Updated studies may move breast cancer drug to first-line treatment

Naomi Pfeiffer

Last year, a 300-patient, randomized phase II study—cited as one of the five "hottest" head-to-head trials presented at the San Antonio Breast Cancer Symposium (SABCS)—showed that weekly treatment of metastatic breast cancer with solvent-free, albumin-bound nab-paclitaxel (Abraxane, Abraxis Bioscience) is better tolerated than, and at least as effective as, standard first-line treatment with docetaxel (Taxotere, Sanofi-Aventis) once every three weeks.

If future trials confirm these findings, the study concluded, nab-paclitaxel should move from second- to first-line treatment status. Currently, nab-paclitaxel is approved only for second-line treatment of metastatic breast cancer.

Fast forward to 2007 American Society of Clinical Oncology (ASCO) Annual Meeting, held recently in Chicago. This year the updated phase II trial compared weekly or every-three-week nab-paclitaxel with every-three-week docetaxel as first-line treatment in patients with metastatic breast cancer.

While the research largely confirmed last year's results, "the data also show some subtle differences from what we presented at San Antonio," said lead investigator William J. Gradishar, M.D., director of breast medical oncology at Northwestern University Feinberg School of Medicine. For example, he said in an interview with Drug Topics, the researchers indicated last year that in the multi-arm trial—when weekly schedules of nab-paclitaxel given either at 100 mg/m² or 150 mg/m2 for three weeks out of four were compared with standard solvent-based docetaxel given once every three weeks—weekly nab-paclitaxel at 100 mg/m2 produced a superior response rate, a longer time to disease progression, and increased survival.

As for the safety profile, "the weekly schedules were very well tolerated, and, notably, among the different treatment arms the 100 mg/m2 weekly schedule was optimal last year…." The researchers also found that progression-free survival (PFS) with nab-paclitaxel included less neutropenia and peripheral neuropathy last year and was even better in 2007.

This year, the trial design had a few additions, Gradishar pointed out, notably an independent radiology review. "Instead of just looking at the investigators' assessments of the patients, we sent all the images to radiologists not connected with the study and, separately but concurrently with the investigators, they assessed the antitumor response rate and time to disease progression."

Combining all the expert data, the new assessment was that nab-paclitaxel 150 mg/m2 weekly is the superior weekly dose of the drug—"more effective than the 100 mg/m2 weekly dose we thought was optimal last year," Gradishar said. Additionally, when the radiology review data were combined with investigators' antitumor response data, "nab-paclitaxel 150 mg/m² weekly produced an even longer PFS than last year's nab-paclitaxel 100 mg/m2."

To date there has been "a very high correlation" of assessments by clinical investigators and independent radiology reviewers concerning response and progression-free survival, emphasized Gradishar. "All these experts agreed that nab-paclitaxel 150 mg/m² weekly produced a longer PFS than nab-paclitaxel 100 mg/m2 weekly."

Summing up, in terms of overall trends, Gradishar told Drug Topics, "Antitumor response rates in the updated 2007 study remain virtually identical to those we reported at SABCS in 2006. However, we now find the most effective and safest treatment regimen is nab-paclitaxel, 150 mg/m² weekly every three out of four weeks."

Going forward, in the large, randomized, phase III pivotal trial planned for later this year, researchers will compare nab-paclitaxel 150 mg/m² weekly for three weeks (followed by one week of rest) with docetaxel 100 mg/m² once every three weeks, as first-line therapy in metastatic breast cancer. "The antitumor response assessments will again undergo independent radiologic review," Gradishar noted.

"We still think one of the major advantages of using solvent-free [and therefore nontoxic] Abraxane rather than solvent-based Taxotere is that the inherent toxicity of taxane chemotherapy is reduced while antitumor effects are enhanced," Gradishar concluded.

Also reported at ASCO 2007 was a Chinese phase III trial called "Randomized Study Comparing nab-Paclitaxel with Solvent-based Paclitaxel in Chinese Patients with Metastatic Breast Cancer." The main goals were to compare the response rates and toxicity of the two drugs.

Both the design and the findings were virtually identical to those of a 2005 study reported by Gradishar and colleagues (published in the Journal of Clinical Oncology) comparing nab-paclitaxel and solvent-based paclitaxel injected every three weeks for up to six treatment cycles.

The only difference was that all 200 of the original patients were Caucasian, while the current ones are all Chinese. But, as it turned out, race did not matter. "Like the original researchers, we found that nab-paclitaxel had greater efficacy with a favorable safety profile," said lead investigator Zhong-Zhen Guan, M.D., from Sun Yat-Sen University Cancer Center.

Also found was that the maximum tolerated dose of nab-paclitaxel in Chinese patients was the same as in Caucasian patients—300 mg/m2 IV over 30 minutes without premedication, treatment repeated every three weeks.

"Essentially, the Chinese results were identical to ours [with Caucasian patients]," commented Gradishar. "The bottom line is there is consistency wherever the drug is tested."

Guan agreed: "The data [matched] those of Dr. Gradishar's phase III study, showing the superiority of nab-paclitaxel to the solvent-based agent—i.e., more efficacious with less toxicity and no steroid pretreatment required."

Chinese oncologists will want this drug when it is approved by their regulatory agency to replace standard paclitaxel, he said. "But will they be able to afford it?"

THE AUTHOR writes frequently about clinical subjects.