November 2013 Edition Vol.11, Issue 11

Pancreatic Cancer May No Longer Be Immune to Therapy as Pipeline Agents Make Progress

Pancreatic Cancer May No longer Be Immune to Therapy as Pipeline Agents Make Progress

This article is brought to you during National Pancreatic Cancer Awareness Month, and sponsored by NewLink Genetics.

 

In the last few years there has been a groundswell of attention paid to this particularly nefarious disease with Former President Jimmy Carter, Actress Dana Delany, and Comedian Mindy Kaling raising awareness through PSAs for the Pancreatic Cancer Action Network. Perhaps the most resounding public wakeup call regarding the particular aggressiveness of pancreatic cancer were the deaths of Apple CEO Steve Jobs and actor Patrick Swayze in 2010 and 2009, respectively. 

According to the American Cancer Society (ACS), in the United States this year, nearly 45,220 people will be diagnosed with pancreatic cancer and 38,460 people will die from the disease. Although it only accounts for 3% of all cancers, pancreatic cancer is the fourth most common cause of cancer death in both men and women in the United States. More troubling still, the ACS estimates that the one-year relative survival rate for all stages of pancreatic cancer is 20%, with the 5-year survival rate only reaching 4%. The very low survival rate of pancreatic cancer patients is largely attributable to genetic alterations leading to drug resistance as well as the fact that it is frequently diagnosed late. Contrary to common belief, not all patients with pancreatic cancer die of widespread metastatic disease. Twelve percent of patients had no evidence of metastasis and this finding was not unique to patients who underwent treatment, nor was it specific to patients initially diagnosed at an early stage. This finding parallels other studies of disease burden at autopsy in pancreatic cancer patients in which 8% to 15% of patients died with locally advanced carcinoma and without metastatic disease, even in the absence of any treatment.1

“The majority of patients treated for pancreatic cancer have either locally advanced or metastatic disease,” said Nicholas N. Vahanian, MD, President and Chief Medical Officer of NewLink Genetics. “This means that it has spread to major blood vessels and/or distant organs. Even if you conduct surgery on those patients, survival outcome doesn’t change.”

More than 95% of pancreatic tumors originate in the exocrine cells and are called adenocarcinomas. These types of tumors are particularly aggressive and highly metastatic; the 5-year relative survival rate for pancreatic ductal adenocarcinoma is 6%, the only major type of cancer with single-digit survival rates. Accounting for less than 5% of pancreatic cancers are neuroendocrine tumors (also known as islet cell tumors), which are decidedly less deadly.

Despite the valiant public outreach campaigns and additional research funds being directed to clinical trials, progress in treating pancreatic cancer, especially adenocarcinomas, has been disconcertingly slow.  The current standard first-line treatment, Gemzar® (gemcitabine; Eli Lilly & Company) was established in 1997, when research demonstrated that an agent could actually extend median overall survival (OS) in pancreatic cancer patients to 5.6 months versus 4.4 months with fluorouracil. It took an additional 8 years to improve median OS from 5.9 months to 6.2 months with the addition of Tarceva® (erlotinib; Roche; Astellas) in 2005; unfortunately, the toxicities associated with treatment made the widespread adoption of this regimen counterproductive. Likewise, the introduction of FOLFIRINOX in 2011 (bolus fluorouracil, oxaliplatin, leucovorin, and irinotecan), increased median OS to 11.1 months, but its use was limited to patients with an excellent performance status because of its debilitating toxicities.

Even the success of Abraxane® (paclitaxel protein-bound particles for injectable suspension, albumin bound; Celgene), in combination with gemcitabine for late-stage pancreatic cancer, has been limited at best, resulting in a median OS of 8.5 months compared with 6.7 months for patients who received gemcitabine alone.

To recap: Over a 15-year period researchers have been able to extend median OS for a very select group of patients by a total of 5.6 months. Obviously, the need for effective agents in the treatment of pancreatic cancer is substantial. Clinical researchers who pursue experimental agents in this cancer area are in a high risk/reward field. In the last 2 years alone, Clovis, Infinity Pharma, and Amgen saw their stocks fall on news that their experimental pancreatic cancer agents failed to improve OS. In 2006, Therion Biologics filed for bankruptcy when its vaccine, PANVAC-VF, failed to meet survival end points in a Phase 3 trial.

Despite the long list of clinical trial failures, manufacturers are diligently pursuing a wide array of investigational pancreatic cancer therapies; immunotherapies in particular have shown great promise, with one-year survival rates climbing past 25%.The new molecular entities populating the landscape hold great potential and the pancreatic cancer community is anxiously awaiting the results of 20 or more clinical trials.

Phase 3 Trials in Pancreatic Cancer

Masitinib

Manufactured by AB Science, a pharmaceutical company specializing in protein kinase inhibitors, masitinib in combination with gemcitabine has been shown to significantly extend OS by 6 and 2.7 months in 2 independent patient populations: patients with a genetic biomarker indicative of aggressive disease progression (Group 1), and patients with cancer pain (Group 2 In Group 1, patients who received masitinib plus gemcitabine had a median OS of 11 months and the patients receiving gemcitabine alone had a median OS of 5 months The OS rates at 12 and 18 months were respectively, 41.4% and 18.5% in the masitinib plus gemcitabine arm versus 11.1% and 4.2% in the placebo arm.

In Group 2 (patients with cancer pain), the median OS was 8.1 months for masitinib plus gemcitabine and 5.4 months for gemcitabine alone The OS rates at 12 and 18 months were respectively, 32.2% and 18.2% in the masitinib plus gemcitabine arm versus 17.8% and 7.8% in the placebo.

Following the success of this trial, the FDA and European Medicines Agency (EMA) have both granted masitinib an orphan drug designation for patients with nonresectable, advanced adenocarcinoma of the pancreas.

S1

Developed by Sanofi in partnership with Taiho, S1 is a multidrug pill for the treatment of late-stage pancreatic cancer that consists of tegafur (a prodrug of 5-FU), gimeracil (5-chloro-2, 4 dihydropyridine, CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) enzyme, and oteracil (potassium oxonate, Oxo), which reduces gastrointestinal toxicity. The regimen has only yielded beneficial results in Asian patients, especially those from Japan; studies in Caucasians have not shown any benefit over standard 5-fluorouracil (5-FU) therapy. In May 2013, researchers from the National Cancer Center Hospital, Tokyo, reported that S1 was associated with noninferior OS and reduced hematologic toxicity compared with gemcitabine alone in Japanese and Taiwanese patients with advanced pancreatic cancer.2

The median OS was 8.8 months in the gemcitabine group, 9.7 months in the S1 group, and 10.1 months in the combination group. Importantly, S1 was associated with significantly lower rates of Grade 3 adverse events such as leukopenia (3.7% vs. 18.7%), neutropenia (8.8% vs. 41.0%), thrombocytopenia (1.5% vs. 11.0%), increased alanine aminotransferase (5.9% vs. 15.0%), and increased aspartate aminotransferase (7.7% vs. 15.0%).

Although S1 plus gemcitabine failed to provide a survival advantage over gemcitabine alone, the better tolerability rates make this combination therapy a viable alternative for specific patient subgroups.

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