Friday, September 6, 2013

FDA Approves Abraxane for Pancreatic Cancer

ABRAXANE® (generic name: nab-paclitaxel) was approved by the FDA as first-line therapy for the metastatic adenocarcinoma of the pancreas when used in combination with gemcitabine. The approval of ABRAXANE is a major development in pancreatic cancer care and is expected to replace gemcitabine alone as a new standard of care for pancreatic cancer. 

ABRAXANE in Celgene-Sponsored Pancreatic Cancer Trials

Phase II data reported at ASCO meeting in Chicago in June 2012
Sixteen patients with resectable or borderline resectable pancreatic cancer received ABRAXANE (125 mg / m sq) and gemcitabine (1000 mg / m sq) on days 1, 8 and 15. This treatment cycle was repeated (ie, total 2 treatment cycles total) and then 12 of these patients had surgery, of which 11 had complete resection (ie, removal of tumor). 
The June 4, 2012 press release reported that 13 of the 16 patients had stable or partial response, and the levels of tumor marker CA19.9 decreased by 70% or more in 8 of 16 (50%) patients.
Phase III MPACT Study
MPACT (Metastatic Pancreatic Adenocarcinoma Clinical Trial) was an open-label, randomized, multinational trial. There were 861 patients enrolled in this study. 
Patients received ABRAXANE (125 mg / m sq) and gemcitabine (1000 mg / m sq) for 3 weeks followed by 1 week rest (= 1 cycle). Then the cycle was repeated. Those in the gemcitabine "control" arm received gemcitabine for 7 weeks followed by 1 week rest (= 1 cycle), followed by repeat cycle.  
The primary endpoint was survival. The secondary endpoints were progression-free survival (PFS), objective tumor response, safety and tolerability.
The Nov 9, 2012 press release disclosed that there was a statistically significant increase in the overall survival in patients in the ABRAXANE arm, but data was not disclosed until January 22, 2013.  
MPACT Study results
The MPACT study data was presented at the ASCO's 2013 Gastrointestinal Cancers Symposium in San Francisco in January 2013 (press release).  
Patients receiving ABRAXANE had significantly better survival, better progression-free survival and overall response rate. Progression-free survival (PFS) is a measure of risk of progression or death. Increased PFS indicates reduced risk of death.
The overall survival in the ABRAXANE group was median 8.5 months vs 6.7 months in the gemcitabine group (HR 0.72, P=0.000015). The one-year survival increased by 59% (35% vs 22%, p=0.0002) and two-year survival rate doubled (9% vs 4%, p=0.02) as compared to gemcitabine alone. 
The median progression-free survival was 31% higher in the ABRAXANE group (5.5 vs 3.7 months (HR 0.69, P=0.000024). The overall response rate (ORR) was 23% vs 7% (response rate ratio of 3.19, p=1.1 x 10-10). 
Finally, the time to treatment failure was significantly increased in the ABRAXANE group (median 5.1 vs 3.6 months) (HR 0.70, P<0.0001).
About ABRAXANE and its side-effects

ABRAXANE is paclitaxel (brand name: Taxol) bound to albumin peptides which makes it water-soluble improving drug delivery (read here). Since less paclitaxel in the form of ABRAXANE is needed to achieve similar result, the side effects are much less than the parent drug. Also, major reason for the toxicity of paclitaxel (parent drug) is the solvent (also called excipient) Cremophor.

ABRAXANE was earlier approved by the FDA for metastatic breast cancer (2005) and non-small cell lung cancer (2012). The prescribing and known side-effects information are available here and here

ABRAXANE has fewer side effects than the parent compound paclitaxel and thus, may have better compliance compared to the other option for pancreatic cancer, a cocktail of four chemotherapy drugs, FOLFIRINOX. The efficacy of FOLFIRINOX is similar to ABRAXANE but the side-effects are often difficult to tolerate resulting in a lot more therapy discontinuations. 

Side-effects of ABRAXANE vs Gemcitabine

Compared to gemcitabine, the current standard of care for pancreatic cancer, the major side effect neutropenia remains with ABRAXANE. The adverse events reported in the MPACT study were:
"The most common grade ≥ 3 treatment-related adverse events in the study for ABRAXANE plus gemcitabine vs. gemcitabine alone were neutropenia (38% vs. 27%), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). In the ABRAXANE plus gemcitabine arm, the median time to neuropathy improvement was 29 days. There was no difference in serious life threatening toxicity (4% in each arm)."

About Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of death from cancer in the United States. Every year 45,000 new cases are diagnosed and 38,000 deaths from pancreatic cancer are reported in the US. Read more here.

Source, Related Posts:

  • Vaccaro V, Sperduti I, & Milella M (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England journal of medicine, 365 (8) PMID: 21864184 
  • Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe Tumeurs Digestives of Unicancer, & PRODIGE Intergroup (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England journal of medicine, 364 (19), 1817-25 PMID: 21561347  
  • Von Hoff DD, Ramanathan RK, Borad MJ, Laheru DA, Smith LS, Wood TE, Korn RL, Desai N, Trieu V, Iglesias JL, Zhang H, Soon-Shiong P, Shi T, Rajeshkumar NV, Maitra A, & Hidalgo M (2011). Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 29 (34), 4548-54 PMID: 21969517   
  • Faris JE, Blaszkowsky LS, McDermott S, Guimaraes AR, Szymonifka J, Huynh MA, Ferrone CR, Wargo JA, Allen JN, Dias LE, Kwak EL, Lillemoe KD, Thayer SP, Murphy JE, Zhu AX, Sahani DV, Wo JY, Clark JW, Fernandez-del Castillo C, Ryan DP, & Hong TS (2013). FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience. The oncologist, 18 (5), 543-8 PMID: 23657686 
  • Final results of a randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas. January 25, 2013. American Society of Clinical Oncology’s (ASCO) 2013 Gastrointestinal Cancers Symposium, San Francisco, CA. Abstract: LBA #148 [Google Web Cache Copy]


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