By all measures, the addition of nab-paclitaxel to gemcitabine for the treatment of patients with advanced pancreatic cancer improved the outcomes in comparison to patients who received only gemcitabine, according to the results of a phase III study led by Dr Daniel Von Hoff, TGen Distinguished Professor and Physician-In-Chief, and Chief Scientific Officer for the Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, a partnership with the Translational Genomics Research Institute (TGen) and Scottsdale Healthcare. The results are published October 16 in the New England Journal of Medicine.
In preclinical studies, albumin-bound paclitaxel particles (nab-paclitaxel) showed anti-tumour activity as a single agent and synergistic activity in combination with gemcitabine in murine models of pancreatic cancer. On the basis of preclinical evidence, a phase I–II clinical trial was conducted that involved previously untreated patients with metastatic pancreatic adenocarcinoma; the efficacy was promising, with a median survival of 12.2 months and a manageable safety profile.
The study design
In this international, multicentre, open-label, randomized, phase III study, the researchers randomly assigned eligible patients, in a 1:1 ratio. A total of 861 patients in North America (63%), Eastern Europe (15%), Australia (14%), and Western Europe (9%) underwent randomization at 151 community and academic centres in 11 countries. A total of 431 patients were randomly assigned to nab-paclitaxel plus gemcitabine, and 430 to gemcitabine alone (intention-to-treat population). A total of 421 patients received nab-paclitaxel plus gemcitabine, and 402 received gemcitabine (treated population).
All demographic and clinical characteristics at baseline were well balanced between the two groups. Patients were stratified according to performance status, presence or absence of liver metastases, and geographic region. Treatment continued until disease progression or until there was an unacceptable level of adverse events. Per protocol, crossover was not allowed at any time after randomization.
The investigators evaluated the tumour response in patients every 8 weeks by spiral computed tomography or magnetic resonance imaging. In addition, all scans were independently assessed by two readers and one adjudicator, all of whom were unaware of the treatment assignments, with the use of RECIST, version 1.0. Serial measurements of the carbohydrate antigen 19-9 (CA19-9) level were performed at baseline and every 8 weeks thereafter.
The primary efficacy endpoint was overall survival. The secondary endpoints were progression-free survival and the response rate as assessed by independent radiographic review. Progression-free survival and response rates were also analysed by investigator assessments. Additional efficacy endpoints included the rate of disease control (defined as stable disease for ≥16 weeks, confirmed complete response, or confirmed partial response) and the time to treatment failure. The percentages of patients with a maximum reduction in the CA19-9 level of at least 20% and at least 90% were also calculated for each treatment group.
The study results
This large, randomised, international, phase III study showed that the nab-paclitaxel plus gemcitabine led to a significant improvement in survival at all time points, according to Dr Von Hoff, who was also the principal investigator for the first clinical trial of gemcitabine - the first therapy that showed improvement in survival for patients with pancreatic cancer. The FDA approved gemcitabine in 1996. On 6 September, 2013 the FDA approved nab-paclitaxel for use in advanced pancreatic cancer patients.
In particular, in this study the survival curves separated early, with a median improvement of 1.8 months and an improvement of 3.4 months at the time point when 25% of the patients were alive. The rate of survival was significantly higher in the nab-paclitaxel/gemcitabine group than in the gemcitabine group — at 1 year 35% vs. 22% and at 2 years 9% vs. 4%. A sensitivity analysis of survival showed that the difference between the treatment groups could not be attributed to the use of second-line therapy.
The treatment effect consistently favoured the nab-paclitaxel/gemcitabine group across the majority of pre-specified subgroups. In general, the patients with more advanced disease — those with poorer performance status (Karnofsky performance-status score of 70 or 80), the presence of liver metastasis, more than three sites of metastatic disease, metastatic pancreatic cancer at the initial diagnosis, or a CA19-9 level that was 59 times the upper limit of the normal range or higher — had the greatest reduction in the risk of death. Similar trends were observed for progression-free survival according to subgroup.
The median duration of treatment was 3.9 months (range, 0.1 to 21.9) in the nab-paclitaxel/gemcitabine group and 2.8 months (range, 0.1 to 21.5) in the gemcitabine group, with 32% and 15% of patients, respectively, receiving treatment for at least 6 months. The median relative dose intensity in the nab-paclitaxel/gemcitabine group was 81% for nab-paclitaxel and 75% for gemcitabine. In the gemcitabine group, 33% of patients had dose reductions, resulting in a median relative dose intensity of 85%.
In the nab-paclitaxel/gemcitabine group, the most frequently reported non-haematological adverse events related to treatment were fatigue (in 54% of patients), alopecia (in 50%), and nausea (in 49%). Treatment-related adverse events of grade 3 or higher that were reported more often in the nab-paclitaxel/gemcitabine group than in the gemcitabine group were neutropenia, leucopoenia, fatigue, and peripheral neuropathy. The incidence of peripheral neuropathy (all grades) leading to the discontinuation of nab-paclitaxel was 8%, and the incidence leading to a dose reduction was 10%. None of the patients had grade 4 neuropathy.
The authors concluded that nab-paclitaxel combined with gemcitabine is superior to gemcitabine alone but causes more myelosuppression and peripheral neuropathy; however, these side effects appear to be reversible. Building on these results, the researchers plan to evaluate new targeted agents in combination with the nab-paclitaxel/gemcitabine regimen.
Comparing the results with FOLFIRINOX study
The study authors commented that the phase II–III trial of FOLFIRINOX versus gemcitabine also showed a clinically meaningful improvement in survival among patients with pancreatic adenocarcinoma. The FOLFIRINOX study differed from the current study in several aspects. It pooled data from the phase II and III portions and excluded patients older than 75 years of age. In this study, 10% of the patients were at least 75 years of age. The FOLFIRINOX study also excluded patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, whereas 8% of the patients in this trial had a poor performance status, corresponding to an ECOG performance status of 2. The relevance of these differences is highlighted by the results of a multivariate Cox regression analysis, in which performance status was an independent predictor of survival. Nevertheless, FOLFIRINOX improved median survival by 4.3 months over gemcitabine and is clearly an active regimen.
The study results were presented in part at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, San Francisco, January 24–26, 2013; and the ASCO Annual Meeting, Chicago, May 31–June 4, 2013.
The study was supported by Celgene.