Expanding Options for Pancreatic Cancer...So Where Do We Go From Here?

In light of two recent positive clinical trials for advanced pancreatic cancer, we are currently facing an interesting situation that those of us who treat this disease have not had to deal with previously: what to do with this expanding array of choices? Both FOLFIRINOX (infusional fluorouracil, leucovorin, irinotecan, and oxaliplatin) and the combination of gemcitabine plus nab-paclitaxel have demonstrated superior activity compared with gemcitabine monotherapy in large, randomized phase III studies.[1,2] Both now represent valid therapeutic options for patients with good–to–reasonably-well-maintained performance status. In this era of increasingly limited resources, and given the current emphasis on biomarker-driven studies and personalized medicine (which pancreatic cancer has, admittedly, lagged behind in), what should be our next priorities in clinical trial design for advanced pancreatic cancer?

While Thota and colleagues include gemcitabine and gemcitabine/erlotinib on their list of regimens to consider, let’s put aside these two options for now and assume that FOLFIRINOX and gemcitabine/nab-paclitaxel represent the leading choices for patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. First question: Given the inherent limitations of cross-study comparisons, does it make sense for us next to pursue a large phase III trial comparing these two regimens directly head-to-head? In my discussions with colleagues, many of whom are leading experts in the field of pancreatic cancer clinical research, the sentiment is decidedly mixed. Such a study is far too mundane and not sufficiently innovative, many argue; does it really advance the field in any meaningful way? On the flip side, might this not, in fact, represent the key question that oncologists today want answered? And if so, at some point, shouldn’t practicality trump innovation? Finally, could a study be creatively designed, and powered, in such a way as to identify a predictive biomarker (whether SPARC [secreted protein acidic and rich in cysteine] or another candidate marker) that might finally be used in this disease to aid in the selection of the best therapy? Of course, left unspoken is the question of who would spearhead such a study. There would not necessarily be a commercial driver, since the components of FOLFIRINOX are all off patent in the United States, while the manufacturer of nab-paclitaxel might not wish to support a trial, even if designed as a sequencing study, that risks relegating its product to second-line status. Would such a “mundane” trial fit within the portfolio, and mission, of the US cooperative groups? Or will Europe end up leading the way to ultimately answer this question, as it seems to be doing increasingly often?

We are also left to confront the intertwined issues of which of these regimens is the most suitable to use as a reference standard in future randomized phase II/III trial designs, and which can and should be built upon as a chemotherapeutic backbone to which targeted agents are added. Absent compelling preclinical data or a mechanistic rationale supporting synergistic activity with one regimen over another, does every novel drug in development now need to be tested in combination with both FOLFIRINOX and gemcitabine/nab-paclitaxel? A number of trials currently underway, or in development, are already using the latter combination as their chemotherapy framework. Conversely, to date there have been relatively few clinical studies attempting to build upon FOLFIRINOX as a backbone,[3] perhaps reflecting underlying concerns that this regimen is too toxic, and that consequently dose-modification schemes would be too complex.

All of these considerations notwithstanding, the increasing number of options for treating pancreatic cancer represents an encouraging and long-awaited change-for patients especially, but also for clinical oncologists and researchers who have spent decades trying to improve outcomes in a meaningful way but have been left coming back to gemcitabine alone time and again. Thus, we should welcome this increasing degree of complexity and confusion in therapeutic decision making and clinical trial design with nothing less than open arms.

Financial Disclosure:Dr. Ko has received research support from and serves on an advisory board for Celgene.

References:

1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364:1817-25.

2. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-703.

3. Ko AH, LoConte NK, Kantoff E, et al. A phase Ib trial of FOLFIRINOX plus saridegib, an oral hedgehog (Hh) inhibitor, in pts with advanced pancreatic cancer (PDAC). [abstract]. J Clin Oncol. 2012;30:3105.