Antitumor Activity of RXDX-105 in Multiple Cancer Types with RET Rearrangements or Mutations

Abstract

Purpose While multikinase inhibitors with RET activity are active in RET-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by RET alterations. Experimental design The RET-inhibitory activity of RXDX-105 was assessed by biochemical and cellular assays, followed by in vivo tumor growth inhibition studies in cell line– and patient-derived xenograft models. Antitumor activity in patients was assessed by imaging and Response Evaluation Criteria in Solid Tumors (RECIST). Results Biochemically, RXDX-105 inhibited wild-type RET, CCDC6-RET, NCOA4-RET, PRKAR1A-RET, and RET M918T with low to subnanomolar activity while sparing VEGFR2/KDR and VEGFR1/FLT. RXDX-105 treatment resulted in dose-dependent inhibition of proliferation of CCDC6-RET–rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in CCDC6-RET, NCOA4-RET, and KIF5B-RET–containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLCγ. Additionally, a patient with advanced RET-rearranged lung cancer had a rapid and sustained response to RXDX-105 in both intracranial and extracranial disease. Conclusions These data support the inclusion of patients bearing RET alterations in ongoing and future molecularly enriched clinical trials to explore RXDX-105 efficacy across a variety of tumor types.

Novel targeted therapeutics for MEN2

“…The compound was actually described as a poorly selective BRAF inhibitor, with potent off-target activity against RET and other kinases (James et al 2012). Recently, its anti-RET activity was characterized in more detail in vitro and in vivo (Li et al 2017). The same paper also reports a rapid PR in a NSCLC patient within the ongoing NCT01877811 trial.…”

The molecular basis for RET tyrosine-kinase inhibitors in thyroid cancer

“…RXDX-105 was modeled as a DFG-out (e.g. type II) RET inhibitor (Li et al 2016). Besides wild type RET, the compound also inhibited at low to subnanomolar concentrations CCDC6-RET, NCOA4-RET, PRKAR1ARET, and RET M918T with activity while sparing VEGFR2 and VEGFR1 in cell-based phsophorylation assays (James et al 2012; Li et al 2016).…”

“…Besides wild type RET, the compound also inhibited at low to subnanomolar concentrations CCDC6-RET, NCOA4-RET, PRKAR1ARET, and RET M918T with activity while sparing VEGFR2 and VEGFR1 in cell-based phsophorylation assays (James et al 2012; Li et al 2016). However, it displayed reduced activity (about 10 fold) against the gatekeeper mutations RET V804L and RET V804M (Li et al 2016). At nanomolar doses, RXDX-105 inhibited growth of CCDC6-RET positive lung adenocarcinoma LC-2/ad cells (IC 50 = 40 nM) and RET C634W positive medullary thyroid carcinoma TT cells (IC 50 = 11 nM).…”

“…Interestingly, at 30 mg/kg oral BID, the compound exerted significant tumor growth inhibition against two patient-derived (PDX) KIF5B-RET positive lung adenocarcinoma xenografts as well as two colorectal PDX harbouring either the CCDC6-RET or NCOA4-RET gene fusions (Li et al 2016). Importantly, one RET fusion positive lung adenocarcinoma patient enrolled in a phase Ib trial featured a 78% decrease in tumor burden from baseline when treated with 350 mg daily RXDX-105 (Li et al 2016). …”

Molecular Testing in Lung Cancer: Where to Draw the Line?

“…In the last few months, promising data have started to emerge about more specific and potent RET inhibitors, including RXDX-105 and LOXO-292. 7,8 Although there is certainly hope that these studies ultimately will yield drugs with high enough activity to warrant further development and FDA approval, currently a patient with a RET-translocated tumor likely is still better served up front getting chemotherapy/immunotherapy rather than one of the available ''dirty'' agents, and targeted therapy certainly is still more experimental than proven therapy.…”