San Francisco, CA—A new “backbone” of therapy for metastatic pancreatic cancer could be the combination of nab-paclitaxel (Abraxane) and gemcitabine (Gemzar). When added to gemcitabine, weekly nab-paclitaxel improved survival in patients with advanced pancreatic cancer by nearly 2 months compared with gemcitabine alone, said Daniel D. Von Hoff, MD, FACP, Physician in Chief and Director of Translational Research, Translational Genomics Research Institute, Phoenix, regarding the results of a large international phase 3 clinical trial.
At present, “gemcitabine-containing combinations or 5-fluorouracil–containing combinations are treatments that clinicians may try first for stage IV disease,” Dr Von Hoff said.
Currently, nab-paclitaxel is approved by the US Food and Drug Administration for the treatment of breast cancer and non–small-cell lung cancer.
In a phase 1/2 study of 67 patients with advanced pancreatic cancer, the combination of nab-paclitaxel and gemcitabine demonstrated an overall response rate of 48%.
The median overall survival (OS) was 12.2 months for the combination at maximum tolerated doses (125 mg/m2 of nab-paclitaxel followed by 1000 mg/m2 of gemcitabine on days 1, 8, and 15 every 4 weeks or to 1000 mg/m2 of gemcitabine weekly for 7 weeks, and then on days 1, 8, and 15 every 4 weeks in the first-line setting).
The results of a phase 3 randomized study powered for OS were presented by Dr Von Hoff at the 2013 Gastrointestinal Cancers Symposium.
The study, which was conducted at 151 sites in 11 countries, enrolled 861 patients with stage IV pancreatic cancer who had no prior treatment for metastatic disease. They were randomized to gemcitabine alone or to nab-paclitaxel added to gemcitabine. Patients were treated until they reached disease progression, and had computed tomography scans every 8 weeks.
The median OS was 8.5 months for patients assigned to nab-paclitaxel plus gemcitabine compared with 6.7 months for those assigned to gemcitabine alone, which represents a hazard ratio (HR) of 0.72 (P = .015). The 1-year survival rate was 22% for patients who were given gemcitabine alone and 35% for patients who were also given nab-paclitaxel—a 59% improvement (P = .002); 2-year survival more than doubled for patients who were given both gemcitabine and nab-paclitaxel, increasing from 4% to 9% (P = .021).
HRs were generally more favorable with nab-paclitaxel in patients with poorer prognostic factors, such as a lower Karnofsky Performance Score, the presence of liver metastases, 3 or more metastatic sites, and a CA19-9 ≥59 times the upper limit of normal, said Dr Von Hoff.
Among the patients who received subsequent therapy, the median survival was 9.4 months in patients randomized to the combination versus 6.8 months in those assigned to gemcitabine alone (HR, 0.68; P = .072).
Progression-free survival was greater in patients who were given nab-paclitaxel and gemcitabine than in patients who were given gemcitabine alone (HR, 0.69; P = .024), as was the overall objective response rate (23% vs 7%, respectively) and the objective disease control rate (48% vs 33%, respectively).
No increase in life-threatening toxicity resulted from adding nab-paclitaxel to the patients’ treatment, despite a median duration of treatment that was 1.2 months longer than that given with gemcitabine alone.
The combination arm had higher rates of fatigue (17% vs 7%, respectively), peripheral neuropathy (PN; 17% vs <1%, respectively), and diarrhea (6% vs 1%, respectively). PN was rapidly reversible in the combination arm, and 44% of the patients in this arm who experienced grade ≥3 PN were able to resume treatment.
Grade ≥3 hematologic adverse events occurred at a higher rate with the addition of nab-paclitaxel. Of this group, 38% experienced grade ≥3 neutropenia and 31% experienced grade ≥3 leukopenia, compared with 27% and 16% of the patients, respectively, with gemcitabine alone. The rates of febrile neutropenia were low—1% with gemcitabine and 3% with nab-paclitaxel and gemcitabine.
Of those in the combination arm, 80% received the per-protocol dose compared with 75.2% of the patients in the gemcitabine arm. “We were able to give the same dose intensity for long periods of time, so the 2 combine well,” said Dr Von Hoff. “Because they combine well, it’s a scaffold you can add other things on to.”
“The immediate question would be the relative role of nab-paclitaxel plus gemcitabine versus FOLFIRINOX [oxaliplatin, irinotecan, fluorouracil, and leucovorin] in our day-to-day practices,” said Philip Agop Philip, MD, PhD, FRCP, Director of Gastrointestinal Oncology, Karmanos Cancer Institute at Wayne State University, Detroit.
“Related to this question is how to sequence these 2 regimens. Obviously, a head-to-head comparison will answer these questions, but I’m not sure that a study like that will happen soon enough. Whenever it happens, we will have to wait several years before we get an answer,” Dr Philip said
