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Drug Profile
Nab-paclitaxel and gemcitabine for the treatment of patients with metastatic pancreatic cancer Expert Rev. Gastroenterol. Hepatol. 8(7), 739–747 (2014)
Erkut Borazanci* and Daniel D Von Hoff Translational Genomics Research Institute, Phoenix, AZ, USA and Virginia G. Piper Cancer Center, Scottsdale, AZ, USA *Author for correspondence: [email protected]
Adenocarcinoma of the pancreas or pancreatic cancer as we will refer to it here, is a cancer of poor prognosis with a high mortality, particularly in the advanced or metastatic setting. Until 2011 and the Phase III results of FOLFIRINOX, standard treatment options were limited to gemcitabine. Combination therapy had shown either a lack of or very limited improvement versus monotherapy with gemcitabine. With the positive results of the MPACT study in 2013 showing improved survival with nab-paclitaxel plus gemcitabine combination therapy, there are now more options for oncologists to treat patients with advanced pancreatic cancer. This paper will highlight the Phase I/II and Phase III trials of nab-paclitaxel plus gemcitabine along with discussing their biology and further possible development in treating patients with pancreatic cancer. KEYWORDS: 5-fluorouracil • FOLFIRINOX • gemcitabine • nab-paclitaxel • pancreatic adenocarcinoma • pancreatic cancer
Pancreatic cancer remains a deadly disease despite decades of research and modern chemotherapy. In 2013, in the USA, approximately 46,420 new cases of pancreatic cancer were diagnosed and 39,590 deaths were reported. The 5-year survival in patients with metastatic pancreatic cancer was estimated to be 2% [1]. More than 80% of patients diagnosed with pancreatic adenocarcinoma have either locally advanced inoperable or metastatic disease at the time of initial presentation. Median survival of patients with metastatic pancreatic cancer has been approximately 6 months [2]. Pancreatic cancer is a complex genetic disease, taking several years to develop, and undergoing several mutations through CDKN2A, SMAD4, TP53 and KRAS [3]. The average pancreatic cancer appears to have several core signaling pathways and processes altered genetically including those involved in apoptosis, DNA damage control, cell cycle, cell adhesion processes, developmental signal pathways and tissue invasion and neovascularization [3,4]. Despite our increasing knowledge of pancreatic adenocarcinoma, prognosis remains to be poor. However, in the past 3 years, there informahealthcare.com
10.1586/17474124.2014.925799
has been significant, clinically meaningful strides regarding the treatment of pancreatic cancer and this paper will discuss one of those advances, specifically the drug combination nab-paclitaxel plus gemcitabine. 5-Fluorouracil (5-FU) was one of the original treatments for patients with advanced pancreatic cancer, although the response rate varied widely between 0 and 67% and overall survival (OS) varied from 2.5 to 6 months [5,6]. In 1997, a landmark study was published comparing gemcitabine with 5-FU in patients with advanced pancreatic cancer. The trial published in 1997 examined 126 patients with advanced pancreatic cancer who were randomized to receive either gemcitabine 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest, then weekly for 3 weeks in a 4-week cycle compared with 5-FU 600 mg/m2 weekly. The primary end point of the study was to determine clinical benefit, which was determined from the measurements of pain, functional impairment and weight loss. Twenty-three percent of patients receiving gemcitabine were determined to derive clinical benefit compared with only 4.8% of patients receiving 5-FU.
2014 Informa UK Ltd
ISSN 1747-4124
739
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Washington University Library on 01/11/15 For personal use only.
Drug Profile
Borazanci & Von Hoff
The median OS was 5.65 months in the gemcitabine group compared with 4.41 months in those treated with 5-FU. Time to progression was determined to be 9 weeks for gemcitabine and 4 weeks for 5-FU. Of note is that the 1-year survival rate was 18% for patients with advanced pancreatic cancer treated with gemcitabine compared with 2% of those treated with 5-FU [7]. Since the publication of gemcitabine in treating patients with advanced pancreatic cancer, there have been several trials in various combinations with gemcitabine or 5-FU examined. Only two Phase III trials have shown improvement on gemcitabine monotherapy for advanced pancreatic cancer. One trial was a combination study of gemcitabine plus erlotinib, an EGFR inhibitor, which was published in 2007. The study was an international double-blinded Phase III study that enrolled 569 patients randomized to receive either erlotinib plus gemcitabine or gemcitabine only. OS was 6.24 months in the combination arm versus 5.91 in the gemcitabine only arm, with a 1-year survival of 23% in the erlotinib plus gemcitabine versus 17% in the gemcitabine only. While this was statistically significant, the total time difference between OS was 10 days [8]. Another trial published in 2005 compared a combination therapy of cisplatin, epirubicin, gemcitabine and 5-FU (termed PEFG) compared with gemcitabine monotherapy [9]. The primary end point of the study of progression-free survival (PFS) at 4 months was met, with 60% PFS at 4 months in the PEFG regimen arm compared with 28% in the gemcitabine only arm. The 1-year OS rate of PEFG was 38.5% compared with 21.3% in gemcitabine only arm, although this was not statistically significant. The 2-year survival was 11.5% in the PEFG arm compared with 2.1% in the gemcitabine arm and this was statistically significant [9]. Unfortunately, from 1997 until 2011 those were the only positive Phase III clinical trials published in patients with advanced pancreatic cancer [4,10]. Several combinations have been examined with gemcitabine including adding cytotoxic chemotherapies such as cisplatin, oxaliplatin, 5-FU, capecitabine, irinotecan or pemetrexed [4,10]. The story was the same with combinations of gemcitabine with novel agents including those that targeted matrix metalloproteinase, farnesyltransferase inhibitors (which targets KRAS), tyrosine kinase inhibitors, monoclonal antibodies to EGFR and monoclonal antibodies to VEGF [4,10]. In 2011, results of a Phase II/III, multicenter, randomized study comparing the drug combination of 5-FU, oxaliplatin, irinotecan and leucovorin (FOLFIRINOX) with gemcitabine was published [11]. The study enrolled 342 patients with an Eastern Cooperative Oncology Group score of 0 or 1, and 57% of the pancreatic cancer tumor location was either the body or tail of the pancreas. The dosing in the FOLFIRINOX combination was oxaliplatin 85 mg/m2, leucovorin at 400 mg/ m2, irinotecan 180 mg/m2. Fluorouracil was given as a bolus 400 mg/m2 followed by a 46-h infusion dose of 2400 mg/m2. This combination was repeated every 2 weeks. FOLFIRINOX was compared with single agent gemcitabine, which was given at a dose of 1000 mg/m2 weekly for 7 weeks followed by a 740
1-week rest, then weekly for 3 weeks in subsequent 4-week courses. The primary end point for the Phase II trial was tumor response and the secondary end point was safety. For the Phase III study, the primary end point was OS with PFS, tumor response, safety and quality-of-life secondary end points. In the FOLFIRINOX combination, the median OS was 11.1 months compared with 6.8 months in the gemcitabine only cohort (hazard ratio [HR] for death 0.57; p < 0.001). PFS was 6.4 months in the FOLFIRINOX combination and 3.3 months in the gemcitabine only group (HR: 0.47; p < 0.001). The most common grade 3 or grade 4 adverse events (AEs) in the FOLFIRINOX combination were neutropenia (45.7%), fatigue (23.6%), vomiting (14.5%), diarrhea (12.7%) and thrombocytopenia (9.1%). Of note, the study involved 48 centers all in France [11]. Intro to drug
Gemcitabine, or difluorodeoxycytidine, is a nucleoside analog whose metabolized product difluorodeoxycytidine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA and inhibits DNA synthesis by masked chain termination [7,12]. Gemcitabine is metabolized intracellularly by deoxycytidine kinase (dCK) to its active products difluorodeoxycytidine diphosphate and triphosphate (difluorodeoxycytidine triphosphate) nucleoside and has a half-life range of 42–94 min with a time to peak in the plasma of 30 min after infusion [12,13]. There are no recommended dosing adjustments for renal or hepatic impairment of gemcitabine, although some suggestions have been made to start the initial dose at 800 mg/m2 if the serum bilirubin is >1.6 mg/dl [14,13]. Gemcitabine is predominantly excreted through the urine (92–98%) and feces (1%) [13]. Various methods of gemcitabine resistance have been elucidated over the years. Gemcitabine requires human equilibrative transporters 1 and 2 and human concentrative nucleoside transporter 1 to mediate transport. Expression levels of these proteins have correlated with varying levels of gemcitabine sensitivity. Efflux transporters such as ATP-binding cassette family of multidrug resistance-associated proteins have also been shown to play a significant role in gemcitabine resistance. Expression of dCK also has been linked to sensitivity and resistance to gemcitabine in pancreatic cancer [12]. Gemcitabine is rendered inactive by cytidine deaminase, which removes the NH2 group from the pyrimidine, which in turn causes the uracil metabolite to be exported from the cell. The now accepted standard of giving weekly gemcitabine in a 3-week schedule every 4 weeks after an initial weekly schedule for 7 weeks with 1 week off was born out of pharmocokinetic studies showing better safety and tolerability. Overcoming resistance to gemcitabine has been difficult and will be touched upon further in this review in regards to the combination of nab-paclitaxel plus gemcitabine. Methods such as using 5-azacytidine, which exerts its effect by reducing methylation, have shown greater efficacy in combination with gemcitabine [12]. Expert Rev. Gastroenterol. Hepatol. 8(7), (2014)
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Washington University Library on 01/11/15 For personal use only.
Nab-paclitaxel & gemcitabine for the treatment of patients with metastatic pancreatic cancer
Paclitaxel is a member of the taxane family, which are isolated from the bark of the Yew tree [12]. The taxol family mechanism of action is inhibiting mitosis by inhibiting the depolymerization of microtubules, which blocks cells moving from the G2 and M phases of the cell cycle [15]. Paclitaxel comes in several different formulations and its natural form has high insolubility in water [15,16]. One formulation of the drug was created by adding polyethoxylated castor oil solvent (Cremaphor) and is termed Cre-paclitaxel, which allowed the drug to be given intravenously [16]. Prior to the development of nab-paclitaxel, paclitaxel had been studied in pancreatic cancer [17,18]. In a Phase II study published in 1997, 45 chemo-naı¨ve patients with advanced pancreatic cancer were treated with paclitaxel given every 3 weeks and had a response rate of only 8% and were deemed to have minimal activity in pancreatic cancer [17]. Another study published in 2010 examined 19 patients with advanced pancreatic cancer who were given paclitaxel and the protein kinase C inhibitor bryostatin-1 that could have had prior treatment. Not a single patient had a confirmed response [18]. The albumin formulation of paclitaxel, nab-paclitaxel is formulated with human serum albumin at a concentration similar to the concentration of albumin in blood and is formulated through high-pressure homogenization in which albumin and paclitaxel are combined to create particles 130 nm in diameter [19]. Nab-paclitaxel may be reconstituted with a simple saline solution [15]. There is a significantly reduced risk of infusion hypersensitivity reactions, decreased risk of neutropenia and faster recovery of peripheral neuropathy [16]. Because of the decreased risk of hypersensitivity reactions of nab-paclitaxel, steroid or antihistamine prophylaxis usually is unnecessary. However, when nab-paclitaxel is combined with gemcitabine, we usually use steroids as antiemetics and to decrease the flu-like syndrome associated with gemcitabine. Nab-paclitaxel has been approved for use in non-small-cell lung cancer, breast cancer and more recently, pancreatic cancer [15,13]. Upon injection the nab-paclitaxel particles dissolve into soluble albumin-paclitaxel complexes, and paclitaxel may bind and unbind albumin. Nab-paclitaxel has been shown in pharmacokinetics studies to have a much higher fraction of unbound paclitaxel when compared with traditional paclitaxel [15]. Nab-paclitaxel achieves a higher plasma clearance and a larger volume of distribution compared with paclitaxel [15,20]. In preclinical models of cancer, albumin has been shown to accumulate in proximity to tumors and that cancer cells use albumin for metabolism [15,21]. Nab-paclitaxel has been hypothesized to take advantage of circulating albumin that crosses endothelial cells to reach tumors and has been reported in two ways: through receptor-mediated transcytosis and the enhanced permeation and retention effect [15,22,23]. Albumin binds to the albumin-specific receptor glycoprotein 60 (gp60), which helps mediate transcytosis. Experiments have been done to show that nab-paclitaxel has a greater than fourfold level of transport through endothelial cells in culture compared with paclitaxel [24]. informahealthcare.com
Drug Profile
Tumor accumulation of nab-paclitaxel may also be utilized by taking advantage of secreted protein acidic and rich in cysteine (SPARC) proteins that appear to be overexpressed in several tumors, especially pancreatic cancer [14,15]. SPARC is a calciumbinding protein, which is present in stromal fibroblasts and its overexpression promotes cancer cell invasion and metastasis [14]. Increased SPARC expression has been suggested to play a role in more effective response to nab-paclitaxel, although this has not been seen in all tumor types [15,25,26]. As discussed in the results of the Phase I/II trial, SPARC expression appeared to play a significant role in treatment efficacy of nab-paclitaxel plus gemcitabine [14,15,27]. A study involving KPC mice, which closely resemble the human model for pancreatic cancer and have mutations in KRAS and P53, was used to study the effects of gemcitabine and nab-paclitaxel together. This study showed that the combination increased apoptosis and that nabpaclitaxel promoted intratumoral gemcitabine levels. This effect was not seen when combining paclitaxel and gemcitabine [28]. The mechanism of this effect was not seen by way of tumor stroma disruption, which was shown as an accompanying study in the Phase I/II trial [27]. Instead, nab-paclitaxel downregulated the enzyme cytidine deaminase, which metabolizes gemcitabine [28]. Both studies came to the same findings of increased intratumoral gemcitabine, but were performed with separate mouse tumor models and dosing [27,28]. Nab-paclitaxel is metabolized by CYP2C8 and CYP3A4 and is metabolized in the liver. For patients with pancreatic adenocarcinoma and mild liver impairment with an aspartate transaminase 1.26 ULN is not recommended. Nab-paclitaxel’s half-life is approximately 27 h and is excreted predominantly through the feces (20%) and less through the urine (4%) [29]. Clinical efficacy
The Phase I/II study of nab-paclitaxel plus gemcitabine was published in December 2011 [27]. The study was an open-label Phase I/II study conducted at four centers in the USA in patients older than 18 years of age with previously untreated metastatic pancreatic cancer. Patients were allowed prior adjuvant treatment with 5-FU or gemcitabine along with radiation therapy as long as it was 6 months prior to enrollment. The Phase I portion was designed to identify the maximum tolerated dose (MTD) and dose-limiting toxicities of nab-paclitaxel. The dosing schedule was treatment on days 1, 8 and 15 on a 28-day cycle using the standard 3+3 Phase I dose escalation design. Three cohorts were studied with the dosing of nab-paclitaxel at either 100, 125 or 150 mg/m2 followed by gemcitabine at 1000 mg/m2. A total of 67 patients were enrolled. The MTD was established at dose level 2 for nab-paclitaxel, 125 mg/m2. In the 44 patients treated at the MTD, the median PFS was 7.9 months, median OS was 12.2 months and the 1-year survival was 48%. For all 67 patients, the median PFS was 741
Drug Profile
Borazanci & Von Hoff
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Table 1. Summary of Phase I/II trial results of nab-paclitaxel plus gemcitabine for those treated at the maximal tolerated dose of nab-paclitaxel 125 mg/m2. Median PFS
Median OS
1-Year survival
ORR
Disease control rate
High-SPARC OS (n = 19)
Low-SPARC OS (m = 17)
7.9 months (95% CI: 5.8–11.1 months)
12.2 months (95% CI: 8.9–17.9 months)
48%
48%
68%
17.8 months
8.1 months
Disease control rate: complete response, partial response, stable disease ‡16 weeks. ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival. Data taken from [27].
7.1 months and median OS was 10.3 months. Additionally, PET scan analysis was done at baseline, and at 6 and 12 weeks. 18-Fluorodeoxyglucose PET scans were available in 55 patients and showed a median decrease in activity of 79% in all three cohorts. Patients with a complete metabolic response as defined by the European Organization for Research and Treatment of Cancer criteria by the absence of 18-fluorodeoxyglucose uptake had a significantly improved OS compared with those patients without a complete metabolic response (median OS of 20.1 vs 10.3 months; p = 0.01). The median number of cycles administered of nab-paclitaxel plus gemcitabine was 6.0. The most common grade 3 or greater AEs at the MTD cohort, nabpaclitaxel at 125 mg/m2, were neutropenia (75%), leucopenia (56%), thrombocytopenia (28%), fatigue (27%), sensory neuropathy (20%) and anemia (14%). Only 2% of patients at the MTD had a grade 3 or greater febrile neutropenia [27]. Further analysis was done in regards to the aforementioned SPARC status, which was evaluated in 36 patients [27]. Patients were classified into those with high-SPARC (n = 19) or lowSPARC (n = 17). There was a significant increase in median OS in patients with high-SPARC, 17.8 months, compared with those with low-SPARC, 8.1 months (p = 0.0431). SPARC level remained a significant predictor of median OS after multivariate COX regression analysis. Patient’s CA 19-9 levels also correlated with PFS and OS, with those patients in the MTD having at least a 50% decrease in CA 19-9 correlating with a 62% overall response rate and 8.0 and 13.6 medians months of PFS and OS, compared with those with less than 50% decrease having a 33% overall response rate and 3.6 and 6.5 months of PFS and OS, respectively [27]. The results of the Phase I/II study are summarized in TABLE 1. The Phase I/II trial of gemcitabine plus nab-paclitaxel also included mouse xenograft studies. The xenograft studies were carried out using fresh pancreatic cancer tissue from 11 patients. What was noteworthy was intratumor concentrations of gemcitabine were significantly higher in combination with nabpaclitaxel compared with gemcitabine–alone-treated mice [27]. The international, multicenter, open-label, randomized, Phase III study of nab-paclitaxel plus gemcitabine was presented at the 2013 Gastrointestinal Cancers Symposium [30]. The Phase III study was published in October 2013 [31]. The trial consisted of 861 patients diagnosed with metastatic pancreatic cancer. As in the Phase I/II study, patients were allowed to receive 5-FU or gemcitabine as a radiation sensitizer in the adjuvant setting if at least 6 months had passed prior to 742
enrollment but otherwise did not receive chemotherapy for metastatic pancreatic cancer. The patients were treated at 151 community and academic centers throughout North America, Western and Easter Europe and Australia, and were randomly assigned to receive either nab-paclitaxel plus gemcitabine or gemcitabine alone. The eligibility criteria consisted of adults of 18 years of age and having a Karnofsky performance status score of 70 or more. Patients were treated on days 1, 8 and 15 in the nab-paclitaxel plus gemcitabine arm at a dose of 125 and 1000 mg/m2, respectively. In the gemcitabine only arm, patients were treated initially on days 1, 8, 15, 29, 36, 43 at a dose of 1000 mg/m2 and then weekly for 3 weeks in a 4-week cycle. The primary end point was OS and the secondary end points were PFS and response rate. The median OS in the nabpaclitaxel plus gemcitabine group was 8.5 months compared with 6.7 months in the gemcitabine only group with a HR for death at 0.72 (95% CI: 0.62–0.83). The 1-year OS was 35% in the combination group versus 22% in the gemcitabine only group (p < 0.001). The 2-year survival in the combination group was 9% compared with 4% in the gemcitabine only group (p = 0.02). PFS was 5.5 months in the nab-paclitaxel plus gemcitabine group compared with 3.7 months in the gemcitabine only group (p < 0.001). The results of this study are shown in TABLE 2. Common AEs that were grade 3 or higher included neutropenia (38%), leucopenia (31%), thrombocytopenia (13%), anemia (13%), fatigue (17%) and peripheral neuropathy (17%). Serious AEs that were reported were sepsis, which was more common in the nab-paclitaxel plus gemcitabine group at 5% compared with 2% in the gemcitabine group along with pneumonitis, which was 4% in the nab-paclitaxel group compared with 1% in the gemcitabine only group. Fatal events were 4% in each treatment group [31]. Due to the results of this trial, the US FDA approved nab-paclitaxel plus gemcitabine as first-line treatment in patients with metastatic adenocarcinoma of the pancreas on 6 September 2013 [13]. An update of the Phase III study of nab-paclitaxel plus gemcitabine was presented at the 2014 Gastrointestinal Symposium meeting. The update reported the 2-year OS rate of nab-paclitaxel plus gemcitabine to be 10 versus 5% in gemcitabine only and the 3-year OS rate of nab-paclitaxel plus gemcitabine to be 4 versus 0% in the gemcitabine only group [32]. Post-marketing surveillance
Post-marketing experience with nab-paclitaxel includes hypersensitivity reactions, which can be fatal, cardiovascular effects Expert Rev. Gastroenterol. Hepatol. 8(7), (2014)
Nab-paclitaxel & gemcitabine for the treatment of patients with metastatic pancreatic cancer
Drug Profile
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Table 2. Summary of Phase III trial results of nab-paclitaxel plus gemcitabine compared with gemcitabine for patients with metastatic pancreatic adenocarcinoma. Nab-paclitaxel plus gemcitabine
Gemcitabine alone
Hazard ratio or response rate ratio (95% CI)
p-value
PFS (in months)
5.5
3.7
0.69 (0.58–0.82)
Drug Profile
Nab-paclitaxel and gemcitabine for the treatment of patients with metastatic pancreatic cancer Expert Rev. Gastroenterol. Hepatol. 8(7), 739–747 (2014)
Erkut Borazanci* and Daniel D Von Hoff Translational Genomics Research Institute, Phoenix, AZ, USA and Virginia G. Piper Cancer Center, Scottsdale, AZ, USA *Author for correspondence: [email protected]
Adenocarcinoma of the pancreas or pancreatic cancer as we will refer to it here, is a cancer of poor prognosis with a high mortality, particularly in the advanced or metastatic setting. Until 2011 and the Phase III results of FOLFIRINOX, standard treatment options were limited to gemcitabine. Combination therapy had shown either a lack of or very limited improvement versus monotherapy with gemcitabine. With the positive results of the MPACT study in 2013 showing improved survival with nab-paclitaxel plus gemcitabine combination therapy, there are now more options for oncologists to treat patients with advanced pancreatic cancer. This paper will highlight the Phase I/II and Phase III trials of nab-paclitaxel plus gemcitabine along with discussing their biology and further possible development in treating patients with pancreatic cancer. KEYWORDS: 5-fluorouracil • FOLFIRINOX • gemcitabine • nab-paclitaxel • pancreatic adenocarcinoma • pancreatic cancer
Pancreatic cancer remains a deadly disease despite decades of research and modern chemotherapy. In 2013, in the USA, approximately 46,420 new cases of pancreatic cancer were diagnosed and 39,590 deaths were reported. The 5-year survival in patients with metastatic pancreatic cancer was estimated to be 2% [1]. More than 80% of patients diagnosed with pancreatic adenocarcinoma have either locally advanced inoperable or metastatic disease at the time of initial presentation. Median survival of patients with metastatic pancreatic cancer has been approximately 6 months [2]. Pancreatic cancer is a complex genetic disease, taking several years to develop, and undergoing several mutations through CDKN2A, SMAD4, TP53 and KRAS [3]. The average pancreatic cancer appears to have several core signaling pathways and processes altered genetically including those involved in apoptosis, DNA damage control, cell cycle, cell adhesion processes, developmental signal pathways and tissue invasion and neovascularization [3,4]. Despite our increasing knowledge of pancreatic adenocarcinoma, prognosis remains to be poor. However, in the past 3 years, there informahealthcare.com
10.1586/17474124.2014.925799
has been significant, clinically meaningful strides regarding the treatment of pancreatic cancer and this paper will discuss one of those advances, specifically the drug combination nab-paclitaxel plus gemcitabine. 5-Fluorouracil (5-FU) was one of the original treatments for patients with advanced pancreatic cancer, although the response rate varied widely between 0 and 67% and overall survival (OS) varied from 2.5 to 6 months [5,6]. In 1997, a landmark study was published comparing gemcitabine with 5-FU in patients with advanced pancreatic cancer. The trial published in 1997 examined 126 patients with advanced pancreatic cancer who were randomized to receive either gemcitabine 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest, then weekly for 3 weeks in a 4-week cycle compared with 5-FU 600 mg/m2 weekly. The primary end point of the study was to determine clinical benefit, which was determined from the measurements of pain, functional impairment and weight loss. Twenty-three percent of patients receiving gemcitabine were determined to derive clinical benefit compared with only 4.8% of patients receiving 5-FU.
2014 Informa UK Ltd
ISSN 1747-4124
739
Expert Review of Gastroenterology & Hepatology Downloaded from informahealthcare.com by Washington University Library on 01/11/15 For personal use only.
Drug Profile
Borazanci & Von Hoff
The median OS was 5.65 months in the gemcitabine group compared with 4.41 months in those treated with 5-FU. Time to progression was determined to be 9 weeks for gemcitabine and 4 weeks for 5-FU. Of note is that the 1-year survival rate was 18% for patients with advanced pancreatic cancer treated with gemcitabine compared with 2% of those treated with 5-FU [7]. Since the publication of gemcitabine in treating patients with advanced pancreatic cancer, there have been several trials in various combinations with gemcitabine or 5-FU examined. Only two Phase III trials have shown improvement on gemcitabine monotherapy for advanced pancreatic cancer. One trial was a combination study of gemcitabine plus erlotinib, an EGFR inhibitor, which was published in 2007. The study was an international double-blinded Phase III study that enrolled 569 patients randomized to receive either erlotinib plus gemcitabine or gemcitabine only. OS was 6.24 months in the combination arm versus 5.91 in the gemcitabine only arm, with a 1-year survival of 23% in the erlotinib plus gemcitabine versus 17% in the gemcitabine only. While this was statistically significant, the total time difference between OS was 10 days [8]. Another trial published in 2005 compared a combination therapy of cisplatin, epirubicin, gemcitabine and 5-FU (termed PEFG) compared with gemcitabine monotherapy [9]. The primary end point of the study of progression-free survival (PFS) at 4 months was met, with 60% PFS at 4 months in the PEFG regimen arm compared with 28% in the gemcitabine only arm. The 1-year OS rate of PEFG was 38.5% compared with 21.3% in gemcitabine only arm, although this was not statistically significant. The 2-year survival was 11.5% in the PEFG arm compared with 2.1% in the gemcitabine arm and this was statistically significant [9]. Unfortunately, from 1997 until 2011 those were the only positive Phase III clinical trials published in patients with advanced pancreatic cancer [4,10]. Several combinations have been examined with gemcitabine including adding cytotoxic chemotherapies such as cisplatin, oxaliplatin, 5-FU, capecitabine, irinotecan or pemetrexed [4,10]. The story was the same with combinations of gemcitabine with novel agents including those that targeted matrix metalloproteinase, farnesyltransferase inhibitors (which targets KRAS), tyrosine kinase inhibitors, monoclonal antibodies to EGFR and monoclonal antibodies to VEGF [4,10]. In 2011, results of a Phase II/III, multicenter, randomized study comparing the drug combination of 5-FU, oxaliplatin, irinotecan and leucovorin (FOLFIRINOX) with gemcitabine was published [11]. The study enrolled 342 patients with an Eastern Cooperative Oncology Group score of 0 or 1, and 57% of the pancreatic cancer tumor location was either the body or tail of the pancreas. The dosing in the FOLFIRINOX combination was oxaliplatin 85 mg/m2, leucovorin at 400 mg/ m2, irinotecan 180 mg/m2. Fluorouracil was given as a bolus 400 mg/m2 followed by a 46-h infusion dose of 2400 mg/m2. This combination was repeated every 2 weeks. FOLFIRINOX was compared with single agent gemcitabine, which was given at a dose of 1000 mg/m2 weekly for 7 weeks followed by a 740
1-week rest, then weekly for 3 weeks in subsequent 4-week courses. The primary end point for the Phase II trial was tumor response and the secondary end point was safety. For the Phase III study, the primary end point was OS with PFS, tumor response, safety and quality-of-life secondary end points. In the FOLFIRINOX combination, the median OS was 11.1 months compared with 6.8 months in the gemcitabine only cohort (hazard ratio [HR] for death 0.57; p < 0.001). PFS was 6.4 months in the FOLFIRINOX combination and 3.3 months in the gemcitabine only group (HR: 0.47; p < 0.001). The most common grade 3 or grade 4 adverse events (AEs) in the FOLFIRINOX combination were neutropenia (45.7%), fatigue (23.6%), vomiting (14.5%), diarrhea (12.7%) and thrombocytopenia (9.1%). Of note, the study involved 48 centers all in France [11]. Intro to drug
Gemcitabine, or difluorodeoxycytidine, is a nucleoside analog whose metabolized product difluorodeoxycytidine triphosphate competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA and inhibits DNA synthesis by masked chain termination [7,12]. Gemcitabine is metabolized intracellularly by deoxycytidine kinase (dCK) to its active products difluorodeoxycytidine diphosphate and triphosphate (difluorodeoxycytidine triphosphate) nucleoside and has a half-life range of 42–94 min with a time to peak in the plasma of 30 min after infusion [12,13]. There are no recommended dosing adjustments for renal or hepatic impairment of gemcitabine, although some suggestions have been made to start the initial dose at 800 mg/m2 if the serum bilirubin is >1.6 mg/dl [14,13]. Gemcitabine is predominantly excreted through the urine (92–98%) and feces (1%) [13]. Various methods of gemcitabine resistance have been elucidated over the years. Gemcitabine requires human equilibrative transporters 1 and 2 and human concentrative nucleoside transporter 1 to mediate transport. Expression levels of these proteins have correlated with varying levels of gemcitabine sensitivity. Efflux transporters such as ATP-binding cassette family of multidrug resistance-associated proteins have also been shown to play a significant role in gemcitabine resistance. Expression of dCK also has been linked to sensitivity and resistance to gemcitabine in pancreatic cancer [12]. Gemcitabine is rendered inactive by cytidine deaminase, which removes the NH2 group from the pyrimidine, which in turn causes the uracil metabolite to be exported from the cell. The now accepted standard of giving weekly gemcitabine in a 3-week schedule every 4 weeks after an initial weekly schedule for 7 weeks with 1 week off was born out of pharmocokinetic studies showing better safety and tolerability. Overcoming resistance to gemcitabine has been difficult and will be touched upon further in this review in regards to the combination of nab-paclitaxel plus gemcitabine. Methods such as using 5-azacytidine, which exerts its effect by reducing methylation, have shown greater efficacy in combination with gemcitabine [12]. Expert Rev. Gastroenterol. Hepatol. 8(7), (2014)
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Nab-paclitaxel & gemcitabine for the treatment of patients with metastatic pancreatic cancer
Paclitaxel is a member of the taxane family, which are isolated from the bark of the Yew tree [12]. The taxol family mechanism of action is inhibiting mitosis by inhibiting the depolymerization of microtubules, which blocks cells moving from the G2 and M phases of the cell cycle [15]. Paclitaxel comes in several different formulations and its natural form has high insolubility in water [15,16]. One formulation of the drug was created by adding polyethoxylated castor oil solvent (Cremaphor) and is termed Cre-paclitaxel, which allowed the drug to be given intravenously [16]. Prior to the development of nab-paclitaxel, paclitaxel had been studied in pancreatic cancer [17,18]. In a Phase II study published in 1997, 45 chemo-naı¨ve patients with advanced pancreatic cancer were treated with paclitaxel given every 3 weeks and had a response rate of only 8% and were deemed to have minimal activity in pancreatic cancer [17]. Another study published in 2010 examined 19 patients with advanced pancreatic cancer who were given paclitaxel and the protein kinase C inhibitor bryostatin-1 that could have had prior treatment. Not a single patient had a confirmed response [18]. The albumin formulation of paclitaxel, nab-paclitaxel is formulated with human serum albumin at a concentration similar to the concentration of albumin in blood and is formulated through high-pressure homogenization in which albumin and paclitaxel are combined to create particles 130 nm in diameter [19]. Nab-paclitaxel may be reconstituted with a simple saline solution [15]. There is a significantly reduced risk of infusion hypersensitivity reactions, decreased risk of neutropenia and faster recovery of peripheral neuropathy [16]. Because of the decreased risk of hypersensitivity reactions of nab-paclitaxel, steroid or antihistamine prophylaxis usually is unnecessary. However, when nab-paclitaxel is combined with gemcitabine, we usually use steroids as antiemetics and to decrease the flu-like syndrome associated with gemcitabine. Nab-paclitaxel has been approved for use in non-small-cell lung cancer, breast cancer and more recently, pancreatic cancer [15,13]. Upon injection the nab-paclitaxel particles dissolve into soluble albumin-paclitaxel complexes, and paclitaxel may bind and unbind albumin. Nab-paclitaxel has been shown in pharmacokinetics studies to have a much higher fraction of unbound paclitaxel when compared with traditional paclitaxel [15]. Nab-paclitaxel achieves a higher plasma clearance and a larger volume of distribution compared with paclitaxel [15,20]. In preclinical models of cancer, albumin has been shown to accumulate in proximity to tumors and that cancer cells use albumin for metabolism [15,21]. Nab-paclitaxel has been hypothesized to take advantage of circulating albumin that crosses endothelial cells to reach tumors and has been reported in two ways: through receptor-mediated transcytosis and the enhanced permeation and retention effect [15,22,23]. Albumin binds to the albumin-specific receptor glycoprotein 60 (gp60), which helps mediate transcytosis. Experiments have been done to show that nab-paclitaxel has a greater than fourfold level of transport through endothelial cells in culture compared with paclitaxel [24]. informahealthcare.com
Drug Profile
Tumor accumulation of nab-paclitaxel may also be utilized by taking advantage of secreted protein acidic and rich in cysteine (SPARC) proteins that appear to be overexpressed in several tumors, especially pancreatic cancer [14,15]. SPARC is a calciumbinding protein, which is present in stromal fibroblasts and its overexpression promotes cancer cell invasion and metastasis [14]. Increased SPARC expression has been suggested to play a role in more effective response to nab-paclitaxel, although this has not been seen in all tumor types [15,25,26]. As discussed in the results of the Phase I/II trial, SPARC expression appeared to play a significant role in treatment efficacy of nab-paclitaxel plus gemcitabine [14,15,27]. A study involving KPC mice, which closely resemble the human model for pancreatic cancer and have mutations in KRAS and P53, was used to study the effects of gemcitabine and nab-paclitaxel together. This study showed that the combination increased apoptosis and that nabpaclitaxel promoted intratumoral gemcitabine levels. This effect was not seen when combining paclitaxel and gemcitabine [28]. The mechanism of this effect was not seen by way of tumor stroma disruption, which was shown as an accompanying study in the Phase I/II trial [27]. Instead, nab-paclitaxel downregulated the enzyme cytidine deaminase, which metabolizes gemcitabine [28]. Both studies came to the same findings of increased intratumoral gemcitabine, but were performed with separate mouse tumor models and dosing [27,28]. Nab-paclitaxel is metabolized by CYP2C8 and CYP3A4 and is metabolized in the liver. For patients with pancreatic adenocarcinoma and mild liver impairment with an aspartate transaminase 1.26 ULN is not recommended. Nab-paclitaxel’s half-life is approximately 27 h and is excreted predominantly through the feces (20%) and less through the urine (4%) [29]. Clinical efficacy
The Phase I/II study of nab-paclitaxel plus gemcitabine was published in December 2011 [27]. The study was an open-label Phase I/II study conducted at four centers in the USA in patients older than 18 years of age with previously untreated metastatic pancreatic cancer. Patients were allowed prior adjuvant treatment with 5-FU or gemcitabine along with radiation therapy as long as it was 6 months prior to enrollment. The Phase I portion was designed to identify the maximum tolerated dose (MTD) and dose-limiting toxicities of nab-paclitaxel. The dosing schedule was treatment on days 1, 8 and 15 on a 28-day cycle using the standard 3+3 Phase I dose escalation design. Three cohorts were studied with the dosing of nab-paclitaxel at either 100, 125 or 150 mg/m2 followed by gemcitabine at 1000 mg/m2. A total of 67 patients were enrolled. The MTD was established at dose level 2 for nab-paclitaxel, 125 mg/m2. In the 44 patients treated at the MTD, the median PFS was 7.9 months, median OS was 12.2 months and the 1-year survival was 48%. For all 67 patients, the median PFS was 741
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Borazanci & Von Hoff
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Table 1. Summary of Phase I/II trial results of nab-paclitaxel plus gemcitabine for those treated at the maximal tolerated dose of nab-paclitaxel 125 mg/m2. Median PFS
Median OS
1-Year survival
ORR
Disease control rate
High-SPARC OS (n = 19)
Low-SPARC OS (m = 17)
7.9 months (95% CI: 5.8–11.1 months)
12.2 months (95% CI: 8.9–17.9 months)
48%
48%
68%
17.8 months
8.1 months
Disease control rate: complete response, partial response, stable disease ‡16 weeks. ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival. Data taken from [27].
7.1 months and median OS was 10.3 months. Additionally, PET scan analysis was done at baseline, and at 6 and 12 weeks. 18-Fluorodeoxyglucose PET scans were available in 55 patients and showed a median decrease in activity of 79% in all three cohorts. Patients with a complete metabolic response as defined by the European Organization for Research and Treatment of Cancer criteria by the absence of 18-fluorodeoxyglucose uptake had a significantly improved OS compared with those patients without a complete metabolic response (median OS of 20.1 vs 10.3 months; p = 0.01). The median number of cycles administered of nab-paclitaxel plus gemcitabine was 6.0. The most common grade 3 or greater AEs at the MTD cohort, nabpaclitaxel at 125 mg/m2, were neutropenia (75%), leucopenia (56%), thrombocytopenia (28%), fatigue (27%), sensory neuropathy (20%) and anemia (14%). Only 2% of patients at the MTD had a grade 3 or greater febrile neutropenia [27]. Further analysis was done in regards to the aforementioned SPARC status, which was evaluated in 36 patients [27]. Patients were classified into those with high-SPARC (n = 19) or lowSPARC (n = 17). There was a significant increase in median OS in patients with high-SPARC, 17.8 months, compared with those with low-SPARC, 8.1 months (p = 0.0431). SPARC level remained a significant predictor of median OS after multivariate COX regression analysis. Patient’s CA 19-9 levels also correlated with PFS and OS, with those patients in the MTD having at least a 50% decrease in CA 19-9 correlating with a 62% overall response rate and 8.0 and 13.6 medians months of PFS and OS, compared with those with less than 50% decrease having a 33% overall response rate and 3.6 and 6.5 months of PFS and OS, respectively [27]. The results of the Phase I/II study are summarized in TABLE 1. The Phase I/II trial of gemcitabine plus nab-paclitaxel also included mouse xenograft studies. The xenograft studies were carried out using fresh pancreatic cancer tissue from 11 patients. What was noteworthy was intratumor concentrations of gemcitabine were significantly higher in combination with nabpaclitaxel compared with gemcitabine–alone-treated mice [27]. The international, multicenter, open-label, randomized, Phase III study of nab-paclitaxel plus gemcitabine was presented at the 2013 Gastrointestinal Cancers Symposium [30]. The Phase III study was published in October 2013 [31]. The trial consisted of 861 patients diagnosed with metastatic pancreatic cancer. As in the Phase I/II study, patients were allowed to receive 5-FU or gemcitabine as a radiation sensitizer in the adjuvant setting if at least 6 months had passed prior to 742
enrollment but otherwise did not receive chemotherapy for metastatic pancreatic cancer. The patients were treated at 151 community and academic centers throughout North America, Western and Easter Europe and Australia, and were randomly assigned to receive either nab-paclitaxel plus gemcitabine or gemcitabine alone. The eligibility criteria consisted of adults of 18 years of age and having a Karnofsky performance status score of 70 or more. Patients were treated on days 1, 8 and 15 in the nab-paclitaxel plus gemcitabine arm at a dose of 125 and 1000 mg/m2, respectively. In the gemcitabine only arm, patients were treated initially on days 1, 8, 15, 29, 36, 43 at a dose of 1000 mg/m2 and then weekly for 3 weeks in a 4-week cycle. The primary end point was OS and the secondary end points were PFS and response rate. The median OS in the nabpaclitaxel plus gemcitabine group was 8.5 months compared with 6.7 months in the gemcitabine only group with a HR for death at 0.72 (95% CI: 0.62–0.83). The 1-year OS was 35% in the combination group versus 22% in the gemcitabine only group (p < 0.001). The 2-year survival in the combination group was 9% compared with 4% in the gemcitabine only group (p = 0.02). PFS was 5.5 months in the nab-paclitaxel plus gemcitabine group compared with 3.7 months in the gemcitabine only group (p < 0.001). The results of this study are shown in TABLE 2. Common AEs that were grade 3 or higher included neutropenia (38%), leucopenia (31%), thrombocytopenia (13%), anemia (13%), fatigue (17%) and peripheral neuropathy (17%). Serious AEs that were reported were sepsis, which was more common in the nab-paclitaxel plus gemcitabine group at 5% compared with 2% in the gemcitabine group along with pneumonitis, which was 4% in the nab-paclitaxel group compared with 1% in the gemcitabine only group. Fatal events were 4% in each treatment group [31]. Due to the results of this trial, the US FDA approved nab-paclitaxel plus gemcitabine as first-line treatment in patients with metastatic adenocarcinoma of the pancreas on 6 September 2013 [13]. An update of the Phase III study of nab-paclitaxel plus gemcitabine was presented at the 2014 Gastrointestinal Symposium meeting. The update reported the 2-year OS rate of nab-paclitaxel plus gemcitabine to be 10 versus 5% in gemcitabine only and the 3-year OS rate of nab-paclitaxel plus gemcitabine to be 4 versus 0% in the gemcitabine only group [32]. Post-marketing surveillance
Post-marketing experience with nab-paclitaxel includes hypersensitivity reactions, which can be fatal, cardiovascular effects Expert Rev. Gastroenterol. Hepatol. 8(7), (2014)
Nab-paclitaxel & gemcitabine for the treatment of patients with metastatic pancreatic cancer
Drug Profile
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Table 2. Summary of Phase III trial results of nab-paclitaxel plus gemcitabine compared with gemcitabine for patients with metastatic pancreatic adenocarcinoma. Nab-paclitaxel plus gemcitabine
Gemcitabine alone
Hazard ratio or response rate ratio (95% CI)
p-value
PFS (in months)
5.5
3.7
0.69 (0.58–0.82)
