Influence of Prognostic Factors on Survival in Phase III, MPACT Study of Weekly Nab-Paclitaxel plus Gemcitabine in Metastatic Pancreatic Cancer

Highlights from the ESMO 15th World Congress on Gastrointestinal Cancer, 3-6 July 2013, Barcelona, Spain

Dr Josep Tabernero of the Vall d'Hebron University Hospital, Barcelona, Spain presented on the first day of the ESMO 15th World Congress on Gastrointestinal Cancer (3-6 July 2013, Barcelona, Spain) the results from a sub-study on influence of prognostic factors  on overall- and progression-free survival from the MPACT phase III trial of weekly nab-paclitaxel plus gemcitabine in patients with metastatic pancreatic cancer. The most important predictors of longer overall survival (OS) and progression-free survival (PFS) were higher Karnofsky performance status (PS), age < 65 years, absence of liver metastases, and geographic region. A lower number of metastatic sites predicted longer OS, but not PFS. Assignment to nab-paclitaxel plus gemcitabinewas an independent significant predictor of improved survival.

It has been shown in preclinical models that nab-paclitaxel is active as a single agent in pancreatic cancer and furthermore synergizes with gemcitabine. Earlier this year, Dr Daniel Von Hoff presented the main results from the MPACT phase III study at the 2013 Gastrointestinal Cancers Symposium (22-24 January, LBA 148). In this study nab-paclitaxel plus gemcitabine produced a longer median OS (8.5 vs. 6.7 months; hazard ratio [HR], 0.72; p= 0.000015) and median PFS (5.5 vs. 3.7 months; HR, 0.69; p = 0.000024) vs. gemcitabine alone in patients with metastatic pancreatic cancer.

In the MPACT study,861 patients with metastatic pancreatic cancer were randomized 1:1 and stratified by region, presence of liver metastases, and Karnofsky PS to receive nab-paclitaxel/gemcitabine or gemcitabine alone. A step-wise, multivariate Cox proportional hazards model was used to identify predictors of OS and evaluate treatment effect. A separate Cox proportional hazards analysis was performed for PFS.

The following factors were tested: treatment arm, age (< 65 years vs. ≥ 65 years), sex, Karnofsky PS (70-80 vs. 90-100), geographic region (North America used as the reference), primary location of tumour (head vs. other), presence of biliary stent, previous Whipple procedure, presence of liver metastases, presence of pulmonary metastases, peritoneal carcinomatosis, stage at diagnosis (IV vs. other), number of metastatic sites, and serum CA19-9 level.

Region of Eastern Europe, age ≥ 65, Karnofsky PS 70-80, presence of liver metastases, and higher number of metastatic sites all predicted worse OS. The treatment effect for OS remained significant after correcting for these factors in the multivariate analysis (HR, 0.72; p= 0.0001). In another multivariate analysis in which baseline CA19-9 was added to the final model described above, the treatment effect HR was 0.67 (p < 0.0001). Baseline CA19-9, which was a significant predictor of OS by univariate analysis, was not significantly predictive after correction for the above factors. The results of the PFS analysis identified region of Australia, age ≥ 65, Karnofsky PS 70-80, and presence of liver metastases as significant predictors of worse PFS. The treatment effect for PFS remained significant after correcting for these factors (HR, 0.66; p < 0.0001).

Dr Tabernero reported that OS data in intention to treat population favoured the nab-paclitaxel arm. All pre-specified subgroups benefited in term of OS but stepwise multivariate analysis showed that the most important predictors of longer OS and PFS were higher Karnofsky PS, age < 65 years, absence of liver metastases, and region of North America. A lower number of metastatic sites predicted longer OS but not PFS. Baseline CA 19-9 level was not an independent predictor of OS in the multivariate analysis.

Dr Eric Van Cutsem who chaired the session in which Dr Tabernero presented the results from the study questioned on how to benchmark the results achieved with this combination against FOLFIRINOX regimen in the absence of direct comparative studies. Furthermore he asked what would be the biological agent of preference as a backbone to nab-paclitaxel. Dr Tabernero warned that the oncology community should wait first for the full study results publication in the scientific journal and advised to look into scientific data from preclinical models before decision on how further to evaluate nab-paclitaxel in pancreatic cancer.

The Management of Metastatic Pancreatic Cancer: Gemcitabine Monotherapy vs. Doublet Therapy vs. FOLFIRINOX

In the scientific article published in the same supplement issue of the Annals of Oncology, a group of experts provided their recommendations on the management of metastatic pancreatic cancer. It is interesting that the discussion was held a year earlier, in occasion of the ESMO 14th World Congress on Gastrointestinal Cancer. It is in a sense a forward looking manuscript and states that FOLFIRINOX or the nab-paclitaxel/gemcitabine can be considered as reference treatment in fit patients. Fit patients represent 10-35% of the population in that setting and in general concern patients with ECOG PS 0/1, younger than 75 years, those with no or limited comorbidities, and serum bilirubin value < 1.5 ULN. In their article, the experts anticipated that a benefit could be greater with FOLFIRINOX, although toxicity is considered higher for this regimen. The statements in the report have been made based on cross-study comparisons.

The report further states that combination therapy with gemcitabine and erlotinib, platinum derivatives or fluoropyrimidines represent options in fit patients, who are not considered as candidates for FOLFIRINOX or nab-paclitaxel. This patient setting counts 20-30% of the patient population.

The experts summarized in their report that gemcitabine monotherapy may be reserved for patients with poor PS, the elderly and those with significant comorbidities. These settings comprise further 20-30% of the patient population.

Despite some promising data, there are currently no validated predictive markers available for the most effective systemic treatments. The presence of hENT1 on tumour cells may be a relevant predictive marker for gemcitabine, but there are no published validated data for gemcitabine in the setting of advanced disease. For nab-paclitaxel, previous studies suggested that a high expression of SPARC was associated with increased median OS. The data on SPARC expression of the MPACT study may shed light on its role as a prognostic and/or predictive marker in metastatic pancreatic cancer.

In an expert view talk on gemcitabine monotherapy vs. doublet therapy vs. FOLFIRINOX for metastatic pancreatic adenocarcinoma, Dr Jordan Berlin said during the Congress this year, that HR for OS of 0.72 for nab-paclitaxel/gemcitabine treatment is better than for gemcitabine combination with erlotinib or for any drug elaborated in previous meta-analysis. However, the results with FOLFIRINOX regimen represents the most robust data from the phase III study, but it has been done in limited patient subset with PS 0 or 1 only and age < 76 years. The strength is that this regimen includes platinum and therefore minimizes the issue of BRCA2 mutated or other DNA repair deficient tumours. Similarities in studied populations between the two trials are in median age, gender, site of primary tumour, percentage of liver involvement; however highlighted difference isthat MPACT studied included also patients with PS2. Furthermore it has been performed worldwide, while the Groupe Tumeurs Digestives of Unicancer and the PRODIGE Intergroup study was performed in France only.

Dr Berlin stressed also on differences in term of efficacy: OS with FOLFIRINOX regimen was 11,1 months vs. 8,7 months for nab-paclitaxel combination with gemcitabine. Comparison across trials is not really possible – key eligibility criteria (PS and age) differ in two studies. However, gemcitabine control arms achieved the same survival rate in both trials. Combination of nab-paclitaxel and gemcitabine can be tested further with adding another drug and based on currently available scientific data it could be a biological agent, probably one blocking VEGF, according to Dr Jordan.

References:

J. Tabernero et al. Phase III (MPACT) of weekly nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer: Influence of prognostic factors on survival. Ann Oncol 2013; 24 (Suppl. 4): iv11-12. 

C. Verslype et al. The management of metastatic pancreatic cancer: expert discussion and recommendations from the 14th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2012. Ann Oncol 2013; 24 (Suppl.4): iv5-10.