Photo Courtesy © ASCO/Todd Buchanan 2013
Daniel D. Von Hoff, MD
-paclitaxel to gemcitabine improves survival compared with gemcitabine alone in patients with metastatic pancreatic cancer. This combination “could become the backbone” for new regimens for treating this type of cancer, said Daniel D. Von Hoff, MD, physician-in-chief at Translational Genomics Research Institute, Scottsdale, Arizona, and principal investigator of a randomized head-to-head comparison of the two regimens.
Preclinical studies showed synergy between nab
-paclitaxel (Abraxane) and gemcitabine, and a subsequent phase I/II study of 67 patients with advanced pancreatic cancer demonstrated promising activity of the combination at maximum tolerated doses. These studies led to the design of a phase III evaluation, the results of which were presented at the 2013 Gastrointestinal Cancers Symposium held January 24-26 in San Francisco, California.
With a primary endpoint of overall survival (OS), 861 patients with stage IV pancreatic cancer who had no prior treatment for metastatic disease were randomized to nab
-paclitaxel at 125 mg/m2
, followed by gemcitabine 1000 mg/m2
(n = 431), or gemcitabine alone (n = 430). Patients were treated until their disease progressed, with computed tomography scans performed every 8 weeks. The study was conducted at 151 sites in 11 countries.
The median OS was 8.5 months in patients assigned to nab
-paclitaxel plus gemcitabine, compared with 6.7 months in those assigned to gemcitabine monotherapy (hazard ratio [HR] = 0.72; P
=.000015). One-year survival improved from 22% with gemcitabine alone to 35% with the combination (P
= .0002), and 2-year survival increased from 4% to 9% (P
Patient baseline characteristics were well-balanced, noted the researchers, with a median age of 63 years; 43% of patients had head of pancreas lesions. Sixty percent of patients had a Karnofsky performance status of 90-100, and 40% ≤80; 52% of patients had CA19-9 ≥59 times the upper limit of normal. “In general, the poorer the prognostic factor, the more favorable the hazard ratios” with combination therapy, noted Von Hoff.
Among the patients with subsequent therapy (38% of the combination group and 42% of the gemcitabine alone group), median survival was 9.4 months vs 6.8 months in favor of combination therapy (HR = 0.68; P
= .00072). “These data indicate that correcting for second-line treatment gives a slightly stronger improvement in overall survival for the nab
-paclitaxel plus gemcitabine arm,” he said.
Median progression-free survival also favored nab
-paclitaxel/gemcitabine (5.5 months) versus 3.7 months with gemcitabine alone (HR = 0.69; P
= .000024), as did the overall response rate by independent review (23% vs 7%). Time to treatment failure was prolonged with the combination, from a median of 3.6 months in the gemcitabine-only arm, to 5.1 months (HR = 0.70; P
Despite a median treatment duration that was 1.2 months longer in the group assigned to nab
-paclitaxel (3.9 months vs 2.7 months in the group assigned to gemcitabine alone), there was no increase in life-threatening toxicity by adding nab
Of the grade ≥3 nonhematologic treatment-related adverse events, the combination arm experienced higher rates of fatigue (17% vs 7%), peripheral neuropathy (17% vs <1%), and diarrhea (6% vs 1%). Peripheral neuropathy was rapidly reversible in the combination arm, and 44% of the patients in this arm who experienced grade ≥3 peripheral neuropathy were able to resume treatment.
The rate of grade ≥3 hematologic adverse events was higher with the addition of nab
-paclitaxel. Specifically, 38% of this group experienced neutropenia and 31% experienced leukopenia, compared with 27% and 16%, respectively, with gemcitabine alone.