1093PD - Vemurafenib and cobimetinib potently inhibit pS6 signaling in BRAFV600 mutation-positive locally advanced or metastatic melanoma from BRIM7 study

Date 29 September 2014
Event ESMO 2014
Session Melanoma and other skin tumours
Topics Anti-Cancer Agents & Biologic Therapy
Melanoma and other Skin Tumours
Translational Research
Presenter Yibing Yan
Citation Annals of Oncology (2014) 25 (suppl_4): iv374-iv393. 10.1093/annonc/mdu344
Authors Y. Yan1, G.A. McArthur2, T. Gajewski3, I. Puzanov4, O. Hamid5, R. Gonzalez6, Y. Wang7, S. Lu7, M. Wongchenko7, N. Choong7, A. Ribas8
  • 1Oncology Biomarker Development, Genentech, 94080 - South San Francisco/US
  • 2Cancer Therapeutics, Peter MacCallum Cancer Centre, 3002 - East Melbourne/AU
  • 3Oncology, University of Chicago, Chicago/US
  • 4Division Of Hematology-oncology, Vanderbilt University Medical Center, 37232-6307 - Nashville/US
  • 5Melanoma Center, The Angeles Clinic and Research Institute, Los Angeles/US
  • 6Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora/US
  • 7Oncology Biomarker Development, Genentech, South San Francisco/US
  • 8Medical Oncology, David Geffen UCLA School of Mediciine, Los Angeles/US

 

Abstract

Aim

Combined BRAF and MEK inhibition, compared with BRAF inhibitor alone, may delay the onset of resistance. Vemurafenib + cobimetinib (vem + cobi) was evaluated in patients naive to or previously treated with BRAF inhibitor (BRAFi) in a phase Ib trial: BRIM7 (NCT01271803). Modulation of signaling pathways and transcriptional profiles were assessed in tumor samples.

Methods

Tumor tissues were collected at baseline, on-treatment at cycle 1 day 14 (C1D14), and at disease progression (PD). Modulation of cell-signaling pathways was assessed in tumor biopsy specimens by immunohistochemistry (IHC) or reverse-phase protein array (RPPA). Tumor transcriptional profiles were measured on a NanoString platform.

Results

pERK levels were inhibited an average of 86 ± 14% with vem + cobi in paired biopsy specimens (n = 7) at C1D14 compared with baseline, which coincided with enhanced down-regulation of ERK transcriptional targets, compared with vem alone (n = 20). Cytoplasmic pERK was inhibited by 92 ± 3% in BRAFi-naive patients and by 95 ± 3% in patients with PR/CR responses. The inhibition of S6 ribosomal protein phosphorylation (pS6) showed significant differences based on treatment response and prior treatment status. By IHC, pS6 levels were clearly reduced in BRAFi-naive patients (82 ± 8%) compared with patients whose disease progressed with BRAFi treatment (31 ± 22%) and similarly in PR/CR patients (88 ± 11%) vs PD/SD patients (33 ± 19%). These observations were verified in independent samples by RPPA: levels of pS6 (S235/236 and S240/244) and a pS6 downstream effector, p4EBP1 (T37/46), were significantly inhibited in the same patients. At PD, tumor pERK, pS6, and Ki67 inhibition were attenuated to different degrees in each patient, whereas transcriptional programs largely reverted to baseline profiles.

Conclusions

Vem + cobi treatment resulted in robust modulation of tumor cell signaling and transcriptional programs. In concordance with reports for single-agent BRAF or MEK inhibitor treatment, potent inhibition of pS6 was observed in BRAFi-naive patients and patients with PR/CR, which may contribute to the enhanced response to the vem + cobi combination.

Disclosure

Y. Yan: Employee of Genentech, Inc.; G. McArthur: Consultant: Roche-Genentech, Novartis, GSK, BMS, Millenium, Amgen Research: Pfizer, Millenium, Novartis; T. Gajewski: Consultant: Bayer, B-I, Abbvie, Roche/Genentech, Jounce, Dendreon, Amgen Investigator: BMS, Merck, Roche/Genentech, Incyte, Ono; I. Puzanov: Consultant: Roche (honoraria) Investigator: Roche/Genentech (funds to university); O. Hamid: Research/advisory board/consultant/speaker: Genentech; R. Gonzalez: Research/consultant/honoraria: GSK, Roche/Genentech, BMS; Y. Wang: Employee: Genentech; S. Lu: Employee: Genentech; M. Wongchenko: Employee: Genentech; N.W. Choong: Employee: Roche/Genentech Stockholder: Roche; A. Ribas: Consultant: Amgen, GSK, Genentech, Merck Stockholder: Kite Pharma.