Earlier Nab-Paclitaxel/Gemcitabine Explored in Pancreatic Cancer

The FDA approved the combination of nab-paclitaxel and gemcitabine in September 2013, based on findings from the phase III MPACT trial, which compared the combination with gemcitabine alone. Long-term survival data from MPACT were published in early 2015, and showed a sustained overall survival (OS) advantage.¹

The median OS with nab-paclitaxel plus gemcitabine was 8.5 months compared with 6.7 months for gemcitabine alone (HR, 0.72;P<.001). In the extended follow-up, a group of patients survived longer than 24 months in the nab-paclitaxel plus gemcitabine treatment arm, including 4% of patients who survived at least 36 months and 3% of patients who survived at least 42 months.

This success has led some researchers to explore the combination in other settings, outside of the metastatic disease space. The combination is being explored as an adjuvant therapy in the phase III APACT study for patients with pancreatic adenocarcinoma and as either a neoadjuvant or adjuvant therapy in the NEONAX trial for patients with resectable pancreatic cancer.

Neoadjuvant Nab-Paclitaxel/Gemcitabine Shows Early Promise

In a small retrospective case study exploring nab-paclitaxel plus gemcitabine as neoadjuvant therapy for borderline resectable or unresectable locally advanced pancreatic adenocarcinoma, both the R0 resection rate and the response rate were each 20%. Findings from the study were presented at the 2016 Gastrointestinal Cancers Symposium.²

&ldquo;The cases who do the best and are able to undergo a long-term strategy are those who are able to get through surgery,&rdquo; said co-author of the study Arturo Loaiza-Bonilla, MD, assistant professor of clinical medicine at the University of Pennsylvania. &ldquo;An R0 resection means that the cancer was cut out completely, with all the edges completely free from tumor. Those are the ones with prolonged survival, whereas in an R1 resection, the pathologist looks at the sample with a microscope, and sees cancer cells at the margin.&rdquo;

The study looked at 20 patients at a median age of 69 years. The most common ECOG performance status was 1 (55%). A majority of the patients had borderline resectable disease (n = 14; 70%).

&ldquo;An R1 resection is almost the same as having no surgery at all. The outcomes are equally bad,&rdquo; explained Loaiza-Bonilla. &ldquo;Surgery is not really an option for these patients at the moment, so we&rsquo;re trying to use chemotherapy and radiation to shrink the tumor so the patient can go to surgery.&rdquo;

Out of 6 patients who went on to receive surgery, 83% also had preoperative radiation and 67% had R0 resections. All patients with an R0 resection (n = 4) were initially defined as borderline resectable. Two patients with unresectable disease by imaging at presentation were able to undergo potentially curative surgery, although an R0 resection was not achieved. Median progression-free survival was 9.1 months (95% CI, 6.2-12.0).

&ldquo;The good thing about this trial is that the patients are too frail for the three-medicine combination, FOLFIRINOX, but in using only two agents, we&rsquo;re able to achieve almost the same results,&rdquo; said Loaiza-Bonilla. &ldquo;The data we have now indicate that at least about 20% of the patients have a conversion to an R0 resection, and the overall disease control rate is about 90%.&rdquo;

The majority of patients in the study received 6 to 9 doses of nab-paclitaxel and gemcitabine. The partial response rate was 20% and the stable disease rate was 70%. In total, dose reductions were required for 64% of patients, a finding that will be applied to future studies.

&ldquo;We had one patient who was 90 years old, and two more who were over the age of 80, one of whom, an 81-year-old lady, had one of the best responses. She had almost a complete response to therapy without the requirement of any radiation, and did remarkably well for almost 2 years,&rdquo; Loaiza-Bonilla added. &ldquo;She had some breaks. There has been some data published that suggests you can give the combination every two weeks, and the patient can recover within those two weeks from the side effects.&rdquo;

In data published from a single-center experience,³changing the administration schedule for gemcitabine plus nab-paclitaxel from weekly to every other week significantly reduced side effects without impacting efficacy as a frontline treatment for patients with metastatic pancreatic cancer. The less intense treatment schedule demonstrated a median overall survival of 11.1 months and a median progression-free survival of 4.8 months. Moreover, the change in dosing reduced patient medical costs by $5,500 per month.

Neoadjuvant/Adjuvant Trials Assessing Nab-Paclitaxel/Gemcitabine

Larger studies with longer follow-up are planned to determine whether low-dose neoadjuvant nab-paclitaxel and gemcitabine followed by radiation can lead to long-term disease control for patients with borderline resectable or unresectable locally-advanced pancreatic adenocarcinoma. University of Pennsylvania researchers are also doing a small dose escalation study involving 25 patients, in which the dose of both nab-paclitaxel and radiation are increased, with data available in about a year.

Additionally, researchers are now exploring the same strategy in a prospective fashion in a study with 280 patients accrued across the United States, according to the senior author of the poster Peter Hosein, MD, assistant professor of medicine at the University of Kentucky.

Another trial, known as NEONAX, is examining the use of nab-paclitaxel prior to surgery. In this trial, one arm will receive nab-paclitaxel plus gemcitabine both before and after surgery, while the other arm will receive the combination only after surgery. The trial is investigating the treatment in patients with non-metastatic pancreatic cancer.

&ldquo;NEONAX is currently the largest trial worldwide to examine whether neoadjuvant and/or adjuvant&nbsp;treatment with gemcitabine plus nab-paclitaxel improves disease-free survival of patients with resectable ductal pancreatic adenocarcinoma,&rdquo; explained principal investigator Thomas Seufferlein, MD, PhD, a professor in the department of internal medicine at the University of Ulm, in Germany. &ldquo;The major focus is improvement in disease-free survival and overall survival. However, tumor shrinkage and R0 resections are secondary objectives of the trial.&rdquo;

As part of the trial, researchers will also investigate potential biomarkers such as hENT1, CDA, DCK, 5&acute;-nucleotidase, CA19-9, SPARC, and neutrophil-lymphocyte ratio. The NEONAX researchers intend to enroll 166 participants, with a primary completion date of March 2019 (NCT02047513).

Following surgery, the phase III APACT trial is comparing nab-paclitaxel plus gemcitabine with gemcitabine alone in patients with resectable cancer who have already undergone surgery. Investigators intend to enroll 800 patients, with a primary completion date of April 2019. An R0 or R1 resection is required prior to entry into this trial.

&ldquo;There was clinical benefit for patients with metastatic pancreatic cancer demonstrated by MPACT,&rdquo; said Brian Lu, MD, PhD, senior medical director for clinical research and development at Celgene Corporation, which is sponsoring the trial. &ldquo;The question is whether this clinical benefit can be extended to an earlier setting of pancreatic cancer.&rdquo;

In APACT, biomarkers will also be assessed as exploratory endpoints. The primary outcome will measure disease-free survival, with secondary endpoints focused on OS and safety. At this time, gemcitabine alone is the standard adjuvant therapy for patients with pancreatic cancer.

&ldquo;If there are concerns that the tumor is borderline resectable, or locally advanced, they are typically considered for neoadjuvant strategies,&rdquo; said Lu. &ldquo;The treatment plan is to typically avoid R1 resections, but the resection status may not be known until after surgery has happened.&nbsp;R1 resection is associated with a clinical benefit in patients receiving single-agent gemcitabine.&rdquo;

In the study, nab-paclitaxel will be administered at 125 mg/m²along with gemcitabine at 1000 mg/m²on days 1, 8, and 15 for 6 cycles. Gemcitabine will be administered alone at 1000 mg/m²on days 1, 8, and 15. The trial is currently recruiting (NCT01964430).

References

1. Goldstein D, El-Maraghi R, Hammerl P, et al. Nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst. 2015;107(2). doi: 10.1093/jnci/dju413.
2. Peterson S, Loaiza-Bonilla A, Ben-Josef E, et al. Neoadjuvant nab-paclitaxel and gemcitabine (AG) in borderline resectable (BR) or unresectable (UR) locally advanced pancreatic adenocarcinoma (LAPC) in patients ineligible for FOLFIRINOX. J Clin Oncol. 2016;34 (suppl 4S; abstr 328).
3. Krishna K, Blazer M, Wei L, et al. Modified gemcitabine and nab-paclitaxel in patients with metastatic pancreatic cancer (MPC): A single-institution experience. J Clin Oncol. 2015;33 (suppl 3; abstr 366)