Combination of Nab-Paclitaxel and Gemcitabine Improves Survival in Patients with Metastatic Pancreatic Cancer

Summary

In an international randomized phase III trial, patients with metastatic pancreatic cancer who were treated with a combination of albumin-bound paclitaxel (nab-paclitaxel [Abraxane®]) and gemcitabine (Gemzar®) lived longer than patients who were treated with gemcitabine alone. Patients who received both drugs also lived longer without their disease getting worse (progression-free survival).

Source

New England Journal of Medicine, October 31, 2013 (See the journal abstract.)

Background

Although pancreatic cancer is rare—with approximately 45,000 cases diagnosed each year in the United States—it is the fourth leading cause of cancer-related death in this country. At diagnosis, most patients with pancreatic cancer have advanced disease that has spread, or metastasized, to other parts of the body. Only 2 percent of patients with metastatic pancreatic cancer are still alive 5 years after diagnosis.

The chemotherapy drug gemcitabine has been a standard initial treatment for patients with metastatic pancreatic cancer for more than 15 years. Numerous clinical trials have tested new drugs, either alone or in combination with gemcitabine, in these patients. The chemotherapy regimen known as FOLFIRINOX is the only treatment that has been shown in a clinical trial to improve the survival of patients with metastatic pancreatic cancer.

Nab-paclitaxel is a form of the chemotherapy drug paclitaxel that is bound to the human protein albumin and contained in nanoparticles. Binding paclitaxel to albumin eliminates the need for solvents that keep paclitaxel soluble once injected into the body but that can also cause allergic reactions and side effects. Albumin also plays a key role in delivering nutrients to dividing cells. Tumor cells require an abundance of nutrients to survive, so binding paclitaxel to albumin helps deliver paclitaxel to tumor cells.

Studies in mice with tumors derived from human pancreatic cancer cells suggested that the combination of gemcitabine and nab-paclitaxel was more effective than either drug alone. Results from a phase I/II trial strongly suggested that the combination could be effective in previously untreated patients with metastatic pancreatic cancer.

The Study

The Metastatic Pancreatic Adenocarcinoma Clinical Trial—conducted in North America, Europe, and Australia—randomly assigned 861 patients with metastatic pancreatic cancer who had not been treated previously with chemotherapy to receive either nab-paclitaxel plus gemcitabine or gemcitabine alone. Patients were eligible for the study if they had a Karnofsky Performance Status of 70 or higher. (Patients with a Karnofsky score of 70 can care for themselves but are no longer capable of engaging in normal daily activities or work.) The trial’s primary endpoint was overall survival, and the secondary endpoints were progression-free survival and tumor response rate. There was no age limitation for entry into the trial.

The trial was funded by Celgene, the manufacturer of nab-paclitaxel. The trial’s lead investigator was Daniel Von Hoff, MD, of the Translational Genomics Research Institute in Arizona.

Results

Patients who received the drug combination had a median overall survival of 8.5 months, compared with 6.7 months for patients treated with gemcitabine alone. This difference in overall survival was statistically significant.

One year after starting treatment, 35 percent of patients who received both drugs and 22 percent of those who received gemcitabine alone were alive. Two years after starting treatment, 9 percent of patients who received the combination and 4 percent of those who received gemcitabine alone were alive.

Patients who received the drug combination had a median progression-free survival of 5.5 months, compared with 3.7 months for those treated with gemcitabine alone. The tumor response rates were 23 percent for those treated with the combination and 7 percent for those treated with gemcitabine alone.

The improvement in overall and progression-free survival with the drug combination was also seen in patient subgroups defined by prespecified characteristics such as age, sex, and extent of tumor spread.

Patients who received both drugs stayed on treatment longer and received a greater cumulative dose of the drugs than patients who received gemcitabine alone, the researchers reported. 

Several side effects were more common among patients who received the drug combination, including neutropenia, peripheral neuropathy, and fatigue.

In September 2013, the U.S. Food and Drug Administration approved nab-paclitaxel for use in combination with gemcitabine to treat patients with metastatic pancreatic cancer based on the results of the MPACT trial.

Limitations

The trial did not include a measurement of patients’ quality of life. However, in an email, Dr. Von Hoff said that abdominal pain—the most common symptom in pancreatic cancer—often improves in patients treated with the combination. In his own experience, he added, “patients experience improvement of their abdominal pain within weeks of starting this combination.”

About 7 percent of patients in the trial had a Karnosky Performance Score of 70, which is considered to be a poor performance status. But, overall, patients in the trial had a better performance status than many patients diagnosed with pancreatic cancer, said Jack Welch, MD, PhD, of NCI’s Division of Cancer Treatment and Diagnosis. So the findings may not be generalizable to many patients with this disease, he noted.

Comment

The FOLFIRINOX and nab-paclitaxel–gemcitabine regimens have been quickly adopted into clinical practice, Dr. Welch said, with both treatments now recommended as first-line therapies for patients with metastatic disease and good performance status.

“Now the big question is which regimen to lead with, but there is no clear answer to that,” he said.

The FOLFIRINOX regimen “as published, is very active. And for selected patients, it may be a good treatment choice,” Dr. Von Hoff wrote via email. But it’s also “considered by many clinicians as too toxic,” he continued, which may limit its use.