Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is a solvent-free paclitaxel formulation intended to reduce solvent-related adverse reactions and improve tumor penetration via the physiologic transport properties of albumin. The final results of a phase III trial comparing nab-paclitaxel and solvent-based paclitaxel injection in combination with carboplatin as first-line treatment of advanced non–small cell lung cancer (NSCLC) were reported by Socinski and colleagues in Journal of Clinical Oncology.¹ The study showed a significantly greater overall response rate and reduced neuropathy with nab-paclitaxel.

The improved response rate demonstrated in the study supported the recent approval of nab-paclitaxel combined with carboplatin as first-line treatment of advanced NSCLC. (For more on using nab-paclitaxel in this setting, see page 47.) Subset analyses in the trial also suggested potential response and survival advantages with nab-paclitaxel treatment.

Study Design

In this trial,^2,3 1,052 patients with nonresectable stage IIIB or stage IV NSCLC received nab-paclitaxel at 100 mg/m² via weekly infusion (n = 521) or solvent-based paclitaxel at 200 mg/m² every 3 weeks (n = 531). All patients received carboplatin at area under the curve (AUC) 6 mg • min/mL every 3 weeks. Steroid/antihistamine premedication was required in the solvent-based paclitaxel group and used at investigator discretion in the nab-paclitaxel group. Patients were to receive at least six cycles of treatment. The primary endpoint was overall response rate.

The nab-paclitaxel and conventional paclitaxel groups were well matched for age (median = 60 years in both groups, 14% and 15% aged ≥ 70 years), sex (75% male in both), race (80% and 82% white), region, ECOG performance status (1 in 74% and 78%), histology (adenocarcinoma in 49% and 50%, and squamous cell carcinoma in 44% and 42%), disease stage (IV in 79% of both), and smoking status (never smoked in 26% and 27%, still smokes in 41% and 44%). Prior therapy included radiation therapy in 7% of nab-paclitaxel patients and 9% of solvent-based paclitaxel patients and chemotherapy in 3% and 2%, respectively.

Improved Overall Response Rates

Patients in both groups received a median of six cycles of treatment. On independent radiology assessment, overall response rate was 33% in the nab-paclitaxel group vs 25% in the solvent-based paclitaxel group (response rate ratio = 1.313, P = .005). All responses were partial responses, except for one complete response in the conventional paclitaxel group. Overall response rate was significantly greater with nab-paclitaxel among patients with squamous cell histology (41% vs 24%, response rate ratio = 1.680, P < .001); there was no difference between treatments in patients with nonsquamous histology (26% vs 25%) or with adenocarcinoma (26% vs 27%).

There were no significant differences between the nab-paclitaxel and conventional paclitaxel groups in progression-free survival (median = 6.3 vs 5.8 months) or overall survival (median = 12.1 vs 11.2 months). The progression-free and overall survival comparisons met criteria for noninferiority of nab-paclitaxel.

Survival Benefit in Older Patients?

Subgroup analyses suggested potential differences in survival according to geographic region and age. Median progression-free survival was nonsignificantly prolonged with nab-paclitaxel treatment among the 165 patients from the United States and Canada (7.0 vs 5.4 months) and among patients aged ≥ 70 years (8.0 vs 6.8 months). Median overall survival was significantly prolonged with nab-paclitaxel treatment in North American patients (12.7 vs 9.8 months, P = .008) and in patients aged ≥ 70 years (19.9 vs 10.4 months, P = .009); no differences between treatments were observed among the 724 patients from Russia/Ukraine or 149 patients from Japan or among patients aged < 70 years.

By histology subtype, median overall survival was 10.7 months in the nab-paclitaxel group and 9.5 months in the solvent-based paclitaxel group among patients with squamous cell histology and 13.1 and 13.0 months, respectively, among those with nonsquamous histology.

Second-line therapy was used in 53% of the nab-paclitaxel group and 54% of the conventional paclitaxel group. It was most commonly used in Japan (85%), Australia (79%), and North America (69%) and used least in Russia/Ukraine (44%). As in the analysis in the intent-to-treat population, the nab-paclitaxel group had a nonsignificant increase in overall survival among patients receiving second-line therapy.

Reduced Sensory Neuropathy

Safety data were reported as treatment-related adverse events. Grade 3 and 4 thrombocytopenia (13% and 5% vs 7% and 2%, P < .001) and anemia (22% and 5% vs 6% and < 1%, P < .001) were significantly more common in nab-paclitaxel patients and grade 3 and 4 neutropenia (32% and 26% vs 33% and 14%, P < .001) was significantly more common in conventional paclitaxel patients. Febrile neutropenia occurred in 1% of both treatment groups.

Sensory neuropathy of all grades was significantly more common in the conventional paclitaxel group (62% vs 46%, P < .001), as was grade 3 and 4 neuropathy (11% and < 1% vs 3% and 0%, P < .001). Median time to improvement of grade 3 or 4 sensory neuropathy to grade 1 was 38 days in the nab-paclitaxel group and 104 days in the conventional paclitaxel group. Grade 3 myalgia (2% vs <1%, P = .011) and arthralgia (2% vs 0%, P = .008) were more common in the conventional paclitaxel group. One treatment-related death occurred in each group.

Treatment was discontinued due to unacceptable toxicity without progressive disease in 12% of both groups and due to adverse events in 4% of nab-paclitaxel patients and 5% of conventional paclitaxel patients. Paclitaxel dose reductions occurred in 46% of nab-paclitaxel patients vs 23% of conventional paclitaxel patients, primarily due to neutropenia (29% vs 10%), thrombocytopenia (13% vs 4%), anemia (6% vs <1%), and sensory neuropathy (2% vs 6%). Still, paclitaxel dose intensity was 26% higher and cumulative dose was 18% greater in the nab-paclitaxel group. Dose delays occurred in 82% vs 54% of patients.

On the patient-reported Functional Assessment of Cancer Therapy (FACT)-Taxane scale, assessed on day 1 of each treatment cycle, significant improvements in mean change from baseline were reported for the neuropathy subscale, pain subscale, and hearing loss subscale for the nab-paclitaxel group vs the solvent-based paclitaxel group.

Study Implications

The investigators noted that the treatment differences in survival observed in the North American subpopulation may reflect regional differences in baseline characteristics and standards of care. They also noted that the intriguing finding of pronged median overall survival in nab-paclitaxel–treated patients aged ≥ 70 years could have been related to better tolerability of the weekly nab-paclitaxel schedule and should be confirmed in an additional study.

Although the significantly higher overall response rate in nab-paclitaxel patients with squamous cell histology did not translate into significantly greater overall survival in this subgroup, the investigators observed that there was some separation of the survival curves from 6 months to the end of the study. They speculated that this late separation might indicate the presence of a subset of such patients who preferentially benefit from nab-paclitaxel.

In the context of the significant improvement in overall response rate and absence of differences in progression-free and overall survival in the total population, the authors concluded, “The [nab-paclitaxel] regimen produced less severe neuropathy, neutropenia, myalgia, and arthralgia compared with [solvent-based paclitaxel]. The increased risk of thrombocytopenia and anemia in the [nab-paclitaxel] regimen was readily manageable. Taken together, the [nab-paclitaxel] regimen has a favorable risk-benefit profile compared with that of [solvent-based paclitaxel] as first-line therapy for all patients with NSCLC.” ■

Reference

1. Socinski MA, Bondarenko I, Karaseva NA, et al: Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: Final results of a phase III trial. J Clin Oncol 30:2055-2062, 2012.