhea, abdominal pain, rash and muscle weakness. 22 SAEs were reported from 9 pts, with none considered treatment-related. No treatment-related deaths occurred. The most common AEs were: fatigue (17 pts), vomiting (13 pts), abdominal pain (12 pts), nausea (11 pts), decreased appetite (10 pts), and rash (10 pts). At the time of this report, 3 pts have had DLTs; 1 pt at 200 mg with G2 hand and foot syndrome, 1 pt at 275 mg with G3 fatigue, and 1 pt at 275 mg with G3 asymptomatic hypophosphatemia. The protocol was amended to exclude hypophosphatemia as a DLT since it has been observed with approved TKIs and can be managed by supplementation.

The PK data to date have demonstrated that RXDX-105 is absorbed with a median Tmax between 2 and 6 hrs at steady state. RXDX-105 plasma concentrations declined slowly after reaching Cmax with an average terminal half-life of 28 to 42 hrs across dose levels. There was a loss of dose proportionality at doses above 150 mg, possibly due to pH-dependent drug dissolution in the stomach. The impact of the fed state on exposure is being explored.

11 pts have been on treatment for ≥ 12 weeks. No objective responses have been observed; however, 1 pt with BRAF V600E-positive papillary thyroid cancer, previously treated with RAI, EBRT and multiple surgical resections, has been on study with stable disease for almost 2 years (23 cycles). Additionally, 2 heavily pre-treated pts with squamous NSCLC achieved clinical benefit with SD for &gt; 6 months; 1 patient continues.

Conclusions: To date, treatment with RXDX-105 demonstrates an acceptable safety profile. Improvements in bioavailability are being investigated. Dose escalation continues.

Citation Format: Ding Wang, Manish Patel, Marwan Fakih, A. Craig Lockhart, Anthony J. Olszanski, Rupal Patel, Peter D. Brown, Jennifer W. Oliver, Pratik S. Multani. A phase 1 study of RXDX-105, an oral RET, BRAF and EGFR tyrosine kinase inhibitor, in patients with advanced or metastatic cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C188.