Nab-Paclitaxel Therapy in Pancreatic Cancer Deemed Patient Friendly

Francis P. Arena, MD

Director, NYU Langone Arena Oncology

Clinical Associate Professor

NYU Langone Medical Center

New York, NY

E. Gabriela Chiorean, MD

Associate Professor, Medicine

University of Washington

Associate Member, Fred Hutchinson Cancer Research Center

Seattle, WA

A recently approved indication for nab-paclitaxel (Abraxane) in metastatic pancreatic cancer is thought to have similar efficacy to a standard first-line treatment for the disease, but offers several advantages in the eyes of community oncologists and their patients, experts said during an OncLive Peer Exchange roundtable.

The emerging role of nab-paclitaxel was among the topics that Francis P. Arena, MD, and E. Gabriela Chiorean, MD, two leading investigators in the pivotal study that led to the new indication for the drug, discussed during the Peer Exchange program, entitled “Current Therapeutic Advances in Metastatic Pancreatic Cancer.”

The panelists said that the recently approved nab-paclitaxel plus gemcitabine (Gemzar) regimen has demonstrated similar efficacy to FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin), but that the nab-paclitaxel combination has a tendency to improve patients’ performance status. In addition, the combination that includes nab-paclitaxel has been more thoroughly tested in community settings and appears to have a more favorable toxicity profile, they said.

Arena, director of NYU Arena Oncology, and Chiorean, of the Fred Hutchinson Cancer Research Center, are among the authors of the phase III MPACT study¹ that led to the FDA’s September 2013 approval of nab-paclitaxel plus gemcitabine as a first-line treatment for patients with metastatic disease. It is the third indication for Abraxane, an albumin-bound form of paclitaxel. Initially approved in 2005, the microtubule inhibitor also is indicated for the treatment of patients with metastatic breast cancer after recurrence or relapse following other chemotherapy regimens, and for first-line treatment in combination with carboplatin for locally advanced or metastatic non-small cell lung cancer.

Therapeutic Options Compared

For metastatic pancreatic cancer, the recommended nab-paclitaxel dosage is 125 mg/m² intravenously over 30 to 40 minutes on days 1, 8, and 15 of each 28-day cycle, with gemcitabine administered immediately afterward on the same schedule.²In the MPACT trial, the nab-paclitaxel regimen was shown to improve the median overall survival (OS) benefit offered by gemcitabine by 28%. The median OS was 8.5 months in the combination arm, compared with 6.7 months for gemcitabine alone (HR = 0.72; P <.0001) (Table).

Table. Key Clinical Trial Findings for Nab-Paclitaxel¹

Nab-Paclitaxel + gemcitabine (N = 431)

Gemcitabine (N = 430)

Overall Survival (OS)

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^a

<.0001

1-year OS (%)²

35

22

2-year OS (%)²

10

5

3-year OS (%)²

4

0

Progression-free Survival (PFS)

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^a

<.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^b

<.0001

^a Log-rank test stratified by geographic region (North America vs Others), Karnofsky performance score (70 to 80 vs 90 to 100), and presence of liver metastasis (yes versus no).

^b Chi-square test

1. Abraxane [prescribing information]. Updated October 2013. Accessed March 10, 2014.

2. Goldstein et al. J Clin Oncol. 2014;32(suppl 3; abstr 178).

While there have been no head-to-head studies of nab-paclitaxel/gemcitabine versus FOLFIRINOX, the efficacy of the two regimens as first-line treatments seems about the same, the panelists agreed. Response and survival rates were a bit higher in the phase III trial that demonstrated the efficacy of FOLFIRINOX³ in this setting, but Arena argued that study design might have skewed those results.

In the MPACT trial, “about 50% of the patients came from the community, which really is a great reflection of the diversity of all our patients. What’s interesting about pancreatic patients is that some come in as sick as can be and others may come in with a performance status that’s absolutely excellent, but are found to have painless jaundice or pain that needs elucidation,” Arena said.

“When you have this diversity among patients, you really need a study that is going to take a look at all comers,” Arena noted. “The FOLFIRINOX data were based on patients with very good performance status [PS], 0-1. And when you take a look at those patients that were in the nab-paclitaxel and Gemzar trial, it was a more open slate. You could go up to 2 [PS].”

In determining which regimen to use as firstline therapy for his patients with metastatic pancreatic cancer, Arena tends to lean toward the nab-paclitaxel pairing.

“I think we learned, way back when, that gemcitabine has the ability of improving the performance status of many of our patients,” he said. “About a quarter to a third of the patients will improve their performance status on gemcitabine, and I’m sort of old-fashioned in thinking, ‘Why should I give up that one piece that I have? I can make my patient feel better.’”

Patients’ Reactions Described

Chiorean has also found that her patients are happier while taking the nab-paclitaxel/gemcitabine combination.

“In my heart and mind, I have no doubt that FOLFIRINOX is more toxic, even despite all the supportive care that we offer patients,” she said. “There are exceptionally few patients who don’t have side effects with FOLFIRINOX, and the majority have many more side effects. We see in our practices that, when one patient goes on FOLFIRINOX and it doesn’t work, they go on gemcitabine/ Abraxane and almost universally say, ‘This is so much easier.’

“I haven’t yet had a patient who said FOLFIRINOX was a better regimen for him or her,” added Chiorean. “We do see, potentially, a bit more neuropathy and a little bit of an earlier onset of neuropathy with Abraxane, but it’s also easier to reverse, and I think that fatigue and GI toxicities are better with gemcitabine/Abraxane. We have to explain both regimens to the patient and, ultimately, it is the patient who makes the decision.” Arena pointed out that the decision, in many cases, is not truly a choice between the two regimens, but between which should come first.

“I think we’re in the same place that we were with colon cancer when we first had FOLFOX and then we had FOLFIRI, and then there were all these wonderful studies trying to see which should be used first and which could be used second, and it turned out it was a dealer’s choice,” Arena said. “I have a feeling this is going to be dealer’s choice, because, let’s face it, everybody is going to relapse.”

If the scientific community can work out which regimen to use first and which to use second in specific patients, thus extending survival long enough that a third option will be needed, Arena said, “I think we’ll have made some major headway.”

NCCN Recommendations

The nab-paclitaxel/gemcitabine combination was being used to treat metastatic pancreatic cancer before the FDA’s approval in that setting, and the regimen already had been incorporated into the National Comprehensive Cancer Network guidelines as a category 2B recommendation. Now, it has been upgraded to a category 1 classification.

In the MPACT trial, 861 patients with stage IV pancreatic cancer who had undergone no prior treatment for metastatic disease were randomized to nab-paclitaxel 125 mg/m² followed by gemcitabine 1000 mg/m² (n = 431), or to gemcitabine alone (n = 430), roughly weekly. Patients were treated until their disease progressed, with computed tomography scans performed every 8 weeks.

In addition to meeting its primary OS endpoint, the nab-paclitaxel regimen significantly improved progression-free survival and overall response rates as well (Table). Updated results presented during this year’s Gastrointestinal Cancers Symposium3 included 3-year OS values that support the combination’s superiority, investigators reported.

The most frequently reported grade ≥3 hematologic adverse events (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.

References

1. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine [published online October 16, 2013]. N Eng J Med. 2013;369(18):1691-1703.
2. Abraxane [prescribing information]. Summit, NJ: Celgene Corporation. Updated October 2013. Accessed March 10, 2014.
3. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Eng J Med. 2011;364(19):1817-1825.
4. Goldstein D, El Maraghi RH, Hammel P, et al. Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas. J Clin Oncol. 2014;32(suppl 3; abstr 178).