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Median overall survival improved by almost 2 months, and both 1- and 2-year survival improved substantially in patients who received nab-paclitaxel (Abraxane) plus gemcitabine rather than gemcitabine alone, according to Daniel D. Von Hoff, MD, of Scottsdale Healthcare/TGen in Arizona.
The combination significantly slowed disease progression and improved all secondary endpoints, he reported here at the Gastrointestinal Cancers Symposium.
'The combination of nab-paclitaxel and gemcitabine, a new standard for the treatment of patients with metastatic pancreatic cancer, is superior to gemcitabine alone and could become the backbone for new regimens,' said Von Hoff.
Nanoparticle albumin-bound (nab) paclitaxel has demonstrated improved pharmacokinetics and other potential advantages compared with the conventional Cremophor formulation of the taxane. In preclinical studies, nab-paclitaxel demonstrated activity in pancreatic cancer and evidence of synergy with gemcitabine.
Preliminary clinical studies provided additional evidence that the combination of nab-paclitaxel and gemcitabine could improve survival in metastatic pancreatic cancer compared with gemcitabine alone.
Von Hoff presented results of an international, multicenter, randomized trial involving patients with metastatic pancreatic cancer. Investigators at 151 sites in 11 countries enrolled 861 patients, who were randomized equally to nab-paclitaxel plus gemcitabine or to gemcitabine alone.
Treatment continued until disease progression, and patients had CT imaging every 8 weeks to monitor disease status.
The primary endpoint was overall survival.
The patients had a median age of 62 to 63, men accounted for about 60% of the patients, and about 60% of study participants had Karnofsky Performance Status of 90% to 100%.
The location of the primary tumor was the pancreatic head in 43% of patients, the body in 31%, and the tail in 25%. About 85% of patients had liver metastases, and 93% of the patients had two or more metastatic sites.
The results showed that patients in the combination arm had a median overall survival of 8.5 months compared with 6.7 months in the gemcitabine arm. The difference represented a 28% reduction in the hazard ratio (P=0.000015).
At every survival assessment -- from 6 to 24 months -- the nab-paclitaxel arm had significantly better survival compared with gemcitabine monotherapy.
The 1-year survival was 32% with nab-paclitaxel plus gemcitabine and 22% with gemcitabine alone (P=0.0002). At 2 years more than twice as many patients were alive in the nab-paclitaxel group (9% versus 4%, P=0.021).
Analysis of prespecified subgroups showed a consistent survival benefit in favor of combination therapy.
A sensitivity analysis accounting for subsequent therapy showed that censoring at the start of second-line therapy resulted in a larger survival difference in favor of nab-paclitaxel (9.4 versus 6.8 months, HR 0.68, P=0.000072).
The median progression-free survival was 5.5 months with the combination and 3.7 months with gemcitabine alone (HR 0.69, P=0.000024). The difference was consistent across the prespecified subgroups.
The response rate, as assessed by independent review, was 23% with combination therapy and 7% with monotherapy. By investigator assessment the rates were 29% and 8%, respectively.
Disease control rates (response plus stable disease) were 48% with the combination and 33% with gemcitabine alone, as determined by independent review.
The safety analysis showed that the nab paclitaxel-gemcitabine combination was more toxic compared with gemcitabine alone. Grade 3+ hematologic and nonhematologic adverse events occurred more often in the combination arm, including:
Neutropenia -- 38% versus 27% Leukopenia -- 31% versus 16% Thrombocytopenia -- 13% versus 9% Anemia -- 13% versus 12% Fatigue -- 17% versus 7% Peripheral neuropathy -- 17% versus <1% Diarrhea -- 6% versus 1% The positive results mean that clinicians have several options for patients with advanced pancreatic cancer, including the FOLFIRINOX combination (a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) and gemcitabine with or without erlotinib (Tarceva). Randomized clinical trials would be the ideal way to compare the regimens, but those trials are unlikely to happen soon, if at all, said invited discussant Philip A. Philip, MD, of Wayne State University in Detroit.
Side-by-side comparison of results with nab-paclitaxel/gemcitabine and FOLFIRINOX provides more questions than answers, he continued. Neither regimen has a clear safety advantage over the other.
Survival data would appear to favor FOLFIRINOX (11.1 versus 8.5 months), but Philip suggested the difference could reflect differences in the study populations. Studies that provided positive results with FOLFIRINOX exclusively involved patients from France, whereas the trial reported by Von Hoff involved patients from different parts of the world.
Philip called for clinical evaluation of nab-paclitaxel -- alone or with gemcitabine or other agents -- in patients with earlier-stage pancreatic cancer and in combinations that include biological agents. He also urged investigators to examine tissue samples from the trial for evidence of biomarkers associated with clinical activity.
The addition of another regimen with activity in metastatic pancreatic cancer does not obscure the need for additional progress, he added.
The evaluation of nab-paclitaxel and gemcitabine is the 'fourth positive
clinical trial in advanced pancreatic cancer in more than four decades,' said
Philip. 'That's something to keep in mind. We have to do much better.'
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