Elsevier

Annals of Oncology

Volume 23, Supplement 9, September 2012, Page ixe19
Annals of Oncology

LBA28_PR - Phase IB Study of Vemurafenib in Combination with the Mek Inhibitor, GDC-0973, in Patients (PTS) with Unresectable or Metastatic BRAFV600 Mutated Melanoma (BRIM7)

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ABSTRACT

Background

Preclinical models show that combined inhibition of BRAF and MEK can delay the acquisition of resistance compared to BRAF inhibitor monotherapy. BRIM7 evaluated safety/tolerability of combined BRAF + MEK inhibition with vemurafenib (vem) + GDC-0973.

Methods

Eligible pts had BRAFV600-mutated unresectable or metastatic melanoma, and ECOG PS 0–1. Pts were either naïve to vem or had disease progression on vem. The study consisted of dose-escalation and expansion stages. Pts received vem 720 mg or 960 mg BID continuously. GDC-0973 was used at doses of 60 mg, 80 mg or 100 mg QD 14 days (d) on/14 d off (14/14); 21 d on/7 d off (21/7); or continuously. Primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety and PK.

Results

Of the 44 pts treated as of 17 April 2012, 72.7% are male, the median age is 55 y (range: 27–74), 77.3% are M1c and 68.2% had prior systemic therapy. The median no. of cycles to date is 3. One DLT (Grade 3 QT prolongation related to vem, leading to discontinuation of vem) was observed in the vem 960 mg BID + GDC-0973 60 mg QD 21/7 cohort (n = 6). Most common adverse events (AEs) for all pts regardless of attribution were diarrhoea (54.5%), rash (50.0%), nausea (38.6%), fatigue/asthenia (34.1%), liver function abnormality (25.0%) and photosensitivity/sunburn (25.0%). Most frequent treatment-related Grade ≥3 AEs were diarrhoea (6.8%), rash (6.8%), increased creatine phosphokinase (6.8%) and liver function abnormality (4.5%). Only 1 pt developed cutaneous squamous cell carcinoma. Dose reduction was required for vem in 1 pt, GDC-0973 in 2 pts and both drugs in 1 pt. Two dose levels: vem (720 mg & 960 mg BID) + GDC-0973 60 mg QD 21/7 were selected for expansion. Preliminary efficacy data in 8 evaluable vemurafenib-naïve pts showed that all 8 pts had tumour reduction. Updated efficacy/safety will be reported.

Conclusions

GDC-0973 in combination with vem was tolerable and AEs were manageable. The combination can be delivered safely at the respective single-agent MTDs of vem (960 mg BID) and GDC-0973 (60 mg 21/7). Plans are underway for phase 3 testing of vem + GDC-0973.

Disclosure

R. Gonzalez: Roche/Genentech consulting, advisory boards and also corporate sponsored research for Roche/Genentech

A. Ribas: A compensated consultant for Roche-Genentech.

A. Daud: I have research funding from Roche and Genentech. No honoraria or advisory boards in the last year.

A. Pavlick: I have participated in Genentech advisory boards and been part of the speakers bureau for Genentech.

T.F. Gajewski: I participated in a Roche advisory board last year.

I. Puzanov: Advisory board, speaker at the Zelboraf World Wide launch conference.

M.S.L. Teng: I am a full time employee of Genentech.

I. Chan: I am a full time employee of Genentech.

N.W. Choong: I am a full time employee of Genentech.

G. McArthur: Research support Pfizer, Novartis & Millennium

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