Pancreatic Cancer Vaccine Makes Progress in Two Late-Stage Trials

Thomas J. George, Jr, MD

The novel therapeutic vaccine algenpantucel-L, which is genetically engineered from human cell lines, is being evaluated in two phase III trials in patients with resected pancreatic cancer (IMPRESS) and borderline resectable or locally advanced unresectable pancreatic cancer (PILLAR). According to the manufacturer, NewLink Genetics, both trials have completed patient enrollment, and top-line results from IMPRESS will be available later this year.

In developing the immunotherapy agent, researchers are seeking to change the equation for patients with pancreatic cancer, where the current 5-year survival rate is a dismal 7.2%, according to the National Cancer Institute.

“Unfortunately, the vast majority of patients with pancreatic cancer, even those who are candidates for surgical resection, will relapse,” said Thomas J. George, Jr, MD, a principal investigator at one of the more than 70 US sites where the IMPRESS trial is being conducted.

The current standard of care for this patient population consists of surgery, followed by postoperative adjuvant chemotherapy and/or chemoradiation, said George, an associate professor and director of the Gastrointestinal Oncology Program, University of Florida Health Cancer Center. “Offering additional treatment after surgery, whether it is chemotherapy or chemoradiation, definitely benefits patients, more so than surgery alone,” he said.

Algenpantucel-L is an allogenic pancreatic cancer vaccine based on the concept of hyperacute rejection, a primary barrier to xenotransplantation. It is comprised of two human pancreatic ductal adenocarcinoma cell lines (HAPa-1 and HAPa-2) that have been genetically engineered to express α(1,3)- galactosyl epitopes (αGal) by using retroviral transfer of the murine αGT gene. This manufacturing process is highly reproducible, making it suitable for use in a larger scale manufacturing platform for administration as a potential “off-the-shelf” vaccine.

IMPRESS (NCT01072981) is a randomized, two-arm, open-label study that was launched in April 2010 and has accrued 722 participants. Patients who have undergone surgical resection are randomized to receive an adjuvant regimen of either algenpantucel-L (up to 18 immunizations of 300 million cells) plus gemcitabine (1000 mg/ m²/d, once a week for 3 weeks) with or without 5-fluorouracil (5-FU) (200-250 mg/m²/d over 5.5 weeks) with radiation or gemcitabine with or without 5-FU chemoradiation.

The primary endpoint is overall survival (OS). The secondary objective of the trial is to assess disease- free survival (DFS) and to conduct correlative scientific studies of subject samples to determine the mechanism of any observed antitumor effect. Data analysis is ongoing, said George, and “there have been several data monitoring assessments, with no signs of futility issues. This has been a well-tolerated intervention, with only injection site irritation reported.”

Algenpantucel-L Phase III Trials in Pancreatic Cancer

5-FU, 5-fluorouracil; CA 19-9, cancer antigen 19-9; FOLFIRINOX, oxaliplatin, ironotecan, leucovorin, and fluorouracil; RO, complete resection with grossly and microscopically negative margins of resection; R1, grossly negative but microscopically positive margins of resection.

Source: NewLink Genetics website. http://goo.gl/AibtcP. Accessed February 29, 2016.

The median age of patients is 65 years and 52% of patients are male, with 80% of tumors resected from the head of the pancreas. Nodal status (N+) is 70% and 55% of patients had tumor size ≥3.0 cm. NewLink Genetics reports that a second interim analysis demonstrated a median OS of 28.5 months from time of randomization for both cohorts blended together.

The impetus for the IMPRESS trial was the positive outcomes reported from an earlier phase II trial, in which patients with completely resected pancreatic cancer received algenpantucel-L in addition to chemotherapy and chemoradiation in the adjuvant setting. In this study, 73 patients were enrolled, with 69 meeting the criteria.

After a median follow-up of 21 months, the 1-year DFS was 62%, and the 12-month OS was 86%. The median DFS was 14.1 months. There were 34 patients with a documented site of recurrence. The most common grade 1 and 2 adverse events (AEs) were induration, fatigue, and injection site reaction. Twelve percent of patients experienced grade 3 AEs and no grade 4 events; grade 3 events included fatigue, injection site reaction, pain, and lymphopenia.

PILLAR (NCT01836432), launched in October 2012, is a two-arm, open label, randomized study that has accrued 280 patients. Patients with borderline resectable or locally advanced unresectable pancreatic cancer receive either a regimen of FOLFIRINOX or gemcitabine/nab-paclitaxel with or without algenpantucel-L.

The primary endpoint for PILLAR is OS and secondary endpoints include progression-free survival, safety (frequency and grade of adverse events) of administration of algenpantucel-L, and immune response to the immunotherapy agent. NewLink Genetics reports that enrollment was completed in December 2015.

A vaccine like algenpantucel-L has a mechanism of action that is different from other immunotherapy agents such as the checkpoint inhibitors nivolumab and pembrolizumab, George explained.

“The checkpoint inhibitors affect one particular switch. Once that switch is flipped, immune activation can proceed normally,” he said. “Pancreatic cancer is so complex and this mode of immune stimulation [algenpantucel-L] is much more comprehensive.”

NewLink Genetics suggests its HyperLink Cellular Immunotherapies platform is able to take advantage of a hyperacute response by the immune system that is metabolically active and uses whole-cell immunotherapy with multiple antigens. The resulting immune response consists of activated antibodies, T cells, and eosinophils.

With the emergence of checkpoint inhibitors, the question of optimal sequencing is also a concern. George believes that the sequence of treatment demonstrated in the phase III trial design is likely the best way—that is, giving the immunotherapy after surgery once the majority of the cancer has been removed. “It’s a numbers game in which there is less cancer for the immune system cells to have to find and attack,” he said. “In addition, the immune system is most potent when there’s the least amount of physical cancer present.”

Most impressive was how well the vaccine was tolerated when combined with standard care, said George. “It is promising that we don’t have to abandon our standard of care,” he concluded.