Alfredo Romano

SPARC Expression Did Not Predict Efficacy of nab-Paclitaxel plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial

Purpose: nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of secreted protein acidic and rich in cysteine (SPARC) levels with efficacy as an exploratory endpoint. Experimental Design: Patients with previously untreated MPC (N = 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in pancreatic cancer mouse models in which SPARC was intact or deleted. Results: SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), from the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level [high (n = 71) vs. low (n = 185)] was not associated with overall survival (OS; HR, 1.019; P = 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC was associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy. Conclusions: SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression. Clin Cancer Res; 21(21); 4811–8. ©2015 AACR.

Prognostic Factors of Survival in a Randomized Phase III Trial (MPACT) of Weekly nab-Paclitaxel Plus Gemcitabine Versus Gemcitabine Alone in Patients With Metastatic Pancreatic Cancer

BACKGROUND nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. MATERIALS AND METHODS Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. RESULTS Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. CONCLUSION The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials.

Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer.

Background:This exploratory analysis evaluated second-line (2L) therapy for metastatic pancreatic cancer in a large phase 3 trial (MPACT).Methods: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.Results: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.Conclusions: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.

Immunomodulatory effects in a phase II study of lenalidomide combined with cetuximab in refractory KRAS-mutant metastatic colorectal cancer patients.

This study assessed the immunomodulatory effects in previously treated KRAS-mutant metastatic colorectal cancer patients participating in a phase II multicenter, open-label clinical trial receiving lenalidomide alone or lenalidomide plus cetuximab. The main findings show the T cell immunostimulatory properties of lenalidomide as the drug induced a decrease in the percentage CD45RA+ naïve T cells 3-fold while increasing the percentage HLA-DR+ activated T helper cells and percentage total CD45RO+ CD8+ memory T cytotoxic cells, 2.6- and 2.1-fold respectively (p<0.0001). In addition, lenalidomide decreased the percentage of circulating CD19+ B cells 2.6-fold (p<0.0001). Lenalidomide increased a modest, yet significant, 1.4-fold change in the percentage of circulating natural killer cells. Our findings indicate that lenalidomide significantly activates T cells, suggestive of an immunotherapeutic role for this drug in settings of maintenance therapy and tumor immunity. Furthermore, reported for the first time is the effect of lenalidomide in combination with cetuximab on T cell function, including increases in circulating naïve and central memory T cells. In summary, lenalidomide and cetuximab have significant effects on circulating immune cells in patients with colorectal carcinoma. Trial Registration ClinicalTrials.gov NCT01032291

Phase II Open-Label Study to Assess Efficacy and Safety of Lenalidomide in Combination with Cetuximab in KRAS-Mutant Metastatic Colorectal Cancer

This study aimed to assess the efficacy and safety of combination treatment with lenalidomide and cetuximab in KRAS-mutant metastatic colorectal cancer patients. This was a phase II multicenter, open-label trial comprising a safety lead-in phase (phase IIa) to determine the maximum tolerated dose, and a randomized proof of concept phase (phase IIb) to determine the response rate of lenalidomide plus cetuximab combination therapy. Phase IIa treatment comprised oral lenalidomide (starting dose 25 mg/day) and intravenous cetuximab (400 mg/m2 followed by weekly 250 mg/m2) in 28-day cycles. In phase IIb patients were randomized to either the phase IIa treatment schedule of lenalidomide plus cetuximab combination therapy or lenalidomide 25 mg/day monotherapy. Eight patients were enrolled into phase IIa. One patient developed a dose-limiting toxicity and the maximum tolerated dose of lenalidomide was determined at 25 mg/day. Forty-three patients were enrolled into phase IIb proof of concept. Best response was stable disease in 9 patients and study enrollment was terminated prematurely due to lack of efficacy in both treatment arms and failure to achieve the planned response objective. The majority of adverse events were grade 1 and 2. In both phases, the adverse events most commonly attributed to any study drugs were fatigue, rash and other skin disorders, diarrhea, nausea, and stomatitis. Thirty-nine deaths occurred; none was related to study drug. The combination of lenalidomide and cetuximab appeared to be well tolerated but did not have clinically meaningful activity in KRAS-mutant metastatic colorectal cancer patients. Trial Registration Clinicaltrials.gov NCT01032291

Dose modification and efficacy of nab -paclitaxel plus gemcitabine vs . gemcitabine for patients with metastatic pancreatic cancer: phase III MPACT trial

BACKGROUND Dose modifications following adverse events (AEs) are an important part of the management of patients with pancreatic cancer treated with chemotherapy. While dose modifications are utilized to ensure patient safety, the subsequent influence of dose adjustments on treatment exposure and efficacy have not been reported in detail. This exploratory analysis examined the influence of dose modifications on treatment exposure and efficacy in the phase III MPACT trial, which demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) to Gem alone for the treatment of metastatic pancreatic cancer. METHODS Patients received either nab-P 125 mg/m(2) + Gem 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1,000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥2). The protocol allowed up to 2 dose reductions per agent. Dose delays were also used to manage toxicities. RESULTS Toxicities that most commonly led to dose modifications were neutropenia, peripheral neuropathy, thrombocytopenia, and fatigue for nab-P and neutropenia, thrombocytopenia, and fatigue for Gem alone. Baseline characteristics were similar in patients with dose modifications and the intent-to-treat (ITT) population. Among the 421 treated patients in the nab-P + Gem arm, all patients initiated treatment at the per-protocol nab-P starting dose of 125 mg/m(2); 172 (41%) had a nab-P dose reduction, and 300 (71%) had a nab-P dose delay during the study. Most dose modifications occurred after the first 3 months (2 cycles) of treatment. The majority of patients (104/172, 60%) required only 1 nab-P dose reduction, and over half of patients (163/300) had either 1 or 2 dose delays. Patients who underwent dose modifications of nab-P had greater treatment exposure than those who did not in terms of treatment duration, number of cycles administered, and cumulative dose of nab-P delivered. Overall survival (OS) was shorter in the nab-P + Gem arm for patients who did not vs. did undergo dose reduction [median, 6.9 vs. 11.4 months; hazard ratio (HR), 1.93; 95% CI, 1.53-2.44; P<0.0001] and for those who did not vs. did undergo a dose delay (median, 6.2 vs. 10.1, HR, 2.05; 95% CI, 1.60-2.63; P<0.0001). Progression-free survival (PFS) and overall response rate (ORR) were also improved in patients with dose modifications. Similar trends were observed in the Gem-alone arm. Multivariate analyses confirmed that both dose delay and dose reduction were significantly associated with OS. CONCLUSIONS This analysis suggests that although most doses of nab-P were given at the starting dose of 125 mg/m(2) the first 3 of 4 weeks, dose reductions and delays were effective when necessary to ameliorate toxicity allowing greater treatment exposure without compromising efficacy.

693PNAB-PACLITAXEL (NAB-P) PLUS GEMCITABINE (GEM) VS GEM ALONE FOR PATIENTS (PTS) WITH METASTATIC PANCREATIC CANCER (PC): SUBGROUP ANALYSES OF THE MPACT TRIAL BASED ON THE PRESENCE OF LIVER METASTASES (LMS) AND NUMBER OF METASTATIC SITES

ABSTRACT Aim: Metastatic PC is associated with one of the worst prognoses among all the types of solid tumors. The presence of LMs and multiple sites of metastasis are factors associated with poorer prognosis. In the MPACT trial, nab-P + Gem demonstrated superior overall survival (OS, primary endpoint) vs Gem alone as first-line treatment for metastatic PC (Table). We report the efficacy and safety of nab-P + Gem vs Gem alone based on the presence of LMs and the number of metastatic sites. Methods: Previously untreated pts (N = 861) with metastatic PC were randomized 1:1 (stratified by performance status, region, and the presence of LMs) to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle or Gem alone 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: Treatment arms were well balanced with respect to LMs and the number of metastatic sites: 84% of pts had LMs and 79% had 2 or 3 metastatic sites. In pts with LMs, median OS was significantly longer with nab-P + Gem vs Gem alone (Table). Similar trends were seen for PFS (5.4 vs 3.6 mo; HR 0.65; P Patient Population n Median OS, mo nab-P + Gem Gem nab-P + Gem Gem HR P Value ITT 431 430 8.5 6.7 0.72 Subgroups With LMs 365 360 8.3 5.9 0.69 No. of metastatic sites 1 33 21 13.5 9.0 0.41 0.021 2 202 206 8.3 7.1 0.75 0.015 3 136 140 8.0 5.9 0.79 0.093 > 3 60 63 8.6 5.0 0.50 0.001 Conclusions: In the MPACT trial, nab-P + Gem demonstrated longer OS vs Gem alone in the ITT population. The results for pts with LMs and in subgroups defined by the number of metastatic sites were consistent with the ITT findings. No new safety signals were observed. Disclosure: C. Weekes: has received honoraria for advisory board participation in the past 3 years from Celgene F. Parnis: servied on the advisory board for Specialised Therapeutics; A. Santoro: is a consultant/advisor to Celgene; A. Romano, D. McGovern and D. Penenberg: is an employee of Celgene and owns stock; D.D. Von Hoff: is a consultant/advisory for Celgene and receives honoraria from them. He also receives research funding from TGen Clinical Research Service. All other authors have declared no conflicts of interest.

nab-Paclitaxel plus gemcitabine in metastatic pancreatic adenocarcinoma: Australian subset analyses of the phase III MPACT trial

The phase III MPACT trial (N = 861) demonstrated superior overall survival (OS) with first‐line nab‐paclitaxel plus gemcitabine versus gemcitabine alone (median, 8.7 months vs 6.6 months; hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.62–0.83; P < 0.001) in patients with metastatic pancreatic cancer. The efficacy benefit of the combination over gemcitabine alone was observed across patient subgroups, including those based on region. This subset analysis was designed to examine the safety and efficacy of nab‐paclitaxel plus gemcitabine in patients treated in Australia to understand whether differences in patient population or regional variations in patient care had any impact on clinical outcomes.

Phase III study of nab-paclitaxel (nab-P) plus gemcitabine (Gem) versus Gem alone in patients (pts) with metastatic pancreatic adenocarcinoma (mPC): Subgroup analysis of Canadian pts from the MPACT trial.

439 Background: Weekly nab-P + Gem is a new option for first-line treatment (Tx) of mPC. In the MPACT trial, nab-P/Gem demonstrated superior overall survival (OS; primary endpoint) vs Gem alone as first-line Tx of mPC (Table). Here we report a subgroup analyses evaluating the efficacy and safety outcomes with nab-P + Gem vs Gem alone from the Canadian cohort of the MPACT trial. Methods: Previously untreated pts (N = 861) with mPC were randomized 1:1 (stratified by Karnofsky Performance Status [KPS], region, and the presence of liver metastases) to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle or Gem 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: 63 pts from Canada enrolled in the MPACT trial. Baseline pt characteristics were well balanced. Median age was 61 years and KPS was similar for both groups and comparable to the intent-to-treat (ITT) populations. Primary lesion in the panc...

691PREGIONAL SUBANALYSIS OF THE PHASE III MPACT TRIAL: NAB-PACLITAXEL (NAB-P) PLUS GEMCITABINE (GEM) VS GEM ALONE FOR PATIENTS (PTS) WITH METASTATIC PANCREATIC CANCER (PC)

ABSTRACT Aim: nab-P + Gem demonstrated superior efficacy over Gem alone in the MPACT trial of patients with metastatic PC. An updated analysis confirmed the superior OS (primary endpoint) of nab-P + Gem vs Gem alone (8.7 vs 6.6 mo; HR 0.72; P Methods: Previously untreated pts with metastatic PC were randomized 1:1—stratified by performance status, region (Australia [AU], Eastern Europe [EE], Western Europe [WE], or North America [NA]), and the presence of liver metastases—to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on d 1, 8, and 15 of each 28-day cycle or Gem 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then d 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: The analysis included 861 pts. An updated OS analysis (data cutoff 9 May 2013) revealed that OS was longer for nab-P + Gem vs Gem alone in each region, although the difference was not statistically significant in all cases (table). Similar trends were observed for PFS and ORR. White blood cell growth factors were used at the following rates (nab-P + Gem vs Gem): NA, 28% vs 16%; EE, 16% vs 13%; AU, 16% vs 12%; WE, 37% vs 11%. The safety profile of each treatment arm was similar across the regions. Differences in the proportion of pts receiving post-progression therapies were noted for some regions (nab-P + Gem vs Gem): NA, 40% vs 42%; EE, 20% vs 31%; AU, 39% vs 41%; WE, 45% vs 55%. The rates of use were different across regions for 5-FU/capecitabine-based therapies (NA, 26% vs 31%; EE, 17% vs 26%; AU, 26% vs 22%; WE, 42% vs 47%) and FOLFIRINOX (NA, 6% vs 7%; EE, 0 vs 2%; AU, 2% vs 2%; WE, 3% vs 8%). nab-P + Gem Gem HR (95% CI) P Value n Median OS, mo n Median OS, mo North America 268 8.8 271 6.6 0.69 (0.57-0.82) Eastern Europe 64 7.7 62 5.9 0.84 (0.58-1.23) 0.372 Australia 61 9.4 59 6.7 0.59 (0.40-0.88) 0.010 Western Europe 38 10.7 38 6.9 0.82 (0.48-1.40) 0.471 Conclusions: nab-P + Gem was associated with improved survival compared with Gem alone in pts with metastatic PC, regardless of region. Variations in postprogression therapy use were noted across regions. Disclosure: R.K. Ramanathan: a consultant/advisor to Celgene, receives honoraria and research funding from them as well; D. Goldstein: is a consultant/advisor for Celgene and receives research funding from them; A. Romano: is a Celgene employee and owns stock; D. Penenberg: is a an employee of Celgene and owns stock; D.D. Von Hoff: is a consultant/advisor for Celgene and receives honoraria from them. He also receives research funding from TG Clinical Research. All other authors have declared no conflicts of interest.