Pancreatic Cancer Therapeutic Sequencing

Transcript:Tanios Bekaii-Saab, MD: Now that we’ve established that we have acceptable regimens, or regimens that have activity in the first-line, the question is, what options do we have for second-line? For many, many years, we have had a suboptimal first-line regimen and no options in the second-line. And then we had gemcitabine and nab-paclitaxel and FOLFIRINOX that were made available to us in the first-line. And, again, we still suffered from the lack of a standard in the second-line. Many oncologists used FOLFOX, some used FOLFIRI, some used 5-FU. And if there wasn’t a trial, patients were sent essentially to best supportive care and palliative care.

Recently, nanoliposomal irinotecan, or MM-398, and 5-FU, in a study called NAPOLI-1, showed superiority versus 5-FU alone. There was another arm with MM-398, so the nanoliposomal irinotecan alone, which did not show more activity than 5-FU. So, the standard has shifted from essentially 5-FU, or no therapy, to 5-FU plus MM-398. That would be, today, our gold standard of care in treating patients first-line; a gemcitabine-based regimen in the first-line with metastatic pancreas cancer.

The question that remains is, we have a study from the mid-2000s with oxaliplatin and 5-FU (OFF); that’s the CONKO study of Germany. And, essentially, that study suggested an improvement of OFF versus 5-FU and then led to a lot of United States oncologists using FOLFOX. Then comes another study from Canada, 2 years ago it was presented, showing that FOLFOX-6 is no better than 5-FU. In fact, the survival was even worse with FOLFOX than with 5-FU, and there may have been reasons for that. But, at this point of time, oxaliplatin does not seem to have the same level of evidence as 5-FU/MM-398. And therefore, oxaliplatin and oxaliplatin’s activity remains with a question mark in pancreas cancer.

Another question that always comes is, how about FOLFIRI? Since MM-398 is a nanoliposomal formulation of irinotecan, how about the cheaper version of irinotecan? Unfortunately, there hasn’t been much done with FOLFIRI, so there are theoretical advantages for the nanoliposomal formulation of irinotecan. But, clinically, we do not have that data in pancreas cancer. We do not have data about FOLFIRI. And, therefore, unfortunately, at this point of time, it is difficult to recommend FOLFIRI as an option. And because of the confusing data with oxaliplatin, I would not recommend oxaliplatin in the second-line. I think the standard would be 5-FU/MM-398 in patients who fail gemcitabine and nab-paclitaxel or gemcitabine formulations in the first-line.

Then, there is a small group of patients in the United States that receives FOLFIRINOX in the first-line. It’s about 10%, 15% of the patients, and shrinking. Those patients would not receive 5-FU/MM-398 in the second-line. That is a little bit more difficult space, because we don’t really have a lot of options that were studied in this line. Some folks would use gemcitabine single-agent, which doesn’t have much activity, or gemcitabine/nab-paclitaxel. But the concern would be the overlapping neurotoxicity. FOLFIRINOX has neurotoxicity. Gemcitabine/Abraxane can compound that. A more rational approach, which goes back to another part of the discussion, is to actually think rationally about a two-drug combination followed by a two-drug combination. So, a sequential gemcitabine/nab-paclitaxel followed by 5-FU/MM-398 would be the most rational sequence at this point of time when treating most patients with pancreas cancer.

In terms of selecting patients who go on gemcitabine-based regimens versus 5-FU—based regimens in the first-line, the drugs are FOLFIRINOX versus gemcitabine and nab-paclitaxel. FOLFIRINOX is a three-drug regimen, is more aggressive, and has more toxicities. Gemcitabine/nab-paclitaxel is essentially active, but probably has a lesser response rate. But, overall, it seems to be quite effective. And the question is, how do you pick one versus the other, the gemcitabine versus the 5-FU–based regimens? So, I think the answer is two-fold.

First, three-drug regimens are more toxic in the disease at stage IV, where you’re mostly looking for palliation. It doesn’t make as much sense. The second issue is that we do have an active regimen in the second-line in patients who failed gemcitabine-based regimens—and that’s 5-FU and MM-398. So, using a sequential approach with two drugs followed by two drugs would make more sense. I think, in absolute terms, if we actually take away the second-line option and then you have to choose between the 5-FU-based regimen, FOLFIRINOX, and gemcitabine/nab-paclitaxel—which is a gemcitabine-based regimen—then a patient who is very young and has an excellent performance status may go on FOLFIRINOX, while all others would go on gemcitabine/nab-paclitaxel unless they have a very poor performance status, and then treatment is not an option. However, today, with the presence of the second-line regimen that has activity, one would question the all—kitchen sink approach with throwing all these three drugs together versus adopting a more sequential approach.

Transcript Edited for Clarity