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Nab-paclitaxel shows promise in treatment of metastatic melanoma
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NEW YORK — Nanoparticle albumin-bound paclitaxel is an active agent in the treatment of malignant melanoma, but its role in relationship to targeted agents and immunotherapies remains unclear, according to a presenter at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.
The potential combination of nab-paclitaxel (Abraxane, Celgene) with other agents, including those that target the BRAF mutation, will have to be determined in future controlled investigations, Evan M. Hersh, MD, of the Arizona Cancer Center at the University of Arizona, said during a presentation.
Evan M. Hersh
Nab-paclitaxel — a formulation in which the widely used cancer drug paclitaxel is bound to the human protein albumin — is approved for treatment of breast cancer and non–small cell lung cancer. The FDA likely will approve the drug for treatment of pancreatic cancer, Hersh said.
Nab-paclitaxel originally was designed to avoid the toxicity associated with the Cremophor EL (polyethoxylated castor oil, BASF Corp.) formulation of paclitaxel.
Because tumor cells have albumin receptors and also have another albumin-accumulating substance within them — SPARC (serum protein acidic and rich in cysteine) — nab-paclitaxel tends to accumulate selectively in tumors. The particles break down and circulate, which results in a 33% higher paclitaxel concentration within tumors and a more rapid intratumoral accumulation of the drug.
“The albumin drug complexes bind to the albumin receptor, are incorporated into the caveolae, and are transported across the endothelial membrane and into the tumor cells,” Hersh said. “They are retained by the presence of SPARC, and melanoma cells often are rich in that substance.”
Hersh and colleagues conducted a phase 2 study designed to evaluate nab-paclitaxel in both previously untreated and heavily pretreated patients with metastatic melanoma.
All patients received 30-minute IV infusion doses of 150 mg/m2 weekly for 3 of every 4 weeks.
Among the 37 chemotherapy-naive patients, researchers reported a 22% partial response rate and 49% disease control rate. Median PFS was 4.5 months and median OS was 9.6 months.
In 2009, Hersh and colleagues initiated the phase 3 CA033 trial.
The international, multicenter, randomized study compared nab-paclitaxel with dacarbazine (DTIC) in chemotherapy-naive patients with metastatic malignant melanoma.
The investigation included 529 patients with stage IV disease, a performance status of 0 to 1, and no brain metastasis.
The researchers assigned 264 patients to receive nab-paclitaxel 150 mg/m2 IV on days 1, 8 and 15 every 4 weeks. The other 265 patients received dacarbazine 1,000 mg/m2 once every 3 weeks.
Patient characteristics — including age (media, 63 years; range, 21 to 87 years), sex, region of the world, ECOG performance status and metastatic stage — were similar between the two arms.
PFS served as the primary endpoint and OS served as the secondary endpoint. Other endpoints included overall response rate, disease control rate and safety/tolerability.
The results, presented in November at the Society for Melanoma Research Congress, showed that patients assigned to nab-paclitaxel demonstrated superior median PFS (4.8 months vs. 2.5 months; HR=0.792; 95.1% CI, 0.631-0.992).
At the time of planned interim analysis, nab-paclitaxel also was associated with longer OS (12.8 months vs. 10.7 months; HR=0.831; 99.9% CI, 0.578-0.1.196).
Patients assigned to nab-paclitaxel achieved a higher overall response rate (15% vs. 11%; P=.239), a higher disease control rate (39% vs. 27%; P=.004) and a lower rate of progressive disease (35% vs. 48%; P=.005).
The percentage of patients who required at least one dose reduction was higher in the nab-paclitaxel arm (32% vs. 20%).
Nab-paclitaxel was associated with higher rates of grade 3 or higher adverse events, including peripheral neuropathy (25% vs. 0), neutropenia (20% vs. 10%) and leukopenia (12% vs. 7%).
“We have found that neuropathy can be reasonably well ameliorated with drugs like [pregabalin (Lyrica, Pfizer)],” Hersh said. “We’ve also found neuropathy development can be markedly delayed by a prolongation of the infusion time to 90 minutes from 30 minutes. However, that has not been studied in a controlled investigation.”
Hersh also discussed results of a phase 2 study by Boasberg and colleagues designed to evaluate the combination of nab-paclitaxel and bevacizumab (Avastin, Genentech) as first-line therapy in 50 patients with unresectable melanoma. Thirty-two patients were men.
Patients received nab-paclitaxel 150 mg/m2 weekly for 3 of 4 weeks, and bevacizumab 10 mg/m2 every 2 weeks.
PFS served as the primary endpoint. Secondary endpoints included overall response, OS and safety/tolerability.
Researchers reported an overall clinical benefit of 80%. Four percent of patients experienced complete remission, 32% had partial remission and 44% had stable disease.
Median PFS was 7.6 months and median OS was 16.8 months.
“This is a small group of patients, but these data are reasonably encouraging,” Hersh said. “We hope they will be further evaluated in more clinical trials.”
Treatment-related grade 3 adverse events included neutropenia (10%), neuropathy (7%), mucositis (4%) and fatigue (3%).
“The potential combination of nab-paclitaxel with other targeted therapies, such as bevacizumab and possibly others, will have to be determined in phase 3 studies before we’ll know how important it will be,” Hersh said. “There is an off-label, private practice use of the combination of nab-paclitaxel and bevacizumab and, consequently, it is critically important that this be pursued in phase 3, controlled clinical trial.”
For more information:
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Boasberg PD. Abstract 8543. Presented at: 2011 ASCO Annual Meeting; June 3-7, 2011; Chicago.
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Hersh EM. Cancer. 2010;116:155-163.
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Hersh EM. Phase 3, randomized, open-label, multicenter trial of nab-paclitaxel (nab-P) versus dacarbazine (DTIC) in previously untreated patients with metastatic malignant melanoma (MMM). Presented at: Society for Melanoma Research Congress; Nov. 8-11, 2012; Hollywood, Calif.
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Hersh EM. Taxanes in melanoma: Are they the new chemotherapy standard? Presented at: HemOnc Today Melanoma and Cutaneous Malignancies meeting; March 22-23, 2013; New York.
Disclosure: Hersh reports research support from Celgene and Genentech; a consulting role with Genentech; and speakers’ bureau roles with Bristol-Myers Squibb, GlaxoSmithKline and Pfizer.