A phase II randomized study of ramucirumab (IMC-1121B) with or without dacarbazine (DTIC) in patients (pts) with metastatic melanoma (MM).
Authors: R. D. Carvajal, M. K. Wong, J. A. Thompson, M. S. Gordon, K. D. Lewis, A. C. Pavlick, J. D. Wolchok, F. E. Fox, J. D. Schwartz, A. Y. Bedikian
Journal: Journal of Clinical Oncology (2010)

8519^ Background: Vascular endothelial growth factor (VEGF)-mediated angiogenesis contributes to MM pathogenesis. Ramucirumab is a recombinant human monoclonal antibody (MAb) that inhibits VEGF receptor-2 (VEGFR-2) binding and signaling. This study in chemotherapy- naïve pts investigates ramucirumab in combination with DTIC and as monotherapy. Methods: Eligible pts had stage IV disease of cutaneous origin, ECOG PS 0-1, and adequate hematologic, hepatic and renal function. Therapy (Rx) in Arm A was ramucirumab (10 mg/kg) + DTIC (1,000 mg/m2) and in Arm B was ramucirumab (10 mg/kg) every (q) 3 weeks (wk); tumor assessments were q6 wk. The primary endpoint is progression-free survival (PFS); other endpoints are safety, response, and pharmacokinetic (PK)/pharmacodynamic (PD) profiles. Results: 105 pts were randomized; 102 received study Rx. On Arm A (n = 52) median age was 63, 71% were male, ≥ 27% had elevated LDH. On Arm B (n = 50) median age was 62, 72% were male, ≥ 36% had elevated LDH. Preliminary median PFS was 2.5 months (m) on Arm A and 1.6 m on Arm B; 6 m PFS rates were 31% and 15%, and 12 m PFS rates were 23% and 15% on Arms A and B, respectively. There were 2 (4%) PR and 25 (48%) SD, and 2 (4%) PR and 19 (38%) SD on Arms A and B, respectively. Nonhematologic adverse events (AEs) considered at least possibly related to ramucirumab included fatigue (29%; 2% grade [G] ≥ 3), hypertension (HTN; 19%; 12% G ≥ 3), infusion related reactions (IRR; 8%; 0 G ≥ 3), proteinuria (PU; 8%; 4% G ≥ 3), headache (HA; 8%; 2% G ≥ 3) on Arm A; and fatigue (24%; 2% G ≥ 3), HTN (20%; 10% G ≥ 3), IRR (14%; 6% G ≥ 3), PU (8%; 2% G ≥ 3), HA (20%; 0 G ≥ 3) on Arm B. IRR incidence on both arms was reduced following a recommendation for premedication after 37 pts began Rx. Hematologic AEs were neutropenia (NP; 29%; 25% G ≥ 3), thrombocytopenia (TP; 31; 12% G ≥ 3), and anemia (A;12%; 4% G ≥ 3) on Arm A; and NP (0%), TP (8%; 2% G ≥ 3) and A (2%; 0 G ≥ 3) on Arm B. Cmin concentrations beyond Cycle 1 exceeded the target trough concentration associated with preclinical efficacy (20 mg/mL). Conclusions: Ramucirumab is well tolerated in MM. Ramucirumab/DTIC may be associated with improved 6m PFS relative to monoRx; long-term disease control was noted in each study arm. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Genomic Health, sanofi-aventis Amgen, Genomic Health, sanofi-aventis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.