No abstract

Purpose: To describe the Food and Drug Administration review and marketing approval considerations for panitumumab (Vectibix) for the third-line treatment of patients with epidermal growth factor receptor^expressing metastatic colorectal carcinoma. Experimental Design: Food and Drug Administration reviewed a single, open-label, multicenter trial in which 463 patients with epidermal growth factor receptor^expressing metastatic colorectal cancer who had progressed on or following treatment with a regimen containing a fluoropyrimidine, oxaliplatin, and irinotecan were randomized (1:1) to receive best supportive care (BSC) with or without panitumumab (6 mg/kg every other week) administered until disease progression or intolerable toxicity. Progression and response were confirmed by an independent review committee masked to treatment assignment. At progression, patients in the BSC-alone arm were eligible to receive panitumumab. Results: Although median progression-free survival (PFS) was similar in both treatment arms (f8 weeks), the mean PFS was f50% longer among patients receiving panitumumab than among those receiving BSC alone (96 versus 60 days, respectively) and the objective response rate in patients receiving panitumumab was 8%. However, no difference in overall survival was shown between the two study arms. Conclusions: Panitumumab received accelerated approval based on improvement in PFS and an independently confirmed response rate of 8%, similar to that observed with other active agents at this advanced stage of disease. Confirmation of clinical benefit will be required for full approval. 5 This accelerated approval was based on the surrogate end point of tumor response. The clinical benefit (i.e., improved PFS or OS) of cetuximab in a study of 572 patients who had failed both irinotecan-and oxaliplatin-based chemotherapy regimens randomized (1:1) to receive best supportive care (BSC) with or without cetuximab administered as an i.v. infusion of 400 mg/m 2 on the first dose and then 250 mg/m 2 . Patients randomized to receive cetuximab showed a statistically 5

OnNovember7,2011,theU.S.FoodandDrugAdministrationapproved cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer. Approval was based on a randomized study of 442 patients conducted outside the U.S. Cisplatin (100 mg/m 2 intravenously) or carboplatin (area under the curve 5 intravenously) on day 1 with 5-fluorouracil (1,000 mg/m 2 /day continuous intravenous infusion days 1-4) were administered every 3 weeks. Cetuximab, 400 mg/m 2 intravenously, was administered initially followed by cetuximab, 250 mg/m 2 intravenously weekly. After completion of six planned treatment courses, cetuximab patients without progression continued cetuximab 250 mg/m 2 weekly. The study used European Union (EU)-approved cetuximab rather than U.S.-approved cetuximab. U.S.-approved cetuximab provides approximately 28% higher exposure relative to EU-approved cetuximab in a pharmacokinetic comparability studyinmonkeys.Overallsurvival,theprimaryefficacyendpoint, was significantly improved in cetuximab-treated patients (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.64 -0.98; p ϭ .034, stratified log-rank test). Median survival times were 10.1 and 7.4 months, respectively. Progression-free survival (PFS) was also significantly improved in patients receiving cetuximab (HR: 0.57; 95% CI: 0.46 -0.72; p Ͻ .0001). Median PFS times were 5.5 and 3.3 months, respectively. Response rates were 35.6% and 19.5% (odds ratio: 2.33; 95% CI: 1.50 -3.60; p ϭ .0001). Adverse reactions (Ն25%) from cetuximab plus chemotherapy treatment included nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia. Conjunctivitis occurred in 10% of cetuximab patients. Other adverse reactions, sometimes severe, included infusion reactions, hypomagnesemia, hypocalcemia, and hypokalemia. The Oncologist 2013;18:460 -466 Implications for Practice: Cetuximab(Erbitux,Branchburg,NewJersey)incombinationwithcisplatinorcarboplatinand5-fluorouracil is shown to prolong survival of patients with recurrent locoregional or metastatic squamous cell head and neck cancer (SCCHN) compared with the same chemotherapy without cetuximab. Other benefits include increased progression-free survival and increased objective response rate. Toxicities observed with the combined treatment were consistent with the known toxicities of the individual drugs and were acceptable in relation to the survival benefit. Thus, there is now an additional treatment option for appropriate SCCHN patients. Learning ObjectivesCompare survival outcomes among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.Compare adverse event profiles among patients with SCCHN treated with a platinum/5 -FU regimen with and without cetuximab.Describe potential risk-benefit issues identified in the EU and US studies.

An increasing number of monoclonal antibodies for cancer diagnosis and treatment are in clinical use and in the development pipeline, with more expected as new molecular targets are identified. As with all drugs, product quality, an appropriate pre-clinical pharmacology-toxicology testing program, and well-designed clinical trials are essential for a successful drug development program. However, protein products such as monoclonal antibodies present unique regulatory concerns. The derivation from biological sources as well as the constantly evolving technologies utilized to develop these products demands continuous appraisal of safety concerns, even while the accumulated experience with these protein products has facilitated their safety evaluations. Because of the complex nature of these products and their inherent heterogeneity, a mechanistic understanding of the mode of action along with careful attention to product design and manufacture are critical to assuring a safe, effective and consistent product. Protein products may be highly species specific, thus pharmacologically relevant animal models are an important component in accurately assessing pre-clinical safety and establishing initial dosing. Furthermore, the immunogenicity of protein products can impact its safety profile, dose exposure, and efficacy. Mechanistic insight should form the basis of biological assays used for monitoring efficacy, safety, lot-to-lot consistency and manufacturing changes. The inherent uniqueness of each product necessitates a flexible case-by-case approach for biologics review that is based on a strong scientific understanding of relative risks. This review will provide an overview of approaches used in the development of antibody-based cancer therapeutics and the scientific basis of regulatory reviews.