LBA28_PR - Phase IB Study of Vemurafenib in Combination with the MEK inhibitor, GDC-0973, in Patients (pts) with Unresectable or Metastatic BRAFV600 Mutated Me...

Date 29 September 2012
Event ESMO Congress 2012
Session Melanoma
Topics Anti-Cancer Agents & Biologic Therapy
Melanoma and other Skin Tumours
Presenter Rene Gonzalez
Authors R. Gonzalez1, A. Ribas2, A. Daud3, A. Pavlick4, T.F. Gajewski5, I. Puzanov6, M.S.L. Teng7, I. Chan7, N. Choong7, G.A. McArthur8
  • 1Medicine/ Medical Oncology, University of Colorado, Aurora/US
  • 2Oncology, The Jonsson Comprehensive Cancer Center, Los Angeles/US
  • 3Hematology/oncology Division, University of California, San Francisco/US
  • 4Hematology-oncology, New York University, New York/US
  • 5Department Of Pathology And Department Of Medicine, University of Chicago, Chicago/US
  • 6Division Of Hematology-oncology, Vanderbilt University Medical Center, 37232-6307 - Nashville/US
  • 7Oncology Dept, Genentech, South San Francisco/US
  • 8Oncology, Peter MacCallum Cancer Center, East Melbourne/AU

 

 

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.