The novel cancer agent, commercialized in Europe by Ortho Biotech, the biopharmaceutical division of Janssen-Cilag, was recently approved by the European Commission (26 April) to treat multiple myeloma patients who have received at least two prior therapies and demonstrated disease progression on their last therapy.
"These data show that not only can bortezomib induce important responses in this relapsed and refractory patient population, but it can also significantly extend survival", said Dr Paul Richardson, Clinical Director of the Jerome Lipper Myeloma Center at the Dana-Farber Institute, Boston, USA and lead Investigator of the study. "The benefit offered by bortezomib is especially encouraging in this patient population in whom resistance to treatment and shortened survival constitutes a major challenge."
Investigators designed an extension of the phase II SUMMIT trial (which included a total of 202 patients) allowing a subset of patients who had achieved a response to VELCADETM in the original trial (N=46) to continue treatment or receive retreatment with the drug. In addition they followed the progress of the 156 patients from the SUMMIT trial who were not receiving extended therapy.
The Results:
The study sought to determine the overall survival (OS), duration of response (DOR) and time to disease progression (TTP) in the patient group.
- The median overall survival for all treated patients was 17.2 months
- The median DOR for patients who achieved a complete or partial response to VELCADETM was 14.1 months
- For those patients who achieved a complete or partial response the TTP with VELCADETM was 15.3 months
VELCADETM well tolerated in the long-term
Patients in the SUMMIT extension study (which also sought to assess the safety profile of extended VELCADETM therapy) safely received a median of 45 weeks of therapy with one patient receiving nearly two years of therapy. The adverse events observed were very similar to those in phase II trials and no evidence of cumulative or permanent toxicity was reported with continued therapy. High does dexamethasone was part of therapy for 75% of patients during the parent and extension trial. Trial results also confirm that VELCADETM and dexamethasone can be safely combined.
"The survival benefit observed with VELCADETM in this study serves to further reinforce our belief in the far reaching potential of this agent in the treatment of this devastating cancer said, Dr. Jesús San Miguel, Professor of Hematology, University of Salamanca, Spain. "With many ongoing studies investigating the potential usage of VELCADETM in different stages of the disease we will continue to watch the impact of VELCADETM in myeloma patients with keen interest in the coming years".
Important findings from phase III APEX study:
These data further confirm findings from the phase III confirmatory APEX study (which compared VELCADETM (bortezomib) for injection to high-dose dexamethasone) recently presented at American Society of Clinical Oncology (ASCO) in New Orleans, USA. The trial was halted one year early after an independent data monitoring committee concluded the findings of a pre-specified interim analysis showed a statistically significant improvement in time-to-disease progression in favour of VELCADETM. The APEX trial enrolled 669 patients with relapsed or refractory multiple myeloma (patients had received one-to-three prior therapies) at 94 centers in Europe, North America , and Israel.
Results:
A statistically significant survival advantage (p<.01) in patients treated in the VELCADETM alone arm was observed. Importantly, statistical significance was maintained even though approximately 50 percent of patients crossed over to receive VELCADETM after experiencing progressive disease on the dexamethasone arm;
Multiple myeloma is the second most common blood cancer, representing approximately one percent of all cancers and two percent of all cancer deaths. Worldwide in 2000, there were 73,943 cases of multiple myeloma and 57,370 deaths(1). In Europe there were approximately 19,000 cases in 2000 and just under 15,000 deaths (1). Only 30 percent of multiple myeloma patients survive longer than five years (2).
VELCADETM is a completely new approach to treating multiple myeloma that acts on a unique target in cells called the proteasome.
VELCADETM has a generally predictable, manageable safety profile (with appropriate monitoring and if necessary, dose modification). VELCADETM is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. There are approximately 50 ongoing clinical trials (in Europe and the US) investigating the use of VELCADETM in all stages of multiple myeloma and other cancers.
Ortho Biotech, a Johnson & Johnson company has an agreement with Millennium Pharmaceuticals, to collaborate on the commercialization and continued clinical development of VELCADETM. Under the agreement, Ortho Biotech and Janssen-Cilag, will commercialize VELCADETM outside of the U.S., including Europe.
About VELCADETM® (bortezomib)
VELCADETM, the first of a new class of medicines called proteasome inhibitors, is the first treatment in more than a decade to be approved for patients with multiple myeloma -- a cancer of the blood. Millennium received approval from the U.S. Food and Drug Administration (FDA) on May 13, 2003 to market VELCADETM for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. The effectiveness of VELCADETM is based on response rates. There are no controlled trials demonstrating a clinical benefit such as an improvement in survival.
Dosing
The recommended starting dose of VELCADETM is 1.3mg/m2body surface area administered as a bolus intravenous injection twice weekly for two weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADETM.
SUMMIT Phase II
Clinical results from a phase II SUMMIT study have shown that VELCADETM can slow, reverse or halt progression of disease in patients who failed on two or more treatments, potentially helping patients live longer. In a study of 202 patients with relapsed and refractory multiple myeloma and who progressed after initial treatments, 35% responded to VELCADETM and 10% had a complete remission (3). This pivotal study was the basis for an accelerated review of VELCADETM by U.S. Food and Drug Administration (FDA) and approval within four months of the New Drug Application submission on 13 May 2003. VELCADETM was also approved by the European Commission on 26 April 2004, for the treatment of patients who have received prior lines of therapy and who are refractory to their last treatment.
About Janssen-Cilag/OrthoBiotech
Ortho Biotech, is the biopharmaceutical division of Janssen-Cilag. It also markets epoetin alfa, a recombinant human erythropoietin, as EPREX®/ERYPO® (epoetin alfa) in Europe. Epoetin alfa has been used for more than a decade to treat cancer-related anaemia in more than 300,000 patients in Europe.
About Millennium
Millennium Pharmaceuticals, Inc., a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADETM, a novel cancer product, co-promotes INTEGRILIN® (eptifibatide) Injection, a market-leading cardiovascular product, and has a robust clinical development pipeline of product candidates. The Company's research, development and commercialization activities are focused in three therapeutic areas: oncology, cardiovascular, and inflammation. By applying its knowledge of the human genome, its understanding of disease mechanisms, and its industrialized drug discovery platform, Millennium is seeking to develop breakthrough products.
References
1) International Agency for Research on Cancer, World Health Organisation; Ferlay J, Bray F, Pisani, P and Parkin DM. Globocan 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. IARC CancerBase No. 5, Lyon IARCPress, 2001; website: www-dep.iarc.fr/dataava/interp.htm
2) Brenner H. Long-term survival rates of cancer patients achieved by the end of the 20th century: a period analysis. Lancet 2002; 360:1131-1135
3) Richardson PG, Barlogie B, Berenson J, Singhal S et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. The New England Journal of Medicine 2003; 348:2609-2617.