For a number of years following the approval of gemcitabine for advanced pancreatic cancer, one phase III clinical trial after the next failed to demonstrate a survival benefit of combination chemotherapy compared to gemcitabine alone. Even the one positive study from the mid-2000s—the PA.3 trial leading to the approval of erlotinib (Tarceva) in combination with gemcitabine as first-line treatment1—was associated with a very modest improvement in survival, and is often cited as an example of a therapy whose benefit may be statistically significant but not necessarily clinically meaningful.
Expanding Options
Thankfully, therapeutic options are now evolving and expanding for patients with advanced pancreatic cancer. Positive results from the international phase III MPACT trial, reported by von Hoff and colleagues in the September 2013 issue of The New England Journal of Medicine2 and reviewed in this issue of The ASCO Post, have led to the recent FDA approval of albumin-bound paclitaxel (nab-paclitaxel [Abraxane]) in combination with gemcitabine for this disease.
The study demonstrated clear (albeit still modest) improvements in overall and progression-free survival and objective response rate of gemcitabine/nab-paclitaxel compared to gemcitabine monotherapy, accompanied by a predictable and manageable toxicity profile. But do these data now place this regimen at the forefront of treatment options for this disease, or does it simply represent one of an expanding number of equally viable alternatives?
Gemcitabine/Nab-Paclitaxel vs FOLFIRINOX: Beware Cross-Study Comparisons
Inevitable comparisons will be made between gemcitabine/nab-paclitaxel and another combination chemotherapy regimen, FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, and oxaliplatin). The French trial (PRODIGE 4/ACCORD 11)3 that led to the adoption of FOLFIRINOX as a front-line standard, however, was conducted in a single country, enrolled fewer than half the number of subjects as the MPACT trial, and included only patients with an Eastern Cooperative Oncology Group performance status of 0 or 1. These differences notwithstanding, the control arm (gemcitabine alone) for both trials had essentially identical median survivals (6.8 months for PRODIGE, 6.7 months for MPACT), suggesting that the patient populations for the two studies may have been, on the whole, fairly similar.
Although we proceed at our own risk when trying to make cross-study comparisons of this sort (which may be overly simplistic), the magnitude of benefit associated with FOLFIRINOX, with a median survival of 11.1 months, does appear superior to that of gemcitabine/nab-paclitaxel (8.5 months). However, unless and until these results are replicated in a successor study directly comparing these two regimens head to head—an initiative that likely will only be led by national cooperative groups, if at all, rather than by industry—we will be left with a fair degree of uncertainty regarding the optimal choice of first-line therapy in the subset of patients who are robust enough to entertain multiple options.
Moreover, as we are now faced in this disease with the positive development of having an expanding array of choices, the question of sequencing treatments through multiple lines, and the need to assess the benefit of each of these (and other) regimens in the second-line setting and beyond, becomes increasingly relevant.
Need for Biomarkers
Such unanswered questions highlight one of the key missing pieces in the treatment of pancreatic cancer: that is, the lack of a predictive biomarker to guide us in therapeutic decision-making. To this day, pancreatic cancer lags behind most other malignancies in terms of identification of a useful biomarker—whether it be at the level of protein expression, mutation of a particular gene, or a multigene panel—that can offer insight into therapies that are particularly effective or, conversely, may be necessary to avoid in any given patient.
In their preclinical and phase I/II study of gemcitabine/nab-paclitaxel,4 von Hoff and colleagues showed that an albumin-binding protein called SPARC (Secreted Protein Acidic and Rich in Cysteine), when expressed at high levels in the stromal compartment of pancreatic tumors, was associated with better survival in patients treated with the gemcitabine/nab-paclitaxel combination. Data on SPARC expression and its correlation with patient outcomes in the phase III MPACT trial are eagerly awaited to offer further validation of its potential prognostic and/or predictive utility, as it may further help identify the subset of patients who respond particularly well to nab-paclitaxel–based therapy.
Further Considerations
Additionally, the positive results associated with nab-paclitaxel raise a whole host of other issues when it comes to both pancreatic cancer clinical research and practical clinical management. Does gemcitabine/nab-paclitaxel now become the new reference standard (ie, the control arm) in randomized phase II/III trial design in the future? And do targeted therapies in clinical development automatically have to be tested in the first-line setting in combination with this two-drug chemotherapy backbone, absent a compelling preclinical rationale? (In this author’s opinion, no.)
From a patient management standpoint, noting the small subset of patients with poorer performance status from the MPACT study who still showed a survival benefit from combination therapy, can gemcitabine/nab-paclitaxel be routinely offered even to frailer patients? Finally, is it appropriate to expand the use of this drug to the locally advanced, neoadjuvant, and/or adjuvant settings before we have firmer data to verify its efficacy in these different contexts? (Again, in this author’s opinion: for locally advanced and borderline resectable disease, yes, it seems reasonable; in the postoperative adjuvant setting, not yet.)
Clearly, the MPACT study is not only practice-changing, providing a welcome new addition to our therapeutic armamentarium for pancreatic cancer, but equally importantly, opens up many new exciting avenues for further exploration in a disease that desperately needs it. ■
Dr. Ko is Associate Professor of Medicine at the University of California, San Francisco.
Disclosure: Dr. Ko has received prior research funding from Celgene to support investigator-initiated clinical trials.
References
1. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960-1966, 2007.
2. Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-1703, 2013.
3. Conroy T, Desseigne F, Ychou M, et al: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817-1825, 2011.
4. Von Hoff DD, Ramanathan RK, Borad MJ, et al: Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: A phase I/II trial. J Clin Oncol 29:4548-4554, 2011.
