Over the past decade, advances in the understanding of tumor biology and driving mutations have led to the discoveries of numerous biomarkers and targeted agents that have revolutionized the fight against cancer. With recent news being so heavily centered on these targeted agents, it seems as though people often forget about the value that chemotherapy has provided over the years and, more importantly, that there is still room for improvement in these older regimens to generate significantly better outcomes for patients. Celgene was looking to take advantage of this sentiment when the company acquired Abraxis BioScience and their leading drug candidate, Abraxane®, an injectable suspension of nanoparticle albumin bound (nab)-paclitaxel.
Pancreatic cancer is a notoriously difficult malignancy to treat, with historical median overall survival hovering around six months from first-line therapy. Pancreatic cancer has remained stubbornly resistant to the modern drug development paradigm, highlighted by the numerous failed studies of targeted agents in combination with gemcitabine (the standard of care). An EGFR monoclonal antibody (Erbitux®, Bristol-Myers Squibb/Eli Lilly), VEGF inhibitors (Avastin®, Genentech/Roche; Nexavar®, Onyx/Bayer; and Inlyta®, Pfizer), an IGF-1R inhibitor (ganitumab, Amgen), and a c-Kit inhibitor (masitinib, AB Science) have all failed to show any additive survival benefit when combined with gemcitabine. The only targeted agent to show a statistically significant benefit and gain regulatory approval was the EGFR tyrosine kinase inhibitor, Tarceva® (erlotinib, Astellas/Roche), and that benefit was only about 10 days of extended overall survival at the median. These failures prompted academics and clinical physicians to re-examine combination chemotherapy, and the quintessential result was presented two years ago at the American Society of Clinical Oncology (ASCO) conference, where the FOLFIRINOX regimen wowed the audience with an 11.1-month median overall survival as first-line therapy (Conroy, J Clin Oncol, 2011). However, the well-publicized toxicity issues associated with FOLFIRINOX do leave the door open for more tolerable regimens to gain utilization, even if they are somewhat less efficacious.
The stage is now set for the Abraxane plus gemcitabine combination to enter the fray. On Friday at the 2013 ASCO Gastrointestinal Cancers Symposium, results were presented from the Phase III MPACT study (NCT00844649) that showed adding Abraxane to gemcitabine increased median overall survival to 8.5 months compared to 6.7 months in the gemcitabine-alone arm (HR=0.72, p=0.000015; Von Hoff, Abstract LBA148). Compared to the historical standard, 8.5 months is an excellent result, but it is also a little bit of a letdown considering that the median overall survival in the Phase II study was 12.2 months. Also, these results will be contrasted with the FOLFIRINOX survival of around 11 months, considering that the trials both enrolled similar “good performance status” patients.
Despite the shorter survival, Abraxane still has the ability to contend with FOLFIRINOX through its other attributes. Comparing the toxicity profiles side by side, as the discussant of the MPACT study did, Abraxane plus gemcitabine looked to be generally more tolerable with lower rates of Grade 3/4 fatigue (17% vs. 24%), diarrhea (6% vs. 13%), neutropenia (38% vs. 46%) and febrile neutropenia (3% vs. 5%) compared to FOLFIRINOX. Although Abraxane plus gemcitabine showed higher rates of Grade 3/4 neuropathy (17% vs. 9%), the discussant pointed out that all neuropathy was not the same and that the neuropathy associated with Abraxane could be resolved relatively quickly through dose delays or reductions, which may not be the case for FOLFIRINOX. However, this side-by-side comparison of toxicities should come with another caveat: The fact that many centers are now favoring the modified FOLFIRINOX regimen, which has the key difference of administering 5-FU in a 48-hour infusion instead of the bolus injection that was used in the original French study. This change has attenuated some of the toxicity of the regimen, but it also highlights another competitive difference between the two regimens. FOLFIRINOX is a complex four-drug regimen requiring a 48-hour infusion, whereas Abraxane plus gemcitabine can be administered concurrently once a week on a three-weeks-on, one-week-off schedule. Could the convenience of administration make the Abraxane plus gemcitabine the regimen of choice outside of large cancer centers? Although not presented at ASCO GI, there’s also the possibility that biomarker data may identify subpopulations of patients who derive even greater benefit with Abraxane; patients with RAS mutations or whose tumors overexpress SPARC are potential biomarkers for patient selection. Stay tuned for this data later this year, possibly at ASCO 2013.
Ultimately, physicians and patients will have to weigh a number of options when choosing their first-line pancreatic cancer therapy, from cost, to ease of administration, to performance status of the patient. It seems likely that FOLFIRINOX will remain the standard of care for the most “fit” patients who are willing to endure the complex regimen, but outside of those patients, Abraxane plus gemcitabine could prove to be a favorable option in the community clinic.
By: Stephanie Hawthorne, PhD, Director, Kantar Health and Josh Garcia, Associate Consultant, Kantar Health
You must be logged in to post a comment