Wednesday, June 14, 2017

ASCO 2017: ERK inhibitor - Ulixertinib (BVD-523) working in NRAS as well as BRAF V600 and non-V600 melanoma

Many "innovative" combinations that would make targeted therapy better have long been discussed, including: Hsp90,   HDAC,   PI3 kinase/AKT,   ERK, and   ERBb3 inhibitors and then some.  Data is more readily available on some than others.  Keeping the diagram posted yesterday in well as this one:

 Here is a report on Ulixertinib, an ERK inhibitor:

First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients with advanced solid tumors: Final results of a phase I dose escalation and expansion study.
ASCO 2017. J Clin Oncol 35, 2017. Li, Janku, Patel, ...Flaherty, ...Sznol, Sosman..., Ribas, ….Infante.

Backkground: Aberrant MAPK pathway activation is known to be an oncogenic driver in many solid tumors, making ERK inhibition an attractive therapeutic strategy. Ulixertinib is an oral ERK1/2 inhibitor that demonstrated potent activity in vitro and tumor regression in BRAF and RAS mutant xenograft models. Methods: This multi-center phase I trial enrolled patients (pts) with advanced solid tumors. Dose escalation utilized an accelerated 3+3 design; expansion cohorts included BRAF or NRAS mutant melanoma and other BRAF or MEK mutant cancers. Study objectives were to characterize dose limiting toxicities (DLTs), maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity by RECIST 1.1. Results: A total of 135 pts were enrolled. Dose escalation enrolled 27 pts (10-900 mg BID) and established the MTD and recommended phase 2 dose (RP2D) of 600 mg BID. DLTs included rash, diarrhea, elevated AST, and elevated creatinine. Drug exposure was dose proportional up to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108 pt expansion cohort, there were no drug related deaths; however, 32% of pts required a dose reduction. The most common adverse events were rash (49%), diarrhea (47%), fatigue (41%), and nausea (37%). In addition to 3 pts with partial responses during escalation (11%), an additional 9 of 83 (11%) evaluable pts at expansion had a partial response: 1 melanoma pt refractory to prior BRAFi/MEKi treatment, 3 NRAS mutant melanoma pts, 2 pts with BRAF V600E mutant lung cancers including response in brain metastases, 1 with BRAF V600E mutant glioblastoma multiforme, 1 with BRAF G469A head and neck cancer, and 1 with BRAFL485W gallbladder cancer. The duration of response ranged from 2 to 24+ months. Conclusions: Ulixertinib at 600 mg twice a day has an acceptable safety profile and has produced durable responses in pts with NRAS mutant melanoma, BRAF V600 and non-V600 mutant solid tumors including melanoma, glioblastoma multiforme, lung cancers with brain metastases, gallbladder and head and neck cancers. These data support further clinical development of ulixertinib. Clinical trial information: NCT01781429

Despite a lot of back and forth about cohorts and expansion best as I can tell, 108 patients with various sold tumors, took ulixertinib, 600 mg orally, twice daily.  Most common side effects were rash, diarrhea, fatigue and drug related deaths, though 32% required a drug reduction.  Of 83 evaluable patients, 9 had a partial response.  Three of these were NRAS mutant melanoma and 4 had tumors that were BRAF V600E mutant, but only one of those had melanoma and they had been refractory to prior BRAFi/MEKi treatment.  

So...incredibly small numbers period...especially in regard to gotta start somewhere!!!  Hang in there ratties. - c

No comments:

Post a Comment