444O - Phase Ib trial trial of RG7116, a glycoengineered monoclonal antibody targeting HER3, in combination with cetuximab or erlotinib in patients with a...

Date 27 September 2014
Event ESMO 2014
Session Developmental therapeutics
Topics Drug Development
Translational Research
Presenter Ulrik N. Lassen
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors U.N. Lassen1, A. Cervantes Ruiperez2, T. Fleitas2, D. Meulendijks3, J. Schellens4, M. Lolkemar5, M. de Jonge6, S. Sleijfer6, M. Mau-Soerensen1, A. Taus7, C. Adessi8, A. Keelara8, F. Michielin8, B. Bossenmaier9, G. Meneses-Lorente10, I. James9, W. Jacob9, M. Weisser9, M. Martinez-Garcia7
  • 1Department Of Oncology, Rigshospitalet, Copenhagen University Hospital, DK-2100 - Copenhagen/DK
  • 2Department Of Haematology And Medical Oncology, Institute of Health Research INCLIVA, University of Valencia, 46010 - Valencia/ES
  • 3Departemtn Of Clinical Pharmacology, Division Of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, 1066 CX - Amsterdam/NL
  • 4Department Of Clinical Pharmacology, Division Of Medical Oncology, The Netherlands Cancer Institute Amsterdam, 1066 CX - Amsterdam/NL
  • 5Department Of Medical Oncology, University Medical Center Utrecht, 3584 - Utrecht/NL
  • 6Department Of Medical Oncology, Erasmus MC Cancer Institue and Cancer Genomics Netherlands, Rotterdam, 3075 EA - Rotterdam/NL
  • 7Department Of Medical Oncology, Hospital del Mar, 08003 - Barcelona/ES
  • 8Pharma Research And Early Development, Roche, 4070 - Basel/CH
  • 9Pharma Research And Early Development, Roche, 82377 - Penzberg/DE
  • 10Pharma Research And Early Development, Roche, AL71TW - Welwyn/GB

Abstract

Aim

To evaluate the safety profile of RG7116 in combination with cetuximab or erlotinib.

Methods

Patients (pts) with advanced or metastatic carcinomas with centrally confirmed HER3 protein expression were included. RG7116 plus cetuximab (400 mg/m2 followed by 250 mg/m2 qw IV) and RG7116 plus erlotinib (150 mg/day p.o.) combinations were evaluated in a dose escalation study with “3 + 3” design at a starting dose of 400 mg IV of RG7116 in a q2w regimen.

Results

Twenty-seven pts were enrolled in 5 cohorts (400 to 2000 mg) in the cetuximab arm. One dose-limiting toxicity (DLT) of grade 3 dehydration was reported in the 800-mg cohort. Twenty-seven pts were enrolled in 4 cohorts (400 to 2000 mg) in the erlotinib arm. One DLT was reported in the 1600-mg cohort (grade 3 diarrhea and grade 3 hypokalemia) and one DLT was reported in the 2000-mg cohort (grade 3 blood bilirubin increase). No maximum tolerated dose was reached. The most frequently reported adverse events of any grade were diarrhea (78%) and rash (59%) for the cetuximab arm and diarrhea (82%) and decreased appetite (48%) for the erlotinib arm. In the erlotinib arm treatment-related grade 3 diarrhea was observed more frequently at higher doses of RG7116 (400 mg: 0%; 800 mg: 17%; 1600 mg: 43%; 2000 mg: 33%). Overall, infusion-related reactions related to RG7116 occurred in 11% of pts. Two of these were grade 3 (4%). The pharmacokinetic profile of RG7116 in combination with cetuximab and erlotinib was comparable to that in the monotherapy setting (Meulendijks et al. J Clin Oncol 31, 2013 suppl; abstr 2522). HER3 membranous protein down-regulation was observed from 400 mg onwards in on-treatment tumor and skin tissue. In the cetuximab arm, two pts with colorectal carcinoma had a confirmed partial response (PR). In the erlotinib arm, one patient with ovarian carcinoma had a confirmed PR. Metabolic PR on FDG-PET occurred in 42% of pts in the cetuximab arm and in 28% of pts in the erlotinib arm.

Conclusions

RG7116 combination with cetuximab or erlotinib was well tolerated, and demonstrated preliminary signs of clinical activity.

Disclosure

U.N. Lassen: discloses Research grants from Roche; A. Cervantes Ruiperez: discloses Research grants, advisory boards and lectures for Roche; C. Adessi, A. Keelara, F. Michielin, B. Bossenmaier, G. Meneses-Lorente, I. James, W. Jacob and M. Weisser: Employee of Roche. All other authors have declared no conflicts of interest.