Welcome to Partners in Pancreatic Cancer. I am Dr. Tanios Bekaii-Saab. I am frequently asked, “What factors need to be taken into consideration in the selection of first-line treatment for patients with advanced metastatic pancreatic cancer?” Today, more than ever, we have more options available to our patients with pancreatic cancer, and these options are available across multiple lines of therapy. It is interesting that in pancreatic cancer we are talking about multiple lines of therapy. For multiple decades, we have barely had one line of therapy, mostly ineffective: 5-FU and then gemcitabine and then for some patients, that would go to 5-FU in the second-line. We spent a lot of time and energy and resources looking at combination therapy with gemcitabine plus drug X and looking at various biologics, mostly with futility. Lately, after the year 2010 at least, we started seeing more activity with regimens that are more active than gemcitabine, so FOLFIRINOX first, then gemcitabine and nab-paclitaxel as a combo. Then in 2015, we had a combination of 5-FU and nanoliposomal irinotecan MM-398 that made its way into the second-line for patients who failed gemcitabine-based regimens in the first-line. This armamentarium went from just single-agent gemcitabine now to three options, two in the first-line, and one in the second-line. We also had more data with oxaliplatin and 5-FU, which had been considered for quite a while as standard for our second-line. How do we actually put all this together? How do we think who is that patient who should get FOLFIRINOX? Who is that patient that should get gemcitabine and nab-paclitaxel, and then who is that patient who perhaps should get gemcitabine or no therapy?
Let's start with the no therapy/gemcitabine. Here, the way to decide which patients should not get treatment or which should get single-agent gemcitabine are those patients with a very poor performance status, 2+, 3, or 4. So, 3 or 4 should not get treatment. Performance status 2, probably bordering the 3 should not get treatment. But, those patients with performance status of 2 bordering the 1, and those are patients who have a lot of pain that is limiting, rather than being limited by other factors, those patients may benefit from gemcitabine plus/minus perhaps nab-paclitaxel.
Most of the patients we end up treating are performance status 0 and 1 and maybe between 1 and 2. For those patients, the question is, how do you choose between FOLFIRINOX and gemcitabine and nab-paclitaxel? The general rule that has been followed in the community and academic practices is, for your best patients ─ those that have best performance status, they are younger and healthier ─ you place them on FOLFIRINOX. Those that have less performance and who are perhaps older, you place them on gemcitabine/nab-paclitaxel. Well, while that could make sense, and FOLFIRINOX is certainly a regimen that has a meaningful activity, it is aggressive and it has toxicity.
It is important to understand how to select those patients for FOLFIRINOX versus gemcitabine and nab-paclitaxel. While clearly FOLFIRINOX is a very aggressive regimen that seems to provide tremendous benefit versus gemcitabine, relatively speaking for pancreatic cancer, of course. The toxicities that come with it can be quite significant as well. The fact that we have a second-line regimen, such as 5-FU and MM-398 or nanoliposomal irinotecan, makes a stronger case to move our practices to a more sequential approach. If you look at lung cancer, breast cancer, even colon cancer, and other cancers, we are moving more and more toward sequencing regimens rather than just an all kitchen sink approach. My preference has been, more and more, to shift patients to gemcitabine and nab paclitaxel in the first-line and then in the second-line with 5-FU and MM-398 rather than that all kitchen sink approach with FOLFIRINOX. Many times, I hear physicians say, "I only see strong solid responses with FOLFIRINOX.” That is true and mostly because we have that selection bias and when we see patients in our clinic, you are choosing the best performing patients who have probably the best biology and who are most likely to respond well to doublets or triplets with FOLFIRINOX; there is this intrinsic bias. I think a much better way to rethink how we treat pancreatic cancer is to really focus on a sequencing approach with gemcitabine and nab-paclitaxel first line and 5-FU and MM-398 on nanoliposomal irinotecan in the second-line. This also still leaves us potentially in the third-line to use oxaliplatin. Why is oxaliplatin now in the third-line, where for many years we have used it in the second-line? It is because of a series of studies that suggested, unlike the CONKO study that initially looked at oxaliplatin and 5-FU and suggested a benefit, the studies that came from Canada and then recently, the SWOG study versus double biologic, these studies suggest that FOLFIRINOX is probably not as active as the irinotecan component. Therefore perhaps moving oxaliplatin now to third-line; I personally rarely use it these days in clinic any more.
I think these are important considerations when we are thinking about patients in the first-line treatment of metastatic pancreatic cancer. The last point, very importantly: patients who are suspected to be BRCA or have BRCA-driven pancreatic cancer, those patients seem to actually have exquisite sensitivity to cisplatin at a lower dose. Those patients could perhaps be considered for gemcitabine and cisplatin. They also could be considered for FOLFIRINOX. Those patients also respond well to irinotecan and respond well to oxaliplatin and to cisplatin. This is a small percentage of your patients, but I think it is very important to keep an eye on those patients with the potential BRCA-driven tumor. When we are thinking about our patients with pancreatic cancer in the first-line, we have to think about what makes the most sense, to try more and more to consider a sequencing approach even in the well-performed patients, and then keep an eye on BRCA. The last word: gemcitabine and nab-paclitaxel; there is a significant challenge with giving the weekly regimen. We published a recent paper on giving gemcitabine and nab-paclitaxel every other week. By skipping day 8, maintaining the same dosage, we have seen very similar progression-free survival. Again, this was mostly retrospective, but the toxicity rate was tremendously improved, historically. The grade 3 neurotoxicity rate with the every other week was less than 1%, versus 17% with the weekly. We had less growth factor support, etc., so that could be another consideration for many of your patients. Finally, keep in mind, as you are thinking about all these factors, that this will lead you into treating those patients in the first-line. Thank you for viewing this activity.