New Indication Solidifies Nab-Paclitaxel Pancreatic Regimen

Ramesh K. Ramanathan, MD

Medical Director, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare

Deputy Director, Translational Research Division at TGen

Scottsdale, AZ

The ability of clinicians to improve treatment outcomes that gemcitabine offers for patients with metastatic pancreatic cancer is expected to move forward now that the FDA has approved a new indication for nab-paclitaxel (Abraxane) as part of a combination regimen, according to researchers.

On September 6, the FDA approved Abraxane in combination with gemcitabine for first-line treatment of patients with adenocarcinoma of the pancreas, which represents approximately 95% of pancreatic tumors. The agent was approved at a recommended dosage of 125 mg/m² intravenously infused on days 1, 8, and 15 of each 28-day cycle, with gemcitabine administered immediately afterward.

The combination already had been incorporated into the National Comprehensive Cancer Network guidelines as a category 2B recommendation, but has been upgraded to a category 1 classification. The dual therapy “could become the backbone for new regimens” in treatment of the disease, noted Daniel D. Von Hoff, MD, chief scientific officer at Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare, physician-in-chief at TGen, and lead author of the study, in presenting pivotal clinical trial results at the 2013 Gastrointestinal Cancers Symposium in January.¹

Although oncologists have been incorporating the combination into treatment plans, the FDA’s approval makes it a standard of care more likely to be reimbursed by insurance plans, observed Ramesh K. Ramanathan, MD, medical director of the Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare and deputy director of the Translational Research Division at TGen, in an interview. Ramanathan served as the principal investigator of the study for the United States.

Efforts to improve upon the clinical benefits of gemcitabine therapy have been under way for more than 20 years, said Ramanathan. He has been investigating the potential efficacy of an Abraxane combination since 2007 and played a leading role in the research that led to the new indication.

Table. Key Outcomes From the MPACT Trial

ABRAXANE + gemcitabine

(N = 431)

Gemcitabine (N = 430)

Overall Survival

Number of deaths, n (%)

333 (77)

359 (83)

Median OS (months)

8.5

6.7

95% CI

7.9- 9.5

6.0- 7.2

HR (95% CI)

0.72 (0.62-0.83)

P value

<.0001

Progression-free Survival

Death or progression, n (%)

277 (64)

265 (62)

Median PFS (months)

5.5

3.7

95% CI

4.5-5.9

3.6-4.0

HR (95% CI)

0.69 (0.58-0.82)

P value

<.0001

Overall Response Rate

Confirmed complete or partial overall response, n (%)

99 (23)

31 (7)

95% CI

19.1-27.2

5.0-10.1

P value

<.0001

HR indicates hazard ratio of Abraxane plus gemcitabine versus gemcitabine alone; OS, overall survival; PFS, progression-free survival. Source: Prescribing information.

MPACT Trial Results

Scottsdale Healthcare’s Virginia G. Piper Cancer Center Clinical Trials was among 151 sites in 11 countries that participated in the pivotal MPACT trial, which accrued from May 2009 and April 2012.

With a primary endpoint of overall survival (OS), 861 patients with stage IV pancreatic cancer who had no prior treatment for metastatic disease were randomized to Abraxane 125 mg/m², followed by gemcitabine 1000 mg/m² (n = 431), or gemcitabine alone (n = 430). Patients were treated until their disease progressed, with computed tomography scans performed every 8 weeks.

The median OS was 8.5 months in patients assigned to Abraxane plus gemcitabine, compared with 6.7 months in those assigned to gemcitabine monotherapy. The combination regimen also provided significant improvements in progression-free survival and overall response rates (Table).

Abraxane is an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nanometers. Ramanathan said researchers believe there are two main reasons that the combination is more effective than monotherapy.

“One reason is that Abraxane causes more of the active component of gemcitabine to be present longer in the cancer cells by inhibiting one of the enzymes,” Ramanathan said. “The other reason is that we think Abraxane weakens the shell (called the stroma) around pancreatic cancers. Pancreatic cancers in particular have a very thick stroma. This can prevent chemotherapy from entering the cancer cells. We think Abraxane weakens this outer shell so chemotherapy can get in.”

The adverse-event (AE) profile experienced by patients on the combination also was favorable, particularly considering that those participants typically received a larger cumulative dosage for a longer period of time than did patients in the monotherapy arm, investigators indicated.

The most frequently reported grade ≥3 hematologic AEs in the combination arm compared with the monotherapy arm were neutropenia (38% vs 27%), leukopenia (31% vs 16%), thrombocytopenia (13% vs 9%), and anemia (13% vs 12%). Fatigue (17% vs 7%) and peripheral neuropathy (17% vs <1%) were the most frequent nonhematologic AEs.

“The side effects are manageable,” said Ramanathan. “So we think this can be applied to most patients in the community.”

The characteristics of patients in the two arms were well balanced, Von Hoff noted in his presentation. Overall, the median age of trial participants was 63.0 years (27 years-88 years). Forty-three percent of participants had a primary pancreatic tumor location in the head of the organ, 32% in the body, and 26% in the tail. In addition, 48% had two metastatic sites and 47% had three or more.

In the area of Karnofsky Performance Status (KPS) scores, 60% of participants had scores of 90-100, while 40% ranged from 70-80. A KPS of 70 corresponds to an ECOG score of 2, Von Hoff said.

The 70-80 KPS group “may be more reflective of what we see in the community setting,” said Ramanathan. “That is the reason we think this treatment can be applied to what you see in a community practice.”

Moving Forward With Abraxane

Ramanathan said research into the use of Abraxane in pancreatic cancer is continuing on several fronts. In one study that is part of a Stand Up to Cancer Dream Team grant, researchers plan to examine the scans and biopsies of the tumors of patients who received the combination regimen to determine how the drugs affected the tumors. In other studies, researchers are adding investigational agents in the laboratory, notably PEGPH20, a pegylated formulation of recombinant human hyaluronidase, to investigate the impact of triple-agent regimens.

Ramanathan encourages oncologists to investigate clinical trials for their patients. “It is very important that we continue to do more research,” he said. “Otherwise, we won’t see any advances.”

Reference

1. Von Hoff DD, Ervin TJ, Arena FP, et al. Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). Presented at: 2013 Gastrointestinal Cancers Symposium; January 24-26, 2013; San Francisco, CA. Abstract LBA148.