Prolonged Survival with FOLFIRINOX Regimen in Locally Advanced Pancreatic Cancer

SUMMARY: The American Cancer Society estimates that in 2016, over 53,000 people will be diagnosed with Pancreatic cancer in the United States and close to 42,000 patients will die of the disease. Some important risk factors for Pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Approximately 35% of patients with Pancreatic cancer have unresectable, locally advanced disease at diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the Pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease.

In a previously published study (N Engl J Med 2011; 364:1817-1825), FOLFIRINOX regimen, a combination of Fluorouracil, Leucovorin, Irinotecan (CAMPTOSAR®) and Oxaliplatin (ELOXATIN®) was significantly superior to single agent Gemcitabine (GEMZAR®), as first-line therapy, in patients with metastatic Pancreatic cancer. FOLFIRINOX resulted in a significantly improved median Overall Survival (OS), median Progression Free Survival (PFS) and Objective Response Rate (ORR).

The researchers in this study evaluated the effectiveness of FOLFIRINOX as first-line treatment in patients with newly diagnosed, locally advanced, unresectable Pancreatic cancer. The authors searched large databases for studies which involved treatment-naive patients of any age, who had received FOLFIRINOX as first-line treatment for locally advanced Pancreatic cancer. They were able to include 689 patients from 13 studies, of whom 355 (52%) patients had locally advanced Pancreatic cancer. FOLFIRINOX regimen consisted of Oxaliplatin 85mg/m2 IV over 2 hours, followed by Leucovorin 400mg/m2 IV over 2 hours given concomitantly with Irinotecan 180mg/m2 IV over 90 minutes, followed by 5-FU 400 mg/m2 IV bolus and 5-FU 2400 mg/m2 given as a 46 hour continuous infusion, with this cycle repeated every 2 weeks. The median number of administered cycles ranged from 3-11 cycles. In his retrospective review, the authors looked at Overall Survival as the Primary outcome. Secondary outcomes were Progression Free Survival, rates of Grade 3 or 4 toxicities, proportion of patients who underwent Radiotherapy or Chemoradiotherapy, surgical resection after FOLFIRINOX and R0 resection (margin-negative resection microscopically, with no gross or microscopic tumor present in the primary tumor bed).

It was noted that across studies, the pooled median OS was 24.2 months, median PFS was 15 months, Grade 3 or 4 adverse events were 60 events per 100 patients and no deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent Radiotherapy or Chemoradiation after FOLFIRINOX ranged from 31% to 100% across studies and the pooled proportion of patients who received any Radiotherapy treatment was 63.5%. The pooled proportion of patients who had surgical resection was 25.9% and the pooled proportion of patients who had R0 resection was 78.4%. There was no significant correlation found across studies, between the median number of FOLFIRINOX cycles administered and median Overall Survival.

The authors concluded that patients with locally advanced Pancreatic cancer treated with FOLFIRINOX had a longer median Overall Survival (24.2 months), compared with single agent GEMZAR® (6-13 months) and future studies should establish which patients might benefit from Radiotherapy or Chemoradiotherapy or Surgical resection, following treatment with FOLFIRINOX. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Suker M, Beumer BR, Sadot, F, et al. Lancet Oncol 2016;17:801-810.

Updated Survival Analysis of ONIVYDE®, 5-FU and Leucovorin Combination in Metastatic Pancreatic Carcinoma

SUMMARY: The American Cancer Society estimates that in 2016, over 53,000 people will be diagnosed with pancreatic cancer in the United States and close to 42,000 patients will die of the disease. Some important risk factors for Pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the Pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

NAPOLI-1 is an open-label phase III study in which 417 patients with Gemcitabine-refractory metastatic Pancreatic adenocarcinoma were randomly assigned in a 1:1:1 ratio to receive either ONIVYDE® monotherapy, ONIVYDE® plus 5-FluoroUracil (5-FU) and Leucovorin or 5-FU with Leucovorin (control group). Sixty one percent (61%) of patients had cancer in the head of the Pancreas and 68% had liver metastases. Treatment consisted of ONIVYDE® 120 mg/m2 IV over 90 minutes every 3 weeks in Group A, ONIVYDE® 80 mg/m2 IV given over 90 minutes followed by 5-FU 2400 mg/m2 given over 46 hours and racemic Leucovorin 400 mg/m2 IV given over 30 minutes every 2 weeks in Group B and 5-FU 2000 mg/m2 IV given over 24 hours plus racemic Leucovorin 200 mg/m2 IV given over 30 minutes weekly for 4 weeks followed by 2 weeks of rest in Group C (Control group). Each of the two ONIVYDE® containing groups was compared with the 5FU/Leucovorin control group. The primary study endpoint was Overall Survival and secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR).

The primary survival analysis was previously reported was based on 313 events. The combination of ONIVYDE®, 5-FU and Leucovorin resulted in a median OS of 6.1 months compared with 4.2 months with 5-FU and Leucovorin alone (HR = 0.67; P=0.012). The median PFS was 3.1 months for the ONIVYDE® combination compared with 1.5 months with 5-FU and Leucovorin alone (HR= 0.55; P=0.0001). The ORR was low in both treatment groups (7.7% vs 0.8%), respectively. ONIVYDE® montherapy was not superior, compared with 5-FU and Leucovorin and was associated with more side effects compared to the combination regimen. In an expanded, pre-specified analyses, patients who received at least 80% of the target dose in the first 6 weeks experienced an even greater Overall Survival benefit (43% improvement) with ONIVYDE® combination, compared with 5-FU and Leucovorin alone (8.9 months vs 5.1 months, HR=0.57, P=0.011).

This publication is an updated analysis of OS along with 6 and 12 month survival estimates and safety, based on 378 events, as of 25 May 2015. The authors noted that that the combination of ONIVYDE®, 5-FU and Leucovorin maintained its median OS of 6.2 months compared with 4.2 months with 5-FU and Leucovorin alone (HR = 0.75; P=0.04). Again, there was no OS advantage with ONIVYDE® monotherapy, when compared with 5-FU and Leucovorin. The 6 month survival estimate was 53% with ONIVYDE®, 5-FU and Leucovorin compared with 38% for 5-FU and Leucovorin alone and 12 month survival estimates were 26% for ONIVYDE®, 5-FU and Leucovorin versus 16% for 5-FU and Leucovorin alone. The impact of ONIVYDE® on Overall Survival was more dramatic, with increasing benefit seen with higher levels of CA 19-9. The most common grade 3/4 adverse events with ONIVYDE® plus 5-FU and Leucovorin were neutropenia, fatigue, diarrhea and vomiting.

The authors following this updated analysis concluded that the median Overall Survival benefit for ONIVYDE® plus 5-FU and Leucovorin was maintained, with no new adverse events and this combination may be a new standard of care for patients with metastatic Pancreatic cancer, previously treated with Gemcitabine based therapy. Updated overall survival analysis of NAPOLI-1: Phase III study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. Wang-Gillam A, Li C, Bodoky G, et al. J Clin Oncol 34, 2016 (suppl 4S; abstr 417)

FOLFIRINOX Associated with Prolonged Survival in Locally Advanced Pancreatic Cancer

SUMMARY: The American Cancer Society estimates that in 2016, over 53,000 people will be diagnosed with pancreatic cancer in the United States and close to 42,000 patients will die of the disease. Some important risk factors for pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Approximately 35% of patients with pancreatic cancer have unresectable, locally advanced disease at diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease.

In a previously published study (N Engl J Med 2011; 364:1817-1825), FOLFIRINOX regimen, a combination of Fluorouracil, Leucovorin, Irinotecan (CAMPTOSAR®) and Oxaliplatin (ELOXATIN®) was significantly superior to single agent Gemcitabine (GEMZAR®), as first-line therapy, in patients with metastatic pancreatic cancer. FOLFIRINOX resulted in a significantly improved median Overall Survival (OS), median Progression Free Survival (PFS) and Objective Response Rate (ORR).

The researchers in this study evaluated the effectiveness of FOLFIRINOX as first-line treatment in patients with newly diagnosed, locally advanced, unresectable, pancreatic cancer. The authors searched large databases for studies which involved treatment-naive patients of any age, who had received FOLFIRINOX as first-line treatment for locally advanced pancreatic cancer. They were able to include 689 patients from 13 studies, of whom 355 (52%) patients had locally advanced pancreatic cancer. In his retrospective review, the authors looked at Overall Survival as the Primary outcome. Secondary outcomes were Progression Free Survival, rates of Grade 3 or 4 toxicities, proportion of patients who underwent Radiotherapy or Chemoradiotherapy, surgical resection after FOLFIRINOX and R0 resection.

It was noted that across studies, the pooled median OS was 24.2 months, median PFS was 15 months, Grade 3 or 4 adverse events were 60 events per 100 patients and no deaths were attributed to FOLFIRINOX toxicity. The proportion of patients who underwent Radiotherapy or Chemoradiation after FOLFIRINOX ranged from 31% to 100% across studies and the pooled proportion of patients who received any Radiotherapy treatment was 63.5%. The pooled proportion of patients who had surgical resection was 25.9% and the pooled proportion of patients who had R0 resection was 78.4%.

The authors concluded that patients with locally advanced pancreatic cancer treated with FOLFIRINOX had a longer median Overall Survival (24.2 months), compared with single agent GEMZAR® (6-13 months) and future studies should establish which patients might benefit from Radiotherapy or Chemoradiotherapy or surgical resection, following treatment with FOLFIRINOX. FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Suker M, Beumer BR, Sadot, F, et al. Published Online: May 6, 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00172-8

ONIVYDE® (Irinotecan liposome injection)

The FDA on October 22, 2015 approved ONIVYDE® injection, administered in combination with Fluorouracil (5-FU) and Leucovorin, for the treatment of patients with metastatic Adenocarcinoma of the Pancreas, whose disease has progressed following Gemcitabine-based therapy. ONIVYDE® injection is a product of Merrimack Pharmaceuticals, Inc

ONIVYDE® in Combination with 5-FU and Leucovorin Improves Overall Survival in Metastatic Pancreatic Carcinoma

SUMMARY: The FDA on October 22, 2015 approved ONIVYDE® (Irinotecan liposome injection) administered in combination with Fluorouracil (5-FU) and Leucovorin , for the treatment of patients with metastatic adenocarcinoma of the Pancreas, whose disease has progressed following GEMZAR® (Gemcitabine) based therapy. The American Cancer Society estimates that in 2015, close to 49,000 people will be diagnosed with pancreatic cancer in the United States and over 40,000 people will die of the disease. Some important risk factors for Pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the Pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

NAPOLI-1 is an open-label phase III study in which 417 patients with Gemcitabine-refractory metastatic Pancreatic adenocarcinoma were randomly assigned in a 1:1:1 ratio to receive either ONIVYDE® monotherapy, ONIVYDE® plus 5-FluoroUracil (5-FU) and Leucovorin or 5-FU with Leucovorin (control group). Sixty one percent (61%) of patients had cancer in the head of the Pancreas and 68% had liver metastases. Treatment consisted of ONIVYDE® 120 mg/m2 IV over 90 minutes every 3 weeks in Group A, ONIVYDE® 80 mg/m2 IV given over 90 minutes followed by 5-FU 2400 mg/m2 given over 46 hours and racemic Leucovorin 400 mg/m2 IV given over 30 minutes every 2 weeks in Group B and 5-FU 2000 mg/m2 IV given over 24 hours plus racemic Leucovorin 200 mg/m2 IV given over 30 minutes weekly for 4 weeks followed by 2 weeks of rest in Group C (Control group).

Each of the two ONIVYDE® containing groups was compared with the 5FU/Leucovorin control group. The primary study endpoint was Overall Survival and secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR). The combination of ONIVYDE®, 5-FU and Leucovorin resulted in a median OS of 6.1 months compared with 4.2 months with 5-FU and Leucovorin alone (HR = 0.67; P=0.012). The median PFS was 3.1 months for the ONIVYDE® combination compared with 1.5 months with 5-FU and Leucovorin alone (HR= 0.55; P=0.0001). The ORR was low in both treatment groups (7.7% vs 0.8%). ONIVYDE® montherapy was not superior, compared with 5-FU and Leucovorin and was associated with more side effects compared to the combination regimen. In an expanded, pre-specified analyses, patients who received at least 80% of the target dose in the first 6 weeks experienced an even greater Overall Survival benefit (43% improvement) with ONIVYDE® combination, compared with 5-FU and Leucovorin alone (8.9 months vs 5.1 months, HR=0.57, P=0.011).

The most common grade 3/4 adverse events with ONIVYDE® plus 5-FU and Leucovorin were neutropenia, fatigue, diarrhea and vomiting. The authors concluded that a combination of ONIVYDE® plus 5-FU and Leucovorin significantly improved Overall Survival compared to 5-FU and Leucovorin with manageable toxicities. Expanded analyses of Napoli-1: Phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. Chen L, Von Hoff DD, Li C, et al. J Clin Oncol 33, 2015 (suppl 3; abstr 234)

Modified GEMZAR® and ABRAXANE® Combination May Preserve Efficacy with Less Toxicity in Metastatic Pancreatic Cancer

SUMMARY: The American Cancer Society estimates that in 2015, close to 49,000 people will be diagnosed with pancreatic cancer in the United States and over 40,000 people will die of the disease. Some important risk factors for pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. The benefit of a combination of GEMZAR® (Gemcitabine) and ABRAXANE® (nab-Paclitaxel regimen in first line treatment for metastatic pancreatic cancer was established following a open-label, randomized, phase III trial (MPACT trial) in which 861 patients with metastatic pancreatic cancer were randomized to receive either a combination of GEMZAR® and ABRAXANE® (n=431) or GEMZAR® alone (n=430). The treatment regimen consisted of GEMZAR® at 1000 mg/m2 IV and ABRAXANE® 125 mg/m2 IV, both administered on days 1, 8, and 15 of a 28 day cycle. There was a statistically significant prolongation of Overall Survival (OS) for patients in the combination group with a 28% reduction in the risk of death [HR= 0.72; P < 0.0001]. The median OS was 8.5 months in the combination group and 6.7 months in the single agent GEMZAR® group and the Progression Free Survival (PFS) in the combination group versus the single agent group was 5.5 months versus 3.7 months, respectively (HR= 0.69; P < 0.0001). In this study however, only 71% of the ABRAXANE® doses and 63% of the GEMZAR® doses were full doses, due to associated toxicities and 17% of the patients had grade 3 or 4 neuropathy.

To circumvent this toxicity, the authors at their institution adopted a modified regimen of GEMZAR® and ABRAXANE® for a similar patient population and the regimen consisted of GEMZAR® 1000 mg/m2 IV and ABRAXANE® 125 mg/m2 IV, both administered on days 1 and 15 of a 28 day cycle. They conducted a retrospective analysis of a prospectively maintained database of 69 patients treated with this modified regimen. A total of 47 patients were evaluable for responses and 63 patients were evaluable for toxicities. The median Progression Free Survival was 4.8 months and median Overall Survival was 11.1 months with the modified regimen. More importantly, the rate of grade 3 or 4 neuropathy was less than 2%. The rate of grade 3 or 4 neutropenia was 10%, and growth factor support was required in only 8% of the patients, compared with 26% for those in the MPACT trial. The authors concluded that a less intense biweekly regimen of GEMZAR® and ABRAXANE® preserves efficacy with significantly less toxicity as well as cost savings and should be a consideration, in the first line treatment of patients with metastatic pancreatic cancer. This study received a Merit Award at the 2015 Gastrointestinal Cancers Symposium. Modified gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer (MPC): A single-institution experience. Krishna K, Blazer MA, Wei L, et al. J Clin Oncol 33, 2015 (suppl 3; abstr 366)

Dual Vaccine Therapy for Metastatic Pancreatic Cancer Improves Overall Survival

SUMMARY: The American Cancer Society estimates that in 2015, close to 49,000 people will be diagnosed with Pancreatic Cancer in the United States and over 40,000 people will die of the disease. Some important risk factors for Pancreatic Cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. The FDA recently granted Breakthrough Therapy Designation status for the combination treatment that consists of two vaccines, GVAX and CRS-207, for patients with advanced Pancreatic Carcinoma. This designation was based on a phase II clinical trial in which the authors took a novel approach and tested a combination of two vaccines in patients with metastatic Pancreatic Adenocarcinoma. Traditional vaccination against specific bacterial and viral infections involves the injection of the specific weakened bacteria/virus or a structural component of the bacteria or virus. The body then mounts an immune response and is ready to respond to an infection associated with that specific bacteria or virus. Use of vaccines in cancer treatment is based on the same principle. The two vaccines studied were GVAX and CRS-207. GVAX is an allogeneic whole cell vaccine developed from Pancreatic Cancer cell lines. These cancer cells are irradiated, to prevent them from dividing and are genetically modified to secrete GM-CSF (Granulocyte Macrophage Colony Stimulating Factor). GM-CSF is important for the growth and activation of dendritic cells also known as Antigen Presenting Cells. This vaccine when injected attracts the dendritic cells to the vaccine injection site and the dendritic cells in turn, pick up the antigens from the vaccine and present them to the patient’s immune system. The immune system then mounts a response by activating tumor specific T-cells. This vaccine therefore theoretically boosts the body’s immune system to fight the patient’s tumor, without causing collateral damage. The second vaccine CRS-207 is live-attenuated (weakened) Listeria monocytogenes bacterium which expresses mesothelin and stimulates innate and adaptive immunity. It is genetically engineered to elicit an immune response against the tumor-associated antigen mesothelin, which has been shown to be expressed at higher levels on Pancreatic Cancer cells than on normal cells. Previous studies have demonstrated that survival can be improved by induction of mesothelin specific T-cell responses. In this study, 90 patients with metastatic Pancreatic Adenocarcinoma were randomly assigned in a 2:1 ratio to receive two doses of GVAX followed by four doses of CRS-207 in Group A and six doses of GVAX alone in the Group B. Treatment was given every 3 weeks and low-dose CYTOXAN® (Cyclophosphamide) was given IV, the day before GVAX in both groups, to inhibit regulatory (suppressive) T-cells. More than 80% of the patients had at least one prior treatment for metastatic disease and 50% had two or more prior treatments. The Primary endpoint was overall survival. Secondary endpoints included safety, clinical and immune responses. At a planned interim analysis, the median Overall Survival (OS) was 6.1 months in Group A patients who had received the combination of two vaccines compared to 3.9 months in Group B patients who received GVAX alone (HR=0.59, P=0.02), resulting in a 41% reduction in risk of death with the combination immunotherapy. The one year survival probability doubled with the dual vaccine with an estimated one year survival of 24% for the combination immunotherapy group (Group A) compared with 12% for the GVAX alone group (Group B). The median OS in an updated analysis of patients who received three total doses which included at least two doses of GVAX and at least one dose of CRS-207 was 9.7 months compared to 4.6 months for those who received three doses of GVAX alone (HR=0.53, P=0.02), a 47% reduction in the risk of death. In the subgroup of patients who had two or more prior chemotherapy regimens, combination immunotherapy given as third line therapy or greater resulted in a median OS of 5.7 months compared to 3.7 months with GVAX alone (HR=0.30, P<0.001), a 70% reduction in risk of death. Stabilization or reduction of tumor marker CA 19-9, was seen in 27% of patients receiving combination immunotherapy compared to 9% in those who received GVAX alone (P=0.08). The median OS in patients with stable or better CA 19-9 response was 10.3 months compared with 4 months in those with CA 19-9 progression (HR=0.43, P=0.02). Toxicities included local reactions after GVAX and transient fevers, chills, and lymphopenia after CRS-207 administration. The authors concluded that immunotherapy with a combination of two vaccines improved Overall Survival with minimal toxicity, for patients with metastatic Pancreatic Carcinoma, who had failed prior therapies. Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes–Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer. Le DT, Wang-Gillam A, Picozzi V, et al. J Clin Oncol 2015; 33:1325-1333

Everolimus (EVE) for the treatment of advanced pancreatic neuroendocrine tumors (pNET) Final overall survival (OS) results of a randomized, double-blind, placebo (PBO)-controlled, multicenter Phase III trial (RADIANT-3) SUMMARY Pancreatic NeuroEndocrine Tumors (PNETs) are uncommon, slow growing neoplasms and their incidence has been on the rise due to heightened awareness of the disease, better diagnostic techniques and increased rate of incidental diagnosis during workup for other conditions They account for approximately 25% of all neuroendocrine tumors Pancreatic NETs may be functional or nonfunctional Functional tumors secrete hormones, such as gastrin, insulin, and glucagon which may be associated with symptoms and signs whereas nonfunctional tumors, which account for 90% of PNETs, do not produce extra amounts of hormones Majority of the functional tumors are benign whereas more than 50% of the nonfunctional tumors are malignant and are often advanced at the time of diagnosis as they do not produce hormones and associated symptoms Patients with metastatic PNETs have a poor prognosis with a median survival of 1-3 years, similar to that of metastatic breast cancer and metastatic colon cancer Predictors of worst survival include advanced stage, higher grade and age Treatment options have included surgery if feasible, Somatostatin analogues, combination chemotherapy with limited success, hepatic artery embolization and availability of two new agents, Everolimus (AFINITOR®), a mTOR (mammalian Target Of Rapamycin) inhibitor and Sunitinib (SUTENT®), a multitargeted Tyrosine Kinase Inhibitor RADIANT-3 is a randomized, double-blind, phase III study in which 410 patients with advanced, low grade or intermediate grade Pancreatic NeuroEndocrine Tumors with progression within the previous 12 months, were randomized to receive AFINITOR® at a dose of 10 mg PO daily (207 patients) or placebo (203 patients), in addition to best supportive care The primary endpoint was Progression Free Survival, and the secondary endpoints included Overall Survival and the safety and tolerability of AFINITOR® Upon progression, patients in the placebo group were allowed to cross over and receive open-label AFINITOR® Further, when all patients were unblinded at the end of the predetermined cutoff date, those in the placebo group were offered open-label AFINITOR® and those in the AFINITOR® arm continued to receive open-label AFINITOR® The authors had reported the results from the primary analysis of this study in 2011 when the primary end point of Progression Free Survival (PFS) was met, with a PFS of 11 months in the AFINITOR® group and 46 months in the placebo group (P < 0001) The authors now report the mature Overall Survival results The median Overall Survival was 44 months in the AFINITOR® group compared with 377 months in the placebo arm The 63 month survival difference in favor of AFINITOR® was not statistically significant (P= 030) The authors attributed the lack of statistically significant survival benefit, to crossover of 85% of patients from placebo to AFINITOR® group, which may have confounded the ability to detect a statistically significant survival advantage with AFINITOR® The most common adverse events associated with AFINITOR® were stomatitis, rash, diarrhea and fatigue The authors concluded that median Overall Survival of 44 months with AFINITOR® for advanced progressive Pancreatic NeuroEndocrine Tumors is unprecedented, confirming that the mTOR pathway plays an important role in the molecular pathogenesis of Pancreatic NeuroEndocrine Tumors Yao J, Pavel M, Lombard-Bohas C, et al ESMO 2014 Congress, Abstract#11320

SUMMARY: Pancreatic NeuroEndocrine Tumors (PNETs) are uncommon, slow growing neoplasms and their incidence has been on the rise due to heightened awareness of the disease, better diagnostic techniques and increased rate of incidental diagnosis during workup for other conditions. They account for approximately 25% of all neuroendocrine tumors. Pancreatic NETs may be functional or nonfunctional. Functional tumors secrete hormones, such as gastrin, insulin, and glucagon which may be associated with symptoms and signs whereas nonfunctional tumors, which account for 90% of PNETs, do not produce extra amounts of hormones. Majority of the functional tumors are benign whereas more than 50% of the nonfunctional tumors are malignant and are often advanced at the time of diagnosis as they do not produce hormones and associated symptoms. Patients with metastatic PNETs have a poor prognosis with a median survival of 1-3 years, similar to that of metastatic breast cancer and metastatic colon cancer. Predictors of worst survival include advanced stage, higher grade and age. Treatment options have included surgery if feasible, Somatostatin analogues, combination chemotherapy with limited success, hepatic artery embolization and availability of two new agents, Everolimus (AFINITOR®), a mTOR (mammalian Target Of Rapamycin) inhibitor and Sunitinib (SUTENT®), a multitargeted Tyrosine Kinase Inhibitor. RADIANT-3 is a randomized, double-blind, phase III study in which 410 patients with advanced, low grade or intermediate grade Pancreatic NeuroEndocrine Tumors with progression within the previous 12 months, were randomized to receive AFINITOR® at a dose of 10 mg PO daily (207 patients) or placebo (203 patients), in addition to best supportive care. The primary endpoint was Progression Free Survival, and the secondary endpoints included Overall Survival and the safety and tolerability of AFINITOR®. Upon progression, patients in the placebo group were allowed to cross over and receive open-label AFINITOR®. Further, when all patients were unblinded at the end of the predetermined cutoff date, those in the placebo group were offered open-label AFINITOR® and those in the AFINITOR® arm continued to receive open-label AFINITOR®. The authors had reported the results from the primary analysis of this study in 2011 when the primary end point of Progression Free Survival (PFS) was met, with a PFS of 11 months in the AFINITOR® group and 4.6 months in the placebo group (P < 0.001). The authors now report the mature Overall Survival results. The median Overall Survival was 44 months in the AFINITOR® group compared with 37.7 months in the placebo arm. The 6.3 month survival difference in favor of AFINITOR® was not statistically significant (P= 0.30). The authors attributed the lack of statistically significant survival benefit, to crossover of 85% of patients from placebo to AFINITOR® group, which may have confounded the ability to detect a statistically significant survival advantage with AFINITOR®. The most common adverse events associated with AFINITOR® were stomatitis, rash, diarrhea and fatigue. The authors concluded that median Overall Survival of 44 months with AFINITOR® for advanced progressive Pancreatic NeuroEndocrine Tumors is unprecedented, confirming that the mTOR pathway plays an important role in the molecular pathogenesis of Pancreatic NeuroEndocrine Tumors. Yao J, Pavel M, Lombard-Bohas C, et al. ESMO 2014 Congress, Abstract#11320

A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma Updated results

SUMMARY: The American Cancer Society estimates that in 2014, over 46,000 people will be diagnosed with Pancreatic Cancer in the United States and close to 40,000 people will die of the disease. Some important risk factors for Pancreatic Cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. The FDA recently granted Breakthrough Therapy Designation status for the combination treatment that consists of two vaccines, GVAX and CRS-207, for patients with advanced Pancreatic Carcinoma. This designation was based on the following study. A phase II clinical trial was conducted in which the authors took a novel approach and tested a combination of two vaccines in patients with metastatic pancreatic adenocarcinoma. Traditional vaccination against specific bacterial and viral infections involves the injection of the specific weakened bacteria/virus or a structural component of the bacteria or virus. The body then mounts an immune response and is ready to respond to an infection associated with that specific bacteria or virus. Use of vaccines in cancer treatment is based on the same principle. The two vaccines studied were GVAX and CRS-207. GVAX is an allogeneic whole cell vaccine developed from pancreatic cancer cell lines. These cancer cells are irradiated, to prevent them from dividing and are genetically modified to secrete GM-CSF (Granulocyte Macrophage Colony Stimulating Factor). GM-CSF is important for the growth and activation of dendritic cells also known as Antigen Presenting Cells. This vaccine when injected attracts the dendritic cells to the vaccine injection site and the dendritic cells in turn, pick up the antigens from the vaccine and present them to the patient’s immune system. The immune system then mounts a response by activating tumor specific T-cells. This vaccine therefore theoretically boosts the body’s immune system to fight the patient’s tumor, without causing collateral damage. The second vaccine CRS-207 is live-attenuated (weakened) Listeria monocytogenes bacterium which expresses mesothelin and stimulates innate and adaptive immunity. It is genetically engineered to elicit an immune response against the tumor-associated antigen mesothelin, which has been shown to be expressed at higher levels on pancreatic cancer cells than on normal cells. Previous studies have demonstrated that survival can be improved by induction of mesothelin specific T-cell responses. In this study, 90 patients with metastatic pancreatic adenocarcinoma were randomly assigned in a 2:1 ratio to receive two doses of GVAX followed by four doses of CRS-207 or six doses of GVAX alone. Treatment was given every 3 weeks and low-dose CYTOXAN® (Cyclophosphamide) was given IV, the day before GVAX in both groups, to inhibit regulatory (suppressive) T-cells. More than 80% of the patients had at least one prior treatment for metastatic disease and 50% had two or more prior treatments. The primary endpoint was overall survival. Secondary endpoints included safety, clinical and immune responses. At a planned interim analysis, the median overall survival was 6.1 months with the combination of two vaccines vs 3.9 months with GVAX alone (HR=0.54, P=0.011), a 46% reduction in risk of death with the combination immunotherapy. The median overall survival in patients who received three total doses which included at least two doses of GVAX and at least one dose of CRS-207 was 9.7 months compared to 4.6 months for GVAX alone (HR=0.44, P=0.0074), a 56% reduction in the risk of death. In the subgroup of patients who had two or more prior chemotherapy regimens, combination immunotherapy given as third line therapy or greater resulted in a median overall survival of 5.1 months vs 3.7 months with GVAX alone (HR=0.34, P=0.001), a 66% reduction in risk of death. Stabilization of tumor marker CA19-9, was seen in 32% of patients receiving combination immunotherapy vs 13% in those who received GVAX alone (P=0.06). The one year survival probability doubled with the dual vaccine with an estimated one year survival of 24% for the combination immunotherapy group and 12% for the GVAX alone group. Toxicities included local reactions after GVAX and transient fevers, chills, and lymphopenia after CRS-207 administration. The authors concluded that immunotherapy with a combination of two vaccines improved overall survival in patients with metastatic pancreatic carcinoma, who had failed prior therapies. Le DT, Wang-Gillam A, Picozzi V, et al. J Clin Oncol 32, 2014 (suppl 3; abstr 177)

Increased Risk of Pancreatic Adenocarcinoma After Acute Pancreatitis

SUMMARY: The American Cancer Society estimates that in 2014, over 46,000 people will be diagnosed with Pancreatic Cancer in the United States and close to 40,000 people will die of the disease. Some important risk factors for Pancreatic Cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease, at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. Early diagnosis may therefore play an important role in treatment outcomes, in patients with Pancreatic Cancer. Pancreatic Cancer can cause acute pancreatitis by obstructing the pancreatic duct and patients diagnosed with Pancreatic Cancer often present initially with acute pancreatitis. With this background information, the authors performed a retrospective study of patients with acute pancreatitis who sought their medical care at the Veterans Health Administration from 1998 through 2007. Patients with pre-existing Pancreatic Adenocarcinoma or those with recurrent acute pancreatitis were excluded from this analysis. A diagnosis of acute pancreatitis was made in 5720 patients and 710 patients were diagnosed with Pancreatic Cancer from 2000 through 2007. They noted that of those who were diagnosed with Pancreatic Adenocarcinoma, 76 patients (10.7%) had acute pancreatitis within 2 years of Pancreatic Cancer diagnosis. This risk for Pancreatic Cancer was greatest during the first year following diagnosis of acute pancreatitis and this risk decreased rapidly thereafter. Patients less than 40 years of age had negligible risk whereas those 70 years of age or older had the highest risk. The authors concluded that a significant number of patients with Pancreatic Adenocarcinoma (12.1%) initially present with acute pancreatitis and the diagnosis of cancer is often delayed by up to 2 years. Acute pancreatitis should be considered as an index event which in turn may identify a population of patients at high risk to develop Pancreatic Adenocarcinoma. They recommend that Endoscopic UltraSound (EUS) should be performed in these high risk patients, following diagnosis of acute pancreatitis, before discharge from the hospital, as this test is highly sensitive in picking up small tumors in the pancreas that are amenable to surgical resection. This is in comparison with contrast enhanced CT scans and pancreatic protocol CT scans that are not as sensitive in identifying tumors less than 2 cm in size. This interesting analysis could potentially open the doors for pancreatic cancer screening in high risk patients. Munigala S, Kanwal F, Xian H, et al. Clinical Gastroenterology and Hepatology 2014;12:1143-1150