MPACT

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Von Hoff DD, et al. "Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine". The New England Journal of Medicine. 2013. 369(18):1691-1703.
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Clinical Question

Among patients with pancreatic adenocarcinoma being treated with first-line chemotherapy for metastatic disease, does gemcitabine plus nab-paclitaxel prolong overall survival compared to gemcitabine alone?

Bottom Line

Among patients with metastatic pancreatic adenocarcinoma receiving first-line therapy, gemcitabine plus nab-paclitaxel significantly prolongs overall survival compared to gemcitabine alone at the expense of higher rates of neuropathy and myelosuppression.

Major Points

Pancreatic cancer is an aggressive malignancy and patients with metastatic disease have an overall dismal prognosis. Traditional chemotherapeutic therapies may be ineffective because of the hypovascular and desmoplastic nature of the tumor's stroma.[1] For many years, a standard of care was elusive; eventually, gemcitabine was compared to 5-fluorouracil (5FU) and demonstrated an overall survival advantage (5.6 vs. 4.4 months).[2] Improved outcomes were seen with leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) in the PRODIGE 4 ACCORD 11 study, which resulted in an overall survival benefit when compared to gemcitabine monotherapy (11.1 vs. 6.8 months; P <0.001).[3] This regimen was found to be fairly toxic, and subsequent efforts sought to reduce toxicity while improving on the efficacy of gemcitabine monotherapy.

Published in 2013, the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT; not to be confused with NCI-MPACT[4]) evaluated the addition of nab-paclitaxel to gemcitabine. Nab-paclitaxel is a water-soluble, albumin-bound paclitaxel nanoparticle that may promote tumor angiogenesis and improve localized chemotherapy delivery.[2] 861 patients with metastatic pancreatic adenocarcinoma who had not received prior chemotherapy (with an exception for adjuvant chemotherapy as part of chemoradiation) were randomized 1:1 to receive gemcitabine plus nab-paclitaxel or gemcitabine monotherapy.

Patients treated with gemcitabine plus nab-paclitaxel had improved overall survival of 1.8 months compared to patients treated with gemcitabine monotherapy (8.5 vs. 6.7 months; P<0.001). The combination was more toxic, associated with higher rates of grade 3-4 neutropenia (38% vs. 27%), fatigue (17% vs. 7%), diarrhea (6% vs. 1%) and peripheral neuropathy (17% vs. 1%). Of note, the patient population differed from the FOLFIRINOX study, in that it did not exclude patients over age 75 (10% in the MPACT study) and patients with worse performance status (8% had an ECOG performance status of 2 in the MPACT study). While overall survival in the FOLFIRINOX study was longer (11.1 months), gemcitabine plus nab-paclitaxel is another standard of care option, especially for older patients with worse performance status.[5] The MPACT trial led to the FDA approval of nab-paclitaxel in metastatic pancreatic adenocarcinoma.[6]

Guidelines

NCCN Guidelines (2016, adapted):[7]

  • For patients with metastatic disease, preferred options for first-line therapy are a clinical trial, FOLFIRINOX (category 1), or gemcitabine/nab-paclitaxel (category 1).

Design

  • Phase III, randomized, open-label, multicenter, international trial
  • N=861
    • Gemcitabine/nab-paclitaxel (N=431)
    • Gemcitabine (N=430)
  • Setting: 151 centers in 11 countries
  • Enrollment: 2009-2012
  • Stratification: Performance status, presence of liver metastases, and geographic region
  • Mean follow-up: 9.1 months (gemcitabine/nab-paclitaxel), 7.4 months (gemcitabine)
  • Analysis: Intention-to-treat
  • Primary outcome: Overall survival

Population

Full eligibility criteria are presented in the supplementary appendix.[8]

Inclusion Criteria

  • Age ≥18 years
  • Karnofsky performance status (KPS) ≥70 (out of 100, higher indicating better functional performance)
  • Metastastic pancreatic adenocarcinoma, confirmed with pathology, diagnosed in prior 6 weeks
  • Measurable disease by RECIST version 1.0 criteria
  • Acceptable bone marrow, hepatic, and kidney function

Exclusion Criteria

  • No prior chemotherapy for adjuvant or metastatic disease except fluorouracil or gemcitabine as a radiation sensitizer in the adjuvant setting at least 6 months prior to enrollment without lingering toxicities
  • Islet cell malignancies
  • Locally-advanced disease
  • Known brain metastases unless previously treated and well-controlled for at least 3 months
  • History of peripheral arterial disease, high cardiovascular risk including history of coronary stenting or myocardial infarction within the last year

Baseline Characteristics

From the gemcitabine/nab-paclitaxel group.

  • Demographics: Age 62 years, 43% female
    • Race/ethnicity: 88% White, 6% Hispanic, 4% Black, 2% Asian
    • Geographic region: 62% North America, 15% Eastern Europe, 14% Australia, 9% Western Europe
  • KPS: 100 - 16%, 90 - 42%, 80 - 35%, 70 - 7%
  • Pancreatic tumor location: 44% head, 31% body, 24% tail
  • Site of metastatic disease: 85% liver, 35% lung, 4% peritoneum
  • Number metastatic sites: 1 - 8%, 2 - 47%, 3 - 32%, >3 - 14%
  • CA19-9: Normal 16%, Median 2294 U/mL, range 1.9-6,159,233 U/mL
  • Prior therapies: 19% biliary stent, 7% Whipple, 5% chemotherapy, 4% radiation therapy

Interventions

  • Randomization 1:1 to one of two groups:
    • Gemcitabine/nab-paclitaxel - Nab-paclitaxel 125 mg/m2 IV followed by gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 4 weeks
    • Gemcitabine - Gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 every 4 weeks
  • Patients were assessed every 8 weeks by CT or MR imaging and CA19-9 level
  • Treatment continued until disease progression or unacceptable level of adverse events; crossover was not allowed

Outcomes

Comparisons are gemcitabine/nab-paclitaxel vs. gemcitabine.

Primary Outcomes

Median overall survival
8.5 months vs. 6.7 months (HR 0.72; 95% CI 0.62-0.83; P<0.001)

Secondary Outcomes

Median progression-free survival
5.5 months vs. 3.7 months (HR 0.69; 95% CI 0.58-0.82; P<0.001)
Overall response rate
23% vs. 7% (response-rate ratio 3.19; 95% CI 2.18-4.66; P<0.001)

Subgroup Analysis

There were no difference or improved efficacy with gemcitabine/nab-paclitaxel for the primary outcome across most subgroups. (See details in figure 2 on page 1700.)

Adverse Events

Any event leading to death
4% vs. 4%
Grade 3 or greater
Neutropenia: 38% vs. 27%
Leukopenia: 31% vs. 16%
Thrombocytopenia: 13% vs. 9%
Anemia: 13% vs. 12%
Receipt of growth factors: 3% vs. 1%
Fatigue: 17% vs. 7%
Peripheral neuropathy: 17% vs. 1%
Diarrhea: 6% vs. 1%

Criticisms

  • There was no quality of life analysis conducted (as there was in the FOLFIRINOX trial)
  • The control arm was gemcitabine monotherapy, and FOLFIRINOX is now the standard of care
  • The trial was open-label, thus patients and physicians were not blinded to study treatments
  • The title may be "inappropriately rosy" given the small improvement in OS, high incidence of side effects, and high cost of the medication[9]

Funding

Celgene, the manufacturer of nab-paclitaxel under the trade name Abraxane.

Further Reading

  1. Frese KK et al. nab-Paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer. Cancer Discov 2012. 2:260-9.
  2. 2.0 2.1 Burris HA et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 1997. 15:2403-13.
  3. Conroy T et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 2011. 364:1817-25.
  4. NCI-MPACT ClinicalTrials.gov listing
  5. Abbruzzese JL & Hess KR New option for the initial management of metastatic pancreatic cancer?. J. Clin. Oncol. 2014. 32:2405-7.
  6. FDA press release announcing approval of nab-paclitaxel for metastatic pancreatic cancer
  7. NCCN Guidelines for Pancreatic Adenocarcinoma, Version 2.2016.
  8. Inclusion and exclusion criteria are detailed on pages 30-32 of the supplementary appendix.
  9. Saltz LB & Bach PB Albumin-bound paclitaxel plus gemcitabine in pancreatic cancer. N. Engl. J. Med. 2014. 370:478.