Positron emission tomography response evaluation from a randomized phase III trial of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas.
ABSTRACT: BACKGROUND:In the phase III MPACT trial, nab-paclitaxel plus gemcitabine (nab-P + Gem) demonstrated superior efficacy versus Gem alone for patients with metastatic pancreatic cancer. We sought to examine the feasibility of positron emission tomography (PET) and to compare metabolic response rates and associated correlations with efficacy in the MPACT trial. PATIENTS AND METHODS:Patients with previously untreated metastatic adenocarcinoma of the pancreas were randomized 1:1 to receive nab-P + Gem or Gem alone. Treatment continued until disease progression by RECIST or unacceptable toxicity. RESULTS:PET scans were carried out on the first 257 patients enrolled at PET-equipped centers (PET cohort). Most patients (252 of 257) had ?2 PET-avid lesions, and median maximum standardized uptake values at baseline were 4.6 and 4.5 in the nab-P + Gem and Gem-alone arms, respectively. In a pooled treatment arm analysis, a metabolic response by PET (best response at any time during study) was associated with longer overall survival (OS) (median 11.3 versus 6.9 months; HR, 0.56; P < 0.001). Efficacy results within each treatment arm appeared better for patients with a metabolic response. The metabolic response rate (best response and week 8 response) was higher for nab-P + Gem (best response: 72% versus 53%, P = 0.002; week 8: 67% versus 51%; P = 0.014). Efficacy in the PET cohort was greater for nab-P + Gem versus Gem alone, including for OS (median 10.5 versus 8.4 months; hazard ratio [HR], 0.71; P = 0.009) and ORR by RECIST (31% versus 11%; P < 0.001). CONCLUSION:Pancreatic lesions were PET avid at baseline, and the rate of metabolic response was significantly higher for nab-P + Gem versus Gem alone at week 8 and for best response during study. Having a metabolic response was associated with longer survival, and more patients experienced a metabolic response than a RECIST-defined response. CLINICALTRIALSGOV:NCT00844649.
Project description:BACKGROUND:A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial. PATIENTS AND METHODS:Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks. RESULTS:Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively. CONCLUSION:This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.
Project description:The phase 3 MPACT trial in patients with metastatic pancreatic cancer demonstrated superior efficacy of nab-paclitaxel (nab-P)?+?gemcitabine (Gem) vs Gem monotherapy for all endpoints examined including overall survival, the primary endpoint. In the MPACT trial, patients were treated until progressive disease (PD) or unacceptable toxicity. The current exploratory analysis investigated outcomes of patients from the MPACT trial who were treated until PD, in order to understand how to maximize treatment benefit from nab-P?+?Gem.The trial design has been described in detail previously. Progressive disease was determined by the investigator on the basis of radiological imaging.Among patients who were treated until PD, overall survival was significantly longer for those who received nab-P?+?Gem vs Gem (median, 9.8 vs 7.5 months; P?<?0.001). Independently assessed progression-free survival and overall response rate were significantly greater among patients in the treatment-to-PD cohort who received nab-P?+?Gem compared with Gem (P?<?0.001 for each). Although not compared statistically, patients who were treated until PD received greater treatment exposure and experienced more favourable efficacy than the intent-to-treat population of the MPACT trial. Among patients who were treated with nab-P?+?Gem until PD, > 50 % went on to receive a subsequent therapy. The safety profile for patients treated until PD was similar to what was reported in the overall MPACT trial.The nab-P?+?Gem regimen is an active first-line treatment option; most patients were treated until PD, and this exposure was associated with improved efficacy outcomes. Prolonged first-line treatment exposure and ability to receive subsequent therapies likely contributed to the improved survival among these patients. Our data highlight the importance of managing adverse events and indicate that patients should be treated until PD when possible.ClinicalTrials.gov NCT00844649 (MPACT trial); Registration date of this prospective phase III trial: February 13, 2009; current exploratory subanalysis was conducted retrospectively.
Project description:The phase III MPACT trial in patients with metastatic pancreatic cancer (MPC) demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) compared with Gem monotherapy, including the primary endpoint of overall survival (OS; median 8.7 vs. 6.6 months; hazard ratio [HR] 0.72; P < 0.001). A significant treatment difference favoring nab-P + Gem over Gem was observed for OS in patients treated in North America. The majority of patients were from the US (88%) with only 12% from Canada. Healthcare systems and treatment patterns are different between the 2 countries, and there is limited published information on outcomes of Canadian patients treated with first-line nab-P + Gem. This analysis evaluated efficacy and safety outcomes in Canadian patients in the MPACT trial.Treatment-naive patients with MPC (N = 861) received either nab-P 125 mg/m(2) + Gem 1000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle ?2).The MPACT trial enrolled 63 patients in Canada. Baseline characteristics were well balanced and comparable with those of the intent-to-treat population. Both OS (median 11.9 vs. 7.1 months; HR 0.76; P = 0.373) and progression-free survival (median 7.2 vs. 5.2 months; HR 0.65; P = 0.224) were numerically longer and overall response rate (27% vs. 17%; P = 0.312) was numerically higher with nab-P + Gem vs. Gem. The most common grade ?3 adverse events with nab-P + Gem vs. Gem were neutropenia (22% vs. 10%), fatigue (34% vs. 33%), and neuropathy (25% vs. 0%).This subanalysis confirmed that nab-P + Gem is an efficacious treatment option and has a manageable safety profile in patients with MPC treated in Canada.ClinicalTrials.gov identifier, NCT00844649.Celgene Corporation, Summit, NJ, USA.
Project description:This exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT).Patients who received first-line (1L) nab-paclitaxel+gemcitabine (nab-P+Gem) or Gem were assessed for survival based on 2L treatment received. Multivariate analyses tested influence of treatment effect and prognostic factors on survival.The majority of 2L treatments (267 out of 347, 77%) contained a fluoropyrimidine (5-fluorouracil or capecitabine). Median total survival (1L randomisation to death) for patients who received 2L treatment after 1L nab-P+Gem vs Gem alone was 12.8 vs 9.9 months (P=0.015). Median total survival for patients with a fluoropyrimidine-containing 2L therapy after nab-P+Gem vs Gem was 13.5 vs 9.5 months (P=0.012). Median 2L survival (duration from start of 2L therapy to death) was 5.3 vs 4.5 months for nab-P+Gem vs Gem, respectively (P=0.886). Factors significantly associated with longer post-1L survival by multivariate analyses included 1L nab-P+Gem, receiving 2L treatment, longer 1L progression-free survival, and Karnofsky performance status?70 and neutrophil-to-lymphocyte ratio?5 at the end of 1L treatment.These findings support the use of 2L therapy for patients with metastatic pancreatic cancer. Fluoropyrimidine-containing treatment after 1L nab-P+Gem is an active regimen with significant clinical effect.
Project description:BACKGROUND:Nanoparticle albumin-bound paclitaxel (nab-P) plus gemcitabine (Gem) became a standard treatment option for metastatic pancreatic cancer (MPC) following positive results from a global phase III trial (MPACT). A large number of studies have now published results on the use of nab-P/Gem to treat advanced and early-stage disease, warranting a comprehensive review. The main goal of this systematic review is to summarize the efficacy and safety data of nab-P/Gem for the treatment of pancreatic cancer (PC). METHODS:This systematic review includes results from studies that either published results in a peer-reviewed journal or presented the results at a major oncology conference. RESULTS:Sixty-two studies were included (50 in the advanced/metastatic setting and 12 in the locally advanced setting). Most studies on the treatment of MPC were exclusively first line (33/50). Nevertheless, the studies in this review comprised a broad spectrum of patients, including those <65 and ?65 years of age and those with a Karnofsky performance status of 70-100. Median overall survival (OS) in studies of nab-P/Gem in the advanced/metastatic setting ranged from 8.7 to 13.5 months. In addition, 15 studies of patients with advanced/metastatic PC examined nab-P/Gem as a backbone on which to add a variety of agents, including cancer stem cell inhibitors, stromal disrupting agents, and immune-modulating agents (median OS, 6.9-17 months). Ongoing trials are investigating nab-P/Gem with or without other agents across disease settings. DISCUSSION:Studies conducted after MPACT have demonstrated that nab-P/Gem is an effective regimen for the first-line treatment of MPC for a wide range of patients. Regimens using nab-P/Gem as a backbone on which to combine additional agents are being studied actively, particularly in the advanced disease setting. Ongoing studies will yield valuable insights on the utility of nab-P-containing regimens to improve patient outcomes in PC in both earlier-stage and advanced disease.
Project description:Positron emission tomography (PET) is poised to become a useful imaging modality in staging and evaluating therapeutic responses in patients with metastatic pancreatic cancer (mPC). This analysis from a phase 1/2 study examined the utility of early PET imaging in patients with mPC treated with nab-paclitaxel plus gemcitabine.Tumors were measured by [18F]2-fluoro-2-deoxyglucose PET/computed tomography (CT) in patients who received nab-paclitaxel 100 (n = 13), 125 (n = 38), or 150 (n = 1) mg/m2 plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Lesion metabolic activity was evaluated at baseline and 6 and 12 weeks postbaseline.Fifty-two patients had baseline and ≥1 follow-up PET scan. The median maximum standardized uptake values per pancreatic lesion in the nab-paclitaxel 100 mg/m2 and 125 mg/m2 cohorts were 5.1 and 6.5, respectively. Among patients who had a metabolic response by PET, those who received nab-paclitaxel 125 mg/m2 had a 4-month survival advantage over those who received 100 mg/m2. All patients in the nab-paclitaxel 125 mg/m2 cohort experienced an early complete metabolic response (CMR; 34%) or partial metabolic response (PMR; 66%). In the nab-paclitaxel 125 mg/m2 cohort, investigator-assessed objective response rates were 77% and 44% among patients with a CMR and PMR, respectively, with no correlation between PET and CT response (Spearman r s = 0.22; P = 0.193). Patients in the nab-paclitaxel 125 mg/m2 cohort with a CMR experienced a significantly longer overall survival vs those with a PMR (median, 23.0 vs 11.2 months; P = 0.011), and a significant correlation was found between best percentage change in tumor burden by PET and survival: for each 1% decrease in PET score, the risk of death decreased by 2%.The majority of primary pancreatic tumors and their metastases were PET avid, and PET effectively measured changes in tumor metabolic activity at 6 and 12 weeks. These results support the antitumor activity of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 for treating mPC and the utility of PET for measuring treatment response. Treatment response by PET analysis may be considered when evaluating investigational agents in mPC.NCT00398086.
Project description:PURPOSE:The global Phase III MPACT trial demonstrated superior efficacy of nab-paclitaxel plus gemcitabine over gemcitabine alone as first-line treatment for metastatic pancreatic cancer. Region was a randomization stratification factor in the MPACT trial. This subgroup analysis of MPACT examined efficacy and safety of patients treated in Western Europe. PATIENTS AND METHODS:Patients received nab-paclitaxel plus gemcitabine or gemcitabine alone as first-line treatment for metastatic pancreatic cancer as previously described. A total of 76 patients were included in this analysis (n=38 for each arm). RESULTS:Differences between the overall Western European cohort and the intention-to-treat population included lower percentages of male patients (46% and 58%, respectively) and patients with biliary stents (8% and 17%), and higher percentages of patients with Karnofsky performance status of 90-100 (78% and 60%) and primary tumors in the body of the pancreas (48% and 31%). The median overall survival was 10.7 months with nab-paclitaxel plus gemcitabine vs 6.9 months with gemcitabine alone (hazard ratio [HR]: 0.82 [95% confidence interval (CI): 0.48-1.40]; P=0.471). Median progression-free survival was 5.3 vs 3.7 months, respectively (HR: 0.70 [95% CI: 0.37-1.33]; P=0.277). The independently assessed overall response rate was 18% vs 5% (response rate ratio, 3.50 [95% CI: 0.78-15.78]; P=0.076). The most common grade ?3 adverse events with nab-paclitaxel plus gemcitabine and gemcitabine alone were neutropenia (46% vs 33%, respectively), leukopenia (35% vs 19%), anemia (22% vs 0%), asthenia (21% vs 6%), thrombocytopenia (14% vs 3%), and peripheral neuropathy (13% vs 3%). CONCLUSION:Although a statistically significant difference between the treatment arms was not reached for efficacy endpoints, this study does report treatment benefit and a manageable safety profile associated with nab-paclitaxel plus gemcitabine in patients treated in Western Europe with metastatic pancreatic cancer.
Project description:<h4>Background</h4>In the recent phase III trial MPACT the combination of gemcitabine and nab-paclitaxel (Gem/NabP) showed increased overall survival compared to gemcitabine alone in the treatment of advanced pancreatic ductal adenocarcinoma (aPDA). Until now there has been limited information on the clinical benefit and toxicity of the combination regimen in a real world setting. In addition the value for patients with locally advanced rather than metastatic aPDA has been unclear, since the former category of patients was not included in the MPACT trial.<h4>Methods</h4>A multicentre retrospective observational study in the South Eastern Region of Sweden was performed, with the first 75 consecutive patients diagnosed with aPDA (both locally advanced and metastatic disease) who received first-line treatment with Gem/NabP.<h4>Results</h4>In the overall population median progression free survival (PFS) and overall survival (OS) were 5.2 (3.4-7.0 95% CI) and 10.9 (7.8-14.0 95% CI) months, respectively. Patients with metastatic disease displayed a median OS of 9.4 (4.9-13.9) and a median PFS of 4.5 (3.3-5.7) months whereas the same parameters in the locally advanced subgroup were 17.1 (7.6-26.6) and 6.8 (5.2-8.4) months, respectively. Grade 3-4 hematologic toxicity was recorded: Neutropenia, leukopenia, thrombocytopenia, and anaemia were observed in 23, 20, 5, and 4% of patients, respectively. Dose reductions were performed in 80% of the patients.<h4>Conclusion</h4>This study confirms the effectiveness and safety of first-line Gem/NabP in both locally advanced and metastatic PDA in a real world setting.
Project description:Results from the phase 3 Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) led to approval of nab-paclitaxel plus gemcitabine for first-line treatment of metastatic pancreatic cancer. The current analysis evaluated the effects of nab-paclitaxel plus gemcitabine versus gemcitabine on primary pancreatic and metastatic lesions.In this analysis of the previously described MPACT trial, changes in pancreatic and metastatic tumor burden were assessed using independently measured diameters of lesions on computed tomography or magnetic resonance imaging scans. Changes in the sums of longest tumor diameters were summarized using descriptive statistics and were included in a multivariate analysis of overall survival.Primary pancreatic lesion measurement was feasible. Reductions in primary pancreatic tumor burden and metastatic burden from baseline to nadir were significantly greater with nab-paclitaxel plus gemcitabine versus gemcitabine. Baseline pancreatic tumor burden was independently predictive of survival. Both regimens elicited linear reductions in primary pancreatic and metastatic tumor burden through time. There was a high within-patient concordance of tumor changes between primary pancreatic lesions and metastatic lesions.This analysis of MPACT demonstrated significant tumor shrinkage benefit for nab-paclitaxel plus gemcitabine in both primary pancreatic and metastatic lesions, supporting ongoing evaluation of this regimen in locally advanced disease.
Project description:PURPOSE:To determine whether FDG PET can expand eligibility in biomarker-selected clinical trials by providing a means to quantitate response in patients with non-assessable disease by RECIST. EXPERIMENTAL DESIGN:SUMMIT (NCT01953926) is a multicenter phase II "basket" trial of the Pan-HER kinase inhibitor, neratinib. Patients had advanced ERBB2 (HER2)-mutant solid tumors, ?1 measurable lesion, preferably defined unidimensionally by RECIST v1.1, or alternatively metabolically by PET Response Criteria (PRC). The primary aim was to determine the proportion of additional breast cancer patients accrued using PRC who would have otherwise been ineligible based on RECIST criteria alone. The secondary aim was to determine the concordance of response versus non-response between RECIST and PRC. RESULTS:Eighty-one patients with HER2-mutant metastatic breast cancer were accrued; 77 were evaluable for response by RECIST and/or PRC. 63 (82%) were RECIST-evaluable and 14 (18%) were accrued using PRC alone. Bone-only disease (n = 11; 79%) was the most common reason for classification as non-measurable by RECIST. Twenty-nine patients were accrued and followed using both criteria, of which 25 (86%; 95% confidence interval, 68%-96%) were concordant for response versus non-response as defined by RECIST and PRC. CONCLUSIONS:PRC allowed patients with non-RECIST measurable disease access to therapy and facilitated more rapid accrual of patients to this trial of a rare biomarker. PRC and RECIST both provided methods of response assessment and were generally concordant. Thus, PRC was useful as a supplement to RECIST criteria. This provides a rationale for including FDG PET measurements in future clinical trials involving rare tumors or rare genomically defined subpopulations of more common cancers.