The first antibody therapy for cancer: a personal experience.

More than 100 years ago, Paul Ehrlich proposed that antibodies could be used for therapeutic purposes. Little progress was achieved until Köhler and Milstein developed hybridoma technology in the 1970s. In 1997, rituximab, the first antibody for the treatment of cancer, was approved. Its development (laboratory and clinical) broke records, provided proof of concept for antibodies as anticancer agents and opened the floodgates for research in the area. Rituximab, in combination with cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone chemotherapy, was proven to increase the cure rate for patients with diffuse large cell lymphoma. Hopefully, over the next decades, we will find additional indications where antibodies in combination with other agents result in making patients cancer free, provide long-term survival and cures.

Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs?

PURPOSE: Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. METHODS: We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. RESULTS: Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. CONCLUSION: AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

The pharmacokinetics of rituximab following an intravitreal injection.

Rituximab is a monoclonal antibody directed against the CD20 B-cell antigen and is approved for the treatment of B-cell lymphoma. We investigated the pharmacokinetics of rituximab following intravitreal administration to assess the feasibility of treating primary intraocular lymphoma. Intravitreal injections of rituximab 0.1 ml (1 mg) were performed in rabbits. Drug concentrations in the aqueous and vitreous humor were measured at intervals from 2 to 17 days after administration. The half-life of the total amount of rituximab in the two compartments was calculated to be 4.7 days. The aqueous and vitreous humor drug levels decayed in parallel maintaining an average ratio of approximately seven. Fitting the data to a two-compartment model yielded a clearance from the aqueous humor of 1.2 microl/min. The clearance was less than the reported rate of aqueous humor outflow indicating that elimination by this route could have been sufficient to account for the disappearance of the drug from the eye. The duration of time over which sustained levels of rituximab were achieved suggest that intravitreal administration warrants further investigation as an approach to treating vitreous and anterior chamber infiltrates in patients with primary intraocular lymphoma.

90Y-ibritumomab tiuxetan: rationale for patient selection in the treatment of indolent non-Hodgkin's lymphoma.

Radioimmunotherapy with 90Y-ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, San Diego, CA, and Schering AG, Berlin, Germany) was approved in the United States in 2002 for patients with relapsed or refractory, low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma, including patients with rituximab-refractory disease, and in Europe in 2003. This agent has yielded good results in the treatment of patients with relapsed or refractory non-Hodgkin's lymphoma, for whom limited treatment options are available. Radioimmunotherapy with 90Y-ibritumomab tiuxetan is well tolerated and produces statistically and clinically significant higher overall and complete response rates than rituximab alone. Furthermore, treatment can be safely administered on an outpatient basis, with minimal disruption to patients' daily routines. The 90Y-ibritumomab tiuxetan treatment regimen, appropriate patient selection, and risk assessment are discussed in this article.

Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up.

PURPOSE: Long-term follow-up with updated time to disease progression (TTP) and duration of response (DR) data are presented from a multicenter, phase II trial of rituximab/cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) combination therapy in 40 patients with CD20+, B-cell, non-Hodgkin's lymphoma (NHL). Revised response rates based on International Workshop Response Criteria are also provided. PATIENTS AND METHODS: Enrollment began in April 1994 and consisted of patients with histologically confirmed, low-grade, B-cell lymphoma who had received no prior chemotherapy or who had no more than four prior standard therapies. Patients received six cycles of CHOP and six infusions of rituximab. RESULTS: Eight (21%) of the 38 treated patients were classified as International Working Formulation (IWF) A, 16 (42%) were IWF B, 13 (34%) were IWF C, and one (3%) was IWF D. Nine (24%) of 38 patients had received prior chemotherapy. Nine (24%) of 38 were considered poor risk according to the Follicular Lymphoma International Prognostic Index. Overall response rate was 100%; 87% of patients achieved a complete response or unconfirmed complete response. The median TTP and DR were 82.3 months and 83.5 months, respectively. Seven of eight patients who were bcl-2 positive at baseline converted to negative, and three of the seven patients have sustained the molecular remission. CONCLUSION: Although a cure has not been found yet for follicular NHL, the R-CHOP combination provides a lengthy response duration in patients with relapsed or newly diagnosed indolent NHL.

Rituximab (Rituxan/MabThera): the first decade (1993-2003).

The first antibody approved for the treatment of cancer, rituximab (Rituxan/MabThera), underwent clinical development between 1993 and 1996. It fulfilled predictions dating back to the early 1900s regarding the therapeutic effect of antibodies and sparked a renewed interest in this area of research. Rituximab was approved, in the USA in 1997 and in Europe in 1998, for the treatment of patients with non-Hodgkin's lymphoma. Since then, hundreds of thousands of patients have been treated with rituximab. In 2002, rituximab became the number one anticancer drug worldwide. During its first decade of use (1993-2003), rituximab has had an important impact on treatment strategies for lymphoma and other hematologic malignancies. During the 5 years following approval, its applications expanded beyond non-Hodgkin's lymphoma to a variety of malignant and non-malignant B-cell disorders. Also, as a result of its early clinical trials, initiatives came about that eventually led to the development of the new international response criteria for non-Hodgkin's lymphoma. Rituximab has been characterized as the most important therapeutic development of the decade.