Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates
Reporter: Jacob Shabason, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 6 de junio del 2013
Presenter: Daniel D. Von Hoff, MD Presenter's Affiliation: Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale, Abstract #: 4005
Metastatic pancreatic cancer is a lethal disease with a very poor median survival of approximately 6 months.
nab-paclitaxel (130 nm albumin-bound paclitaxel) has demonstrated preclinical activity and synergy with gemcitabine in preclinical models.
Recent phase I/II data showed promising results for the use of nab-paclitaxel and gemcitabine to treat metastatic pancreatic cancer with a median survival (MS) of 12.2 months, progression free survival (PFS) of 7.9 months and overall response rate (ORR) of 46%.
CA19-9 is an important prognostic biomarker in pancreatic cancer and typically correlates with disease response.
Similarly, metabolic response by PET imaging are good indicators of disease response in pancreatic cancer.
Due to promising phase I/II data the authors performed a phase III randomized trial comparing nab-paclitaxel and gemcitabine to gemcitabine monotherapy in metastatic pancreatic adenocarcinoma.
Materials and Methods
861 patients with metastatic pancreatic cancer were accrued from 151 community and academic cancer centers.
Patients were randomized 1:1 to receive nab-Paclitaxel 125 mg/m2 + Gemcitabine 1000 mg/m2 days 1, 8, and 15 every 4 weeks or Gemcitabine alone 1000 mg/m2weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ? 2).
Inclusion criteria included a Karnofsky performance status (KPS) ? 70.
The primary endpoint was OS.
Secondary Endpoints were PFS and ORR by independent review.
PET scans in an initial cohort of patients were performed at baseline prior to any therapy and at week 8 and 16.
CA19-9 levels were obtained at baseline and then every 8 weeks.
The median age was 63 years (range 27 – 88 years).
KPS was 100 (16%), 90 (44%), 80 (32%), and 70 (7%).
Patients had advanced disease with liver metastases (84%), ? 3 metastatic sites (46%), and CA19-9 ? 59 × upper limit of normal (46%).
nab-Paclitaxel + Gemcitabine was superior to Gemcitabine monotherapy for all efficacy endpoints, including:
Median OS of 8.5 vs. 6.7 months (HR 0.72; 95% CI, 0.617 - 0.835; P = 0.000015).
Median PFS of 5.5 vs. 3.7 months (HR 0.69; 95% CI, 0.581 - 0.821; P = 0.000024)
ORR of 23% vs. 7% (P = 1.1 × 10?10) by RECIST v1.0 criteria.
Metabolic response by PET scans in 257 patients was 63% for nab-Paclitaxel + Gemcitabine vs. 38% for Gemcitabine (P = 0.000051). ORR by CT scans in the same cohort was 31% vs. 11% (p=0.0001).
CA19-9 response (as defined by ? 90% decrease) was 31% for nab-Paclitaxel + Gemcitabine arm vs. 14% for the Gemcitabine monotherapy arm (P < 0.0001).
CA19-9 response (as defined by ? 20% decrease) was 61% for nab-Paclitaxel + Gemcitabine arm vs. 44% for the Gemcitabine montherapy arm (P < 0.0001).
Grade ? 3 adverse events (AEs) with nab-Paclitaxel + Gemcitabine vs. Gemcitabine monotherapy included neutropenia (38% vs. 27%), fatigue (17 % vs. 7%), diarrhea (6% vs. 1%), febrile neutropenia (3% vs. 1%) and peripheral neuropathy (17% vs. 1%).
The median duration of treatment was 3.9 months for nab-Paclitaxel + Gemcitabine and 2.8 months for Gemcitabine.
nab-Paclitaxel + Gemcitabine was superior to Gemcitabine for all efficacy endpoints including OS, PFS, ORR, CA19-9 and PET response.
nab-Paclitaxel + Gemcitabine had an acceptable toxicity profile.
This was a large international study that was performed in diverse community and academic centers and is therefore widely applicable.
nab-Paclitaxel + Gemcitabine is a new standard for the treatment of metastatic pancreatic cancer and has the potential to form the backbone for new regimens in the adjuvant and locally advanced setting.
The authors presented the results of the MPACT randomized trial of nab-paclitaxel + gemcitabine vs. gemcitabine alone for the treatment of metastatic pancreatic adenocarcinoma.
The experimental regimen of nab-paclitaxel + gemcitabine was superior in all study endpoints and can be considered a new standard of care option for the treatment of metastatic pancreatic cancer.
The regimen of nab-paclitaxel + gemcitabine (MS 8.5 months) did not perform as well as FOLFIRINOX (MS 11.1 months) in the recent PRODIGE intergroup trial, which compared FOLFIRINOX vs. gemcitabine in metastatic pancreatic cancer. Although difficult to compare regimens across trials, the MS of gemcitabine montherapy was remarkably similar in the two trials (6.7 months and 6.8 months).
Future research needs to address which patients will benefit more from FOLFIRINOX and which patients from nab-paclitaxel + gemcitabine.
Data from the phase I/II study evaluating nab-paclitaxel + gemcitabine identified SPARC (an albumin binding molecule) expression on tumor stromal cells as an important predictor of response to nab-paclitaxel.
nab-paclitaxel is albumin bound paclitaxel and is thought to specifically target the SPARC protein, and therefore help deplete the dense desmoplastic stroma that is typically associated with pancreatic cancer.
Analysis of SPARC expression is not yet complete for this study.
Overall, the regimen of nab-paclitaxel + gemcitabine is an exciting option for the treatment of metastatic pancreatic cancer and should now be studied in the adjuvant and locally advanced setting.
Further understanding of certain biomarkers, such as SPARC will help guide more personalized directed therapy for patients suffering from pancreatic cancer.
Mar 3, 2014 - Incretin-based drugs seem not to have a causal association with pancreatitis or pancreatic cancer, according to research published in the Feb. 27 issue of the New England Journal of Medicine.