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43rd Annual Meeting of the American Society of Clinical Oncology

Chicago, Illinois / June 1-5, 2007

Updated results from a four-arm trial in which a nanoparticle albumin-bound formulation of paclitaxel (nab-paclitaxel) given in higher and lower doses in a weekly or every-three-week schedule confirmed greater efficacy and tolerability than docetaxel given every three weeks.

Dr. William Gradishar, Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, and colleagues compared anti-tumour responses as well as toxicity profiles of four different regimens. A total of 300 patients with metastatic breast cancer were randomized to either first-line nab-paclitaxel 300 mg/m2 every three weeks (arm A), 100 mg/m2 weekly for three weeks out of four (arm B), 150 mg/m2 weekly three out of four weeks (arm C) or docetaxel 100 mg/m2 every three weeks (arm D). No premedications were administered in the nab-treated arms and patients in the docetaxel arm received standard corticosteroids.

In the third of four prospectively planned interim analyses presented in San Antonio in December 2006, it was shown that both weekly and every-three-week regimens of nab-paclitaxel were more effective than the every-three-week docetaxel regimen, but in particular, the two weekly nab regimens produced significantly higher response rates and longer progression-free survival (PFS).

Radiology Data

The fourth interim analysis presented at ASCO this year is important, as Dr. Gradishar indicated, because it both expands on earlier results and includes findings from an independent radiology review by radiologists blinded to both treatment assignment and lesion assessment. With this review, the overall response rate decreased slightly across all treatment arms—“not surprisingly,” as Dr. Gradishar noted, “as this predictably occurs whenever an independent radiology review is applied to any study.” According to investigator-based assessments, responses to nab-paclitaxel occurred in 43% of patients in the 300 mg/m2 every-three-week regimen, in 62% in 100 mg/m2 weekly arm, 70% on 150 mg/m2 weekly, and in 38% of the docetaxel 100 mg/m2 every-three-weeks regimen. Independent radiology review assessments judged responses to be slightly lower at 35%, 45%, 47% and 28%, respectively. Nevertheless, “the overall benefit remains the same,” Dr. Gradishar observed, namely, that weekly nab treatment schedules have greater efficacy than docetaxel given every three weeks (Figure 1).

Figure 1. Comparison of Investigator and Independent Radiology Review Response Assessments

The independent radiology review also confirmed that both nab regimens of 300 mg/m2 every three weeks and 150 mg/m2 weekly demonstrated significantly longer PFS than docetaxel 100 mg/m2 every three weeks. PFS was also greater for nab-paclitaxel 150 mg/m2 weekly compared to the 100 mg/m2 weekly dose. All doses of the nab formulation were better tolerated, with significantly less grade 4 neutropenia, febrile neutropenia and fatigue than docetaxel. The incidence of peripheral neuropathy was similar across the treatment arms, although it was considerably less in the low-dose weekly nab arm. Peripheral neuropathy resolved much more rapidly with nab treatment at a median of 16 to 23 days vs. a median of 41 days with docetaxel.

Dr. Stephen Chia, medical oncologist, BC Cancer Agency, Vancouver, characterized the findings as “encouraging” and that they support proceeding onto a large phase III trial in which the higher dose of weekly nab-paclitaxel is compared with every-three-week docetaxel. However, he cautioned that this phase II study was still a relatively small trial encompassing roughly 75 patients per arm, and as such, awaits confirmation by a phase III study.

Dr. Chia cited a large phase III trial in patients with metastatic breast cancer that demonstrated that the nab formulation was more effective and had a better safety profile than standard paclitaxel (Gradishar et al. J Clin Oncol 2005;23(31):7794-803). Women received nab-paclitaxel at a dose of 260 mg/m2 or standard paclitaxel 175 mg/m2 every three weeks. Based on the results of this phase III trial, Dr. Chia suggested that use of nab-paclitaxel using this dosing schedule is warranted.

Confirming Results in a Chinese Cohort

Another comparison of nab- vs. solvent-based paclitaxel in 212 Chinese women with metastatic breast cancer was presented by principal investigator Dr. Zhongzhen Guan, Sun Yat-Sen University Cancer Centre, Guangzhou, China. The efficacy and toxicity of nab doses of 260 mg/m2 over 30 minutes every three weeks was compared with the solvent-based formulation at a dose of 175 mg/m2, given over three hours. No standard premedication is required with nab-paclitaxel because there is no risk of triggering a hypersensitivity reaction with this formulation, but patients receiving the solvent-based agent received dexamethasone and antihistamines.

Approximately 40% of both groups had received prior chemotherapy for metastatic disease and patients received a mean of 5.6 and 5.2 cycles for nab- and solvent-based paclitaxel, respectively. The overall response rate (complete response and partial response) was highly significant at 54% in the nab treatment arm vs. 29% in the solvent-based treatment arm (P<0.001). The median time to progression as well as median PFS was 7.6 months in the nab-treated arm vs. 6.2 months in the solvent-based taxane arm.

As investigators observed, alopecia and peripheral neuropathy were the most common toxicities and occurred in similar numbers of women in both treatment arms, even though women received a 49% higher dose of the nab formulation than those in the solvent-based arm. Neutropenic adverse events were also statistically similar between the two arms, although the incidence of all grades of neutropenia was higher in the nab-treated arm at 93% compared with 77% in the solvent-based cohort. However, the incidence of grades 3 and 4 neutropenia was similar between the two arms. Skin allergic reactions were the only non-hematological toxicity that occurred significantly more often with nab-paclitaxel, but as investigators indicated, all of the skin reactions seen with the nab formulation were grades 1 or 2 and most resolved without treatment and did not require dose reductions.

Questions and Answers

The following question-and-answer session was conducted with Dr. William Gradishar, Professor of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Q: How is nab-paclitaxel more effective than docetaxel since they are both taxanes?

A: I think the key difference is the platform. Nab-paclitaxel is not given with a solvent [as the other taxanes are] to make them more bioavailable. The solvent corresponds to many of the side effects seen with the taxanes, including myelosuppression and neuropathy, and it is also responsible for less drug getting to the tumour. Nab-paclitaxel allows you to give paclitaxel without the solvent and it also exploits the fact that the platform is albumin, which facilitates drug uptake into the tumour and so more drug gets there.

Q: What role do you see for nab-paclitaxel in metastatic breast cancer?

A: There is going to be a large randomized phase III trial that will compare the 150 mg/m2 weekly dose of nab-paclitaxel to docetaxel but in the absence of results from this trial, I think that clinicians will look at this data and make judgments about the dose based on individual patients. If a patient is doing well and is otherwise healthy, they may choose to use the higher weekly dose; we also know that the lower weekly dose is just as effective as docetaxel, but it is better tolerated. If you have a patient where there is some question about their ability to tolerate the higher dose, you can use the lower dose because it is still effective and it is very well tolerated.