Camptosar in combination with targeted therapies shows survival benefit

06/06/04

Data presented today at the annual meeting of the American Society of Clinical Oncology (ASCO) showed that first-line therapy with a combination of CAMPTOSAR (irinotecan HCL injection) plus bolus 5-flouruocil/leucovrin (5-FU/LV) (IFL) and Avastin (bevacizumab) prolongs survival in patients with metastatic colorectal cancer (MCRC) when compared with a standard first-line MCRC therapy. In a separate report, data from a trial of combination therapy of Erbitux (cetuximab) and CAMPTOSAR plus infusional 5-FU/LV (FOLFIRI) showed the combination to be generally safe and well-tolerated, and active as a first-line MCRC treatment.

"The body of scientific evidence demonstrating the safety and efficacy of CAMPTOSAR combinations with select targeted agents continues to grow," said Paulo Hoff, MD, associate professor in the Department of Gastrointestinal Medical Oncology at the University of Texas, M. D. Anderson Cancer Center in Houston. "The survival advantage of CAMPTOSAR combinations in the treatment of MCRC seems to be further improved when coupled with these promising targeted therapies, making CAMPTOSAR-containing regimens one of the preferred choices for treatment and an excellent candidate for further clinical research."

Data from patients enrolled in a Phase III trial that compared the survival impact of IFL plus Avastin therapy with IFL plus placebo therapy in the first-line treatment of MCRC, who continued to be monitored throughout post-progression therapy (PPT), showed that patients who received first-line treatment with Avastin and IFL, followed by second-line treatment with an oxaliplatin-containing regimen, lived an average of 25.1 months compared with patients who received first-line IFL plus placebo therapy and second-line treatment with a non-oxaliplatin regimen who lived an average of 15.8 months. In separate subgroup analysis, researchers found the first-line survival benefit observed with IFL plus Avastin therapy was present among all pre-defined subgroups with the largest increases in survival noted among patients with rectal cancer and among male subjects.

"It appears from the post-progression analysis that the sequencing of therapeutic regimens may play an important role in further extending survival in advanced colorectal cancer patients," said S. Hariharan, MD, Medical Director at Pfizer Oncology. "The survival data showing an average survival of 25.1 months is the highest we have seen with any sequence of first- and second-line therapies in MCRC."

In another first-line therapy study, preliminary results from a Phase II trial of combination therapy with Erbitux plus CAMPTOSAR and infusional 5-FU/LV (FOLFIRI) in the treatment of EGFR-expressing MCRC indicate the combination is effective, with 10 patients (46%) achieving partial response and 9 patients (41%) achieving stable disease. Safety analysis from additional patients (enrolled later) show the regimen to be well-tolerated.

"CAMPTOSAR is currently being studied in more combinations with targeted therapies than any other chemotherapy agent, added Dr. Hariharan. "With the proven survival advantage of CAMPTOSAR at their core, these new combinations have already increased survival for patients with advanced colorectal cancer beyond what was thought possible only a few years ago and with continued research may one day transform advanced cancers from deadly killers to manageable diseases."

About the Avastin + IFL Trial (#3517)

The randomized Phase III trial (AVF2107) evaluated the safety and efficacy of a combination regimen of Avastin plus CAMPTOSAR and 5-FU/leucovorin (using the bolus IFL regimen) as a first-line treatment for patients with MCRC compared with IFL plus placebo. Interim results from this study were used to support the recent FDA approval of Avastin for use in the first-line treatment of MCRC after demonstrating that the combination provides significant improvement in survival (20.34 months) compared with IFL alone (15.61 months) (p=0.00004).

Patients from the trial also were monitored for survival based on their first-line therapy (IFL + Avastin or IFL + placebo) and whether they received second-line therapy with a regimen containing oxaliplatin.

815 patients were enrolled in two treatment arms for first-line treatment (IFL/Avastin or IFL/placebo). Following disease progression, patients who continued on in the study were divided based on their first-line therapy (IFL + Avastin or IFL + placebo) and their second-line therapy (oxaliplatin, no-oxaliplatin) resulting 4 groups: IFL + placebo and non-oxaliplatin group (122 patients); IFL + placebo and oxaliplatin group (109 patients); IFL + Avastin and non-oxaliplatin group (125 patients); IFL + Avastin and oxaliplatin group (97 patients).

Following first-line treatment, patients who received IFL + Avastin had an overall progression free survival of 10.6 months compared with 6.2 months for IFL alone (p<0.00001). Patients in both treatment arms who received second-line treatment with oxaliplatin had higher overall survival than patients who received the same first-line therapy (IFL + Avastin: non-ox 19.6 months, ox 25.1 months (p<0.05): IFL: non-ox 15.8 months, ox 22.2 (p<0.01). The highest overall survival, 25.1 months, was achieved by patients, who received first-line therapy with IFL + Avastin and second-line treatment with an oxaliplatin containing regimen.

About the Erbitux Trial (#3513)

The Phase II study evaluated the safety and efficacy of combination therapy with Erbitux plus CAMPTOSAR, and 5-FU/LV administered via the FOLFIRI regimen in the first-line treatment of EGFR-expressing MCRC.

All patients received a 400 mg/m2 initial dose of Erbitux and 250 mg/m2 Erbitux weekly for the remainder of the study period. Patients were divided into two treatment arms and received either low-dose FOLFIRI (LD) (180 mg/m2 CAMPTOSAR plus 400 mg/m2 leucovorin (bolus) and 300 mg/m2 5-FU (bolus) followed by 2,000 mg/m2 5-FU (via 46-hour infusion)) or high-dose FOLFIRI (HD) (180 mg/m2 CAMPTOSAR plus 400 mg/m2 leucovorin (bolus) and 300 mg/m2 5-FU (bolus) followed by 2,400 mg/m2 5-FU (via 46-hour infusion)) therapy every two weeks.

The study initially enrolled 10 patients in the LD group and 13 patients in the HD group, who were monitored for dose-limiting toxicities (DLTs), response, and time-to-tumor progression (TTP), and adverse events. Following a low incidence of DLTs in both groups, the HD group was expanded to include an additional 29 patients. No DLTs were observed in the LD arm and 3 DLTs were reported in the HD arm (grade 3 diarrhea, grade 3 allergy, grade 4 neutropenia).

Among the initial 23 patients enrolled, 22 were evaluable for efficacy. Ten patients (46%) achieved partial response, 9 (41%) achieved stable disease, 3 (14%) had progressive disease. Median TTP stands at 10.9 months. Additional safety analysis from the 42 patients in the HD arm show the most frequent grade 3-4 adverse events to be diarrhea (14.3%), neutropenia (11.9%), rash (11.9%), and nausea/vomiting (9.5%).

About CAMPTOSAR® (irinotecan hydrochloride injection)

CAMPTOSAR® is approved in combination with 5-fluorouracil/leucovorin (5-FU/LV) as initial, or first-line, therapy for the treatment of advanced (metastatic) colorectal cancer. The combination shown to increase survival in multiple studies has demonstrated consistent success in first-line treatment in objective tumor response rates and time to tumor progression. CAMPTOSAR is also a central component of combination therapy playing a primary role in the studies that supported the FDA approvals of molecular targeted agents, AvastinTM and ErbituxTM.

CAMPTOSAR is associated with neutropenia and both early and late forms of diarrhea, which can be life threatening if not managed properly.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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