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6th European Breast Cancer Conference

Berlin, Germany / April 15-19, 2008

Despite extensive clinical experience with the taxanes paclitaxel and docetaxel, the five-year survival rate for metastatic breast cancer (MBC) patients is still only about 20%. In patients with MBC, the new nanoparticle albumin-bound (nab)-paclitaxel formulation has demonstrated an overall response rate almost double that of the solvent-based formulation and a six-week longer time to progression. The maximal-tolerated dose of nab-paclitaxel was twofold greater in preclinical studies than the solvent-based formulation, potentially allowing for increased medication exposure.

According to Dr. William Gradishar, Northwestern University Feinberg School of Medicine, Chicago, Illinois, “Based on preclinical models, nab-paclitaxel allows the preferential delivery of paclitaxel to tumours and reduces the risk of hypersensitivity reactions induced by solvent-based taxanes.”

Based on the improved efficacy and tolerability profile compared to solvent-based paclitaxel and docetaxel, Dr. Gradishar reported that all nab-paclitaxel groups in phase II and III studies have achieved a greater overall response rate (ORR) than with docetaxel.

In a phase II randomized comparison of nab-paclitaxel 100 or 150 mg/m2 administered qw or 300 mg/m2 q3w compared to docetaxel 100 mg/m2 q3w as first-line therapy in MBC patients, a significant difference in progression-free survival (PFS) with the 150 mg/m2 dose was achieved vs. docetaxel (14.6 vs. 7.8 months, P=0.012). A non-significant numerical increase was observed for the 300 mg/m2 q3w dose (10.9 vs. 7.8 months) and the 100 mg/m2 qw dose produced a similar median PFS to docetaxel. ORR was significantly higher compared to docetaxel for the two arms of nab-paclitaxel administered weekly (63% and 74% vs. 39%; P=0.002 and P<0.001, respectively) (Figure 1).

Reducing Toxicity

Dr. Gradishar remarked, “Minimizing toxicity by eliminating the steroids and antihistamines that often have to be co-administered with solvent-based paclitaxel and docetaxel, nab-paclitaxel becomes a more patient-friendly drug. There is no routine steroid or antihistamine premedication required, and a phase III trial demonstrated that compared to solvent-based paclitaxel given every three weeks, the response rate was significantly doubled, with a longer time to disease progression, as well as a reduction in grade 4 neutropenia and sensory neuropathy.”

That trial included 454 women with stage IV MBC who had not received prior therapy with taxanes and were randomized to either nab-paclitaxel every three weeks without steroid premedication or solvent-based paclitaxel administered with routine premedications.

“Looking at the clinical end points regardless of the subset of patients in this trial, the response rates for those receiving nab-paclitaxel were significantly higher than for those receiving solvent-based paclitaxel (33% vs. 19%),” he indicated. The response rates among patients who had first-line treatment only were 42% vs. 27%; in those who had second-line treatment or greater, it was 27% vs. 13%; in those who had treatment for metastatic disease with previous anthracycline use, it was 34% vs. 18%; and in those who had visceral disease, the rate was 27% vs. 14%, Dr. Gradishar reported.

“Moreover, there was a significant improvement in objective response rates in general with nab-paclitaxel; time to disease progression was improved by about six weeks among those women receiving nab-paclitaxel. Grade 4 neutropenia, despite the stronger dose of [paclitaxel], was significantly less in patients on nab-paclitaxel, although the sensory neuropathy rate was somewhat higher,” Dr. Gradishar reported. “Nevertheless, the consistent finding across all trials, including early and phase II and III trials, has been that the neuropathy that is observed with nab-paclitaxel tends to resolve much faster than in patients administered solvent-based paclitaxel. This suggests that the presence of [CrEL] in the solvent results in a more irreversible type of sensory neuropathy.” He added that in both trials, patients receiving the nab formulation had resolution and recovery to the point that they could be re-exposed to it within about three weeks, a much shorter time than is typically seen with solvent-based taxane-induced neuropathy. In the phase II trial, grade 3 sensory neuropathy resolved in 19 to 22 days in the nab-paclitaxel arms vs. 37 days in the docetaxel-treated group. In all nab-treated arms, the rate of grade 4 neutropenia was lower (5% for 300 mg/m2 q3w and 100 mg/m2 qw; 9% for the 150 mg/m2 qw) than with docetaxel (75%) (Figure 1). Febrile neutropenia occured at a rate of 1% in all nab-treated arms vs. 8% in the docetaxel arm. In the phase III trial, the rates of grade 3/4 neutropenia were 34% compared to 53% in patients receiving solvent-based paclitaxel, although the doses were 260 mg/m2 vs. 175 mg/m2.

Finding the Optimal Dosing Schedule

Dr. Joyce O’Shaughnessy, Baylor College of Medicine, Houston, Texas, conducted a subset analysis of the nab-paclitaxel arms of the two large randomized phase II and III trials that compared the safety and efficacy of weekly vs. q3w dosing with either solvent-based paclitaxel or docetaxel in 455 patients with MBC. They received i.v. nab-paclitaxel 260 mg/m2 q3w in the phase III trial and 300 mg/m2 q3w, 100 mg/m2 qw 3/4 or 150 mg/m2 qw 3/4 in the phase II trial.

She noted ORRs were higher for both weekly regimens compared to either of the q3w regimens; 46% of patients given 300 mg/m2 q3w responded compared to 33% who received 260/m2 q3w vs. 74% who were given 150 mg/m2 weekly and 63% of those given 100 mg/m2 weekly. Median PFS was longest (14.6 months) among patients taking150 mg/m2 nab-paclitaxel weekly. For the 100 mg/m2 weekly dosing cohort, median PFS was 7.5 months. Patients receiving 300 mg/m2 q3w achieved a median PFS of 10.9 months and those on 260 mg/m2 q3w had a median PFS of 5.2 months (Table 1).

Dr. O’Shaughnessy observed that incidence of grade 3 sensory neuropathy was similar between weekly and q3w groups. Time to resolution was 19 and 22 days for weekly nab-paclitaxel 150 mg/m2 and 100 mg/m2, respectively, and 22 days for both 300 mg/m2 and 260 mg/m2 q3w groups. Incidence of grade 3/4 neutropenia, the most common hematologic treatment-related adverse event, was similar across all arms (45%, 34%, 44% and 25%, respectively, for 300 mg/m2 q3w, 260 mg/m2 q3w, 150 mg/m2 weekly and 100 mg/m2 weekly regimens). She concluded, “This analysis demonstrates that nab-paclitaxel has antitumour activity and a favourable safety profile regardless of the regimen. The 150 mg/m2 dose demonstrated longer PFS than any other regimen and the highest mean dose intensity.”

Figure 1. Response Rates and Adverse Event Rates in Phase II Trial

Table 1. Subset Analysis of Phase I
ase III CA-012 Trial

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