A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105

Abstract

RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI, 30%-93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-KIF5B-RET-containing cancers. Novel approaches to targeting KIF5B-RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.This article is highlighted in the In This Issue feature, p. 305.

Figure 1.. Pharmacokinetics of RXDX-105.

The mean steady state plasma concentration profiles of RXDX-105 at escalating dose levels on day 15 of cycle 1 were plotted following once-daily continuous dosing. For the two fed cohorts, patients were instructed to take RXDX-105 with breakfast (which included solid food) or within 30 minutes after eating breakfast. Instructions regarding food were not provided (food-uncontrolled) for all other cohorts. The estimated target RET inhibition was based on RXDX-105-induced tumor growth inhibition in a RET fusion-containing xenograft mouse model. The estimated target VEGFR2 inhibition was estimated based on the in vitro IC₅₀ of RXDX-105 for VEGFR2 with correction for protein binding and tissue distribution. At the recommended phase 2 dose of 275 mg fed daily (red curve), plasma exposures exceeded RET target coverage, and a wide therapeutic window between calculated RET and VEGFR2 inhibition was observed.

Figure 2.. Antitumor activity of RXDX-105 in patients with RET fusion-positive lung cancers.

A waterfall plot of the best objective response to RXDX-105 in 27 evaluable patients with RET tyrosine kinase inhibitor-naïve RET fusion-positive non-small cell lung cancers is shown. Cases are grouped by upstream partner: KIF5B-RET, non-KIF5B-RET, and unknown (FISH-positive). Each bar represents the maximal percent change from baseline based on the sum of target lesions by RECIST version 1.1. A confirmed partial response, stable disease, and progressive disease are indicated by blue, orange, and red bars, respectively. The patient with a KIF5B-RET fusion-positive NSCLC who had a >50% reduction in target lesions had a best response of progressive disease due to the presence of new non-target lesions on follow-up imaging.

Figure 3.. Duration of RXDX-105 therapy in patients with RET fusion-positive lung cancers.

In this swimmer plot, each bar indicates the duration of RXDX-105 treatment. Arrows indicate patients who remained on treatment at the time of the data cut-off. Bars without arrows represent patients who had discontinued therapy. Black dots indicate the time at which radiologic progression occurred. A partial response, stable disease, progressive disease, and cases unevaluable for response are indicated by blue, orange, red, and gray bars, respectively. An asterisk indicates discontinuation secondary to toxicity. Cases are grouped by upstream partner: KIF5B-RET, non-KIF5B-RET, and unknown (FISH-positive).

Figure 4.. Differential activity of multikinase inhibition by upstream partner.

The activity of RXDX-105 in RET fusion-positive lung cancers is compared to that of other multikinase inhibitors. Data on the latter were derived from prospective trials of cabozantinib, vandetanib (results from two separate vandetanib trials are shown: 1 - a Japanese phase 2 trial, 2 - a South Korean phase 2 trial), and lenvatinib. Each column represents a single prospective trial showing the differential activity of each agent in tumors harboring KIF5B-RET (orange) versus non-KIF5B-RET (blue) fusions. The position of each bubble on the y-axis corresponds to the objective response rate (ORR). The size of each bubble represents the median progression-free survival (PFS), with larger bubbles indicating a longer median PFS. The value of the median PFS is also specified below each bubble when known. When the median PFS was not available or not reached, the size of each bubble was fixed; this corresponded to a median PFS of 3 months for reference. In general, the ORR and/or median PFS with RET-directed multikinase inhibition are numerically improved in tumors that contain non-KIF5B-RET fusions, recognizing that the latter represents a highly heterogenous group with a wide variety of upstream partners.