Disappointing Results of a Phase II Trial Using Angiogenesis Inhibitor

Can the efficacy of the standard-of-care treatment with mFOLFIRINOX be improved by adding another agent that cuts down tumor blood vessel growth?

That’s the question researchers hoped to answer in a phase II double-blind trial comparing mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients. Results of the trial were presented at the 2021 ASCO GI Cancer Symposium.

Ramucirumab is a monoclonal antibody that attaches to and inhibits a molecule called VEGFR-2, a vascular endothelial growth factor receptor. The drug can stop new blood vessel formation which, in turn, reduces the nutrients a tumor needs to grow. It has already received approval for treatment of advanced or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma, metastatic non-small cell lung cancer, metastatic colorectal cancer, and hepatocellular carcinoma.

What is VEGF?

Vascular endothelial growth factor, or VEGF, is a signaling protein that promotes the growth of new blood vessels. It is part of a mechanism that can restore blood supplies to cells if they’ve been deprived of blood due to something as common as poor circulation. But if VEGF is overexpressed it can contribute to a host of issues. For example, solid tumors, like pancreatic cancer tumors, require an increased blood supply if they are to continue growing beyond a certain point. So tumors that express VEGF, like pancreas tumors, are able to continue to grow and spread because they have the ability to develop this blood supply. That process is called angiogenesis.

Researchers are looking for ways to block VEGF expression to prevent angiogenesis and subsequent tumor growth.  “In this study what we wanted to look at was what were the effects of adding ramucirumab to the standard-of-care treatment of mFOLFIRINOX,” explains gastrointestinal oncologist Tanios S. Bekaii-Saab, M.D., F.A.C.P., who serves as the leader of the Gastrointestinal Cancer Program at the Mayo Clinic Cancer Center in Phoenix, Arizona.

“We wanted to see whether adding ramucirumab to standard treatment was going to result in better outcomes, worse outcomes or not have much of an effect,” adds Bekaii-Saab, who also is the medical director of the Cancer Clinical Research Office as well as the Vice Chair and Section Chief for Medical Oncology in the Department of Internal Medicine. “What we were hoping is that it [ramucirumab] would improve the effectiveness of mFOLFIRINOX, but there wasn’t much of an effect across all parameters.”

About the Study

This double-blind study enrolled a total of 86 subjects, 82 of whom were eligible. They were randomized into two arms. In Arm A, participants received the standard treatment of mFOLFIRINOX plus ramucirumab. The second group, Arm B, received mFOLFIRINOX and a placebo. The primary endpoint was progression-free survival at nine months, and the secondary endpoints included overall survival and response rate.

The median progression-free survival was 5.6 months in Arm A compared to 6.7 months in Arm B. At nine months, the progression-free rates were 25.1% versus. 35% for Arms A and B, respectively. The mFOLFIRINOX/ramucirumab combination was well tolerated. Patients in Arm A reported a slightly higher number of adverse events, most commonly diarrhea, fatigue, vomiting, weight loss, and abdominal pain.

Arm B had a slightly higher response rate at 22.58% compared to Arm A at 17.65%. But it was not statistically significant. The median overall survival in Arm A was 10.3 compared to 9.7 months for Arm B. Says Bekaii-Saab, “It was pretty well tolerated, but overall the results were somewhat disappointing. You can’t get much cleaner than a double-blind, randomized study, and it may have sealed the deal on VEGF [inhibition] in pancreas cancer.”

The outcome measures with mFOLFIRINOX were very similar to what is observed with gemcitabine/Abraxane in more recent studies, Bekaii-Saab notes. “As such it appears the two regimens are likely interchangeable except in tumors with BRCA1/2 or PALB2 alterations, where, arguably, mFOLFIRINOX is preferred,” he says. “Although again I have replaced the latter by gem/cis (gemcitabine plus cisplatin) for most patients with these alterations.”

Researchers aren’t sure why some VEGF inhibitors in combination with other drugs seem to work well (but not as well as expected) in some cancers and not in others. “Pancreas cancer is notoriously difficult to treat,” says Bekaii-Saab. “The tumor microenvironment is very hostile and that may play a role, and there might be molecules other than VEGF that need to be looked at to see if they could be targeted to block angiogenesis.”

Looking at More Options

Bekaii-Saab’s research in pancreatic cancer focuses on the multiple facets of the disease, including cancer stem cells, DNA repair, and the immune milieu. He is currently involved in a clinical and translational trial with a class of agents known as poly-ADP-ribose polymerase (PARP) inhibitors, specifically rucaparib, in sequential combination with nanoliposomal irinotecan with a focus on pancreatic cancer with tumors exhibiting DNA repair defects. The trial was part of the Mayo Clinic’s Pancreatic Cancer SPORE initiative, which is specifically committed to reducing the incidence and mortality of pancreatic cancer.

“We are making some progress, and we obviously have to make more significant progress in the metastatic setting,” says Bekaii-Saab. We are specifically looking forward to results from the phase III NAPOLI-3 trial, in which patients with previously untreated metastatic pancreatic cancer will be randomized to liposomal irinotecan (Onivyde; nal-IRI) plus 5-fluorouracil (5-FU)/leucovorin and oxaliplatin (NALIRIFOX) versus the combination of gemcitabine and nab-paclitaxel (Abraxane). “This may give us more definitive answers we need on triplet versus doublet regimens and will help us better understand where things may be moving,” Bekaii-Saab adds.