In a phase III trial reported in The New England Journal of Medicine, Daniel D. Von Hoff, MD, of Translational Genomics Research Institute in Phoenix, and colleagues assessed the addition of albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) to gemcitabine in patients with previously untreated metastatic pancreatic cancer.1 The combination resulted in significantly improved overall survival and progression-free survival but was also associated with increased myelosuppression and peripheral neuropathy.
In this international open-label trial, 861 patients with Karnofsky performance status ≥ 70 and no previous treatment for metastatic disease were randomly assigned to receive either (1) nab-paclitaxel at 125 mg/m2 followed by gemcitabine at 1,000 mg/ m2 on days 1, 8, and 15 every 4 weeks (n = 431) or (2) gemcitabine alone weekly for 7 of 8 weeks during cycle 1 and then on days 1, 8, and 15 every 4 weeks during cycle 2 and subsequent cycles (n = 430).
Patients could have received fluorouracil or gemcitabine as a radiation sensitizer in the adjuvant setting if the treatment had been received ≥ 6 months before randomization. Treatment continued until disease progression. The primary endpoint was overall survival.
The nab-paclitaxel/gemcitabine and gemcitabine groups were generally well balanced for age (median, 62 and 63 years), sex (57% and 60% male), race/ethnic group (88% and 87% white), geographic region (north America for 62% and 63%), Karnofsky performance status (100 in 16% in both, 90 in 42% and 46%, 80 in 35% and 30%), pancreatic tumor location (head in 44% and 42%, body in 31% and 32%), metastatic site (liver in 85% and 84%, lung in 35% and 43%), number of metastatic sites (2 in 47% and 48%, 3 in 32% and 33%, > 3 in 14% and 15%), CA19-9 level (≥ 59 times upper limit of normal in 52% and 53%), and previous therapy (radiation therapy in 4% and 3%, chemotherapy in 5% and 3%, Whipple procedure in 7% in both, and biliary stent in 19% and 6%). In total, 63% of patients were from North America, 15% from Eastern Europe, 14% from Australia, and 9% from Western Europe.
The median duration of treatment was 3.9 months (range, 0.1–21.9 months) in the nab-paclitaxel/gemcitabine group and 2.8 months (range, 0.1–21.5 months) in the gemcitabine group, with 32% and 15% receiving treatment for ≥ 6 months. In the nab-paclitaxel/gemcitabine group, 41% of patients had reductions in nab-paclitaxel dose and 47% had reductions in gemcitabine dose. In the gemcitabine group, 33% of patients had dose reductions.
After discontinuation of study treatment, 38% of nab-paclitaxel/gemcitabine patients and 42% of gemcitabine patients received subsequent therapy, with 6% of the gemcitabine group receiving a regimen including nab-paclitaxel.
Improved Overall Survival
Median overall survival was 8.5 months in the nab-paclitaxel/gemcitabine group vs 6.7 months in the gemcitabine group (hazard ratio [HR] = 0.72, P < .001). Overall survival rates were 35% vs 22% (P < .001) at 1 year and 9% vs 4% (P = .02) at 2 years.
On multivariate analysis including the stratification factors of performance status, presence or absence of liver metastases, and geographic region, the treatment effect remained significant (HR = 0.71, P < .001). Karnofsky performance status and liver metastases status were also independent predictors of survival. When the data were censored at the time of the initiation of subsequent therapy, overall survival was still longer in the nab-paclitaxel/gemcitabine group (median, 9.4 vs 6.8 months, HR = 0.68, P < .001).
Subgroup analyses showed consistent benefit of nab-paclitaxel/gemcitabine across the majority of prespecified subgroups; patients with more advanced disease generally had the greatest reduction in risk of death, including those with Karnofsky performance status of 70 or 80 (HR = 0.61, 95% confidence interval [CI] = 0.48–0.78), presence of liver metastasis (HR = 0.69, 95% CI = 0.59–0.81), more than three sites of metastatic disease (HR = 0.50, 95% CI = 0.33–0.76), metastatic pancreatic cancer at initial diagnosis, and CA19-9 level ≥ 59 times the upper limit of normal (HR = 0.61, 95% CI = 0.48–0.77).
Progression-Free Survival and Objective Response
Median progression-free survival on independent assessment was 5.5 months vs 3.7 months (HR = 0.69, P < .001). Progression-free survival rates at 1 year were 16% vs 9%. On investigator assessment, median progression-free survival was 5.3 vs 3.5 months (HR = 0.61, P < .001).
Subgroup analyses showed consistent benefit of nab-paclitaxel/gemcitabine, similar to the overall survival analyses. Response rates were 23% vs 7% (P < .001) on independent review and 29% vs 8% (P < .001) on investigator assessment. Disease control rates were 48% vs 33% (P < .001) on independent review.
The most common treatment-related nonhematologic adverse events of any grade in the nab-paclitaxel/gemcitabine group were fatigue (54%), alopecia (50%), and nausea (49%).
Treatment-related adverse events of grade 3 or higher reported more frequently in the nab-paclitaxel/gemcitabine group were neutropenia (38% vs 27%), leukopenia (31% vs 16%), fatigue (17% vs 7%), and peripheral neuropathy (17% vs 1%; no grade 4 neuropathy was reported). Febrile neutropenia occurred in 3% vs 1% of patients, sepsis in 5% vs 2%, and pneumonitis in 4% vs 1%. Serious adverse events occurred in 50% vs 43% of patients, and fatal adverse events occurred in 4% of both groups.
Peripheral neuropathy led to discontinuation of nab-paclitaxel in 8% of patients and to dose reduction in 10%. Among patients receiving treatment for 4 months (the average treatment duration), the rate of grade 3 neuropathy was 7%. Median time to first occurrence of grade 3 neuropathy was 140 days; median time to improvement to grade 2 was 21 days and to grade 1 or resolution was 29 days. Of patients with grade 3 peripheral neuropathy, 44% resumed treatment at a reduced dose of nab-paclitaxel at a median of 23 days after onset.
The investigators concluded, “In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased…[although] these side effects appear to be reversible.” ■
Disclosure: The study was funded by Celgene. For full disclosures of the study authors, visit www.nejm.org.
1. Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-1703, 2013.
For a number of years following the approval of gemcitabine for advanced pancreatic cancer, one phase III clinical trial after the next failed to demonstrate a survival benefit of combination chemotherapy compared to gemcitabine alone. Even the one positive study from the mid-2000s—the PA.3 trial...