Making Sense of Emerging Therapies in Pancreatic Cancer: Are We Finally on the Right Track?

Untitled Document

Making Sense of Emerging Therapies in Pancreatic Cancer:
Are We Finally on the Right Track?

Andrew H. Ko, MD
Associate Professor of Clinical Medicine
Department of Medicine
Division of Hematology/Oncology
University of California, San Francisco
San Francisco, California

Tanios Bekaii-Saab, MD, FACP
Chief, Section of Gastrointestinal Oncology Chair, CCC Gastrointestinal
Disease Research Group
Professor of Medicine and Pharmacy
The Ohio State University –
James Cancer Hospital
Columbus, Ohio

Dr. Andrew H. Ko: Thank you very much for the opportunity to share with you today this talk on Making Sense of Emerging Therapies in Pancreatic Cancer: Are We Finally on the Right Track?

The main focus of this discussion is going to be on patients with advanced or metastatic disease, since the vast majority of patients with pancreatic cancer present with disease that is either metastatic or locally advanced and inoperable. At that point, systemic therapy becomes the mainstay of care. Now, over the past decade and a half, the standard of care has been a gemcitabine-based regimen. Gemcitabine was originally approved for use in the treatment of metastatic pancreatic cancer following approval of that drug in 1996, and since that time, a number of phase 3 trials evaluated the combination of gemcitabine with either a second cytotoxic agent or a molecularly targeted therapy. These by and large were negative studies, with the one exception being a trial from NCI Canada showing a very modest improvement in survival with the addition of erlotinib, the epidermal growth receptor inhibitor, to gemcitabine. However, because the results of that study were of questionable clinical significance, erlotinib has not really gained a lot of traction in use for pancreatic cancer today.

Positive Phase 3 Study Results

More recently, over the past few years, we have quite gratifyingly seen a couple of positive phase 3 study results that have led to a shift in the way we now treat patients with advanced metastatic pancreatic cancer. The first of these was a phase 3 study reported from France, called the PRODIGE 4/ACCORD 11 trial, which established a new standard of care called FOLFIRINOX for the frontline treatment of metastatic pancreatic cancer. FOLFIRINOX is a biweekly combination chemotherapy regimen consisting of bolus and infusional 5-FU, leucovorin, oxaliplatin, and irinotecan. This regimen was compared to single-agent gemcitabine for patients with metastatic pancreatic cancer with generally a good performance status. The study showed very clear and unequivocal improvements in survival, progression-free survival, and overall objective response rates for patients receiving FOLFIRINOX compared to gemcitabine. What was particularly striking about this study was that patients’ median survival with administration of FOLFIRINOX was greater than 11 months, with a 1-year survival rate of close to 50%, results not previously seen in a regimen tested in a purely metastatic cohort. I think an important corollary to this trial was an embedded quality of life study in which it was demonstrated that the patients on FOLFIRINOX, despite the greater toxicities, actually had preservation of their quality of life for a longer period of time, presumably because their cancer was controlled for a greater duration than for those receiving gemcitabine. The second positive phase 3 study that has come out in the past 3 years is the MPACT trial, which compared gemcitabine to gemcitabine plus nab-paclitaxel. This study again showed an improvement with the combination regimen when compared to gemcitabine monotherapy, with an overall survival of the combination of 8.5 months compared to about 6.7 months of gemcitabine alone. Improvements in progression-free survival and response rate were also seen with the doublet.

Two New Frontline Standards for Metastatic Pancreatic Cancer

Thus, for now, we are thankful to have two new frontline standards for metastatic pancreatic cancer, FOLFIRINOX, and gemcitabine and nab-paclitaxel. Comparing these two trials, one can see some of the differences between the two studies. The gemcitabine and nab-paclitaxel study was quite a bit larger, with more than twice as many patients enrolled as compared to the French study. It was more of an international study, conducted on multiple continents in both academic and community practices, so the findings are perhaps a little bit more generalizable. I pointed out importantly that patients enrolled to the FOLFIRINOX study really were good performance status patients, with an ECOG performance status of 0 or 1. Eligibility was a little bit more flexible for the gemcitabine and nab-paclitaxel trial, which included patients with a Karnofsky performance status down to 70. I mentioned quality of life data that was included in the FOLFIRINOX study; there was no such quality of life data reported from the MPACT trial. I also think it is fairly important to point out the lack of biomarker data from these studies that would allow some guidance in terms of which regimen to use over another. There was a lot of interest for a period of time in what is called SPARC, a potential predictive biomarker for sensitivity to nab-paclitaxel, suggested by earlier phase 1 and 2 studies of this agent in pancreatic cancer. However, when tested in the MPACT trial, this turned out not to be of prognostic or predictive value, so we are little back to the drawing board in terms of not having any specific biomarker that can direct us to one of these regimens or another.

I think we need to be a little bit cautious about making cross-study comparisons. I mentioned that patients receiving FOLFIRINOX had a median survival of upwards of 11 months whereas it was about 8.5 months for gemcitabine and nab-paclitaxel, and I think there is some value in comparing across the two studies given that patients receiving gemcitabine on the control arm of both of these studies had median survival about 6 and a half months or so; but again, we wanted to be a little bit cautious in terms of comparing the two. I think when you select the most first-line chemotherapy regimens you want to look at important issues like performance status, age, comorbid conditions, convenience, and patient preference. We can talk a little bit later perhaps about the cost effective considerations that might also guide treatment decisions.

So, that is where we are today in terms of frontline treatment, and I think what we are now seeing is a shift in how we are treating patients with the disease. Whereas in the past you maybe had one shot at treatment, and then really fewer than half of patients would be candidates for second-line treatment, I think we are really changing the biology of this disease, especially that patients are now able to receive second- or even third-line therapies and beyond as they are living longer with their disease. However, as it stands now in 2015, we do not yet have any standard care options for treating patients who have progressed beyond frontline therapy. Now empirically, what I do, and I think a lot of my colleagues who see a lot of pancreatic cancer do as well, is that for a patient who starts on FOLFIRINOX, if they are well enough at progression, we will switch them to a gemcitabine-based regimen such as gemcitabine and nab-paclitaxel – although the data for that are fairly limited. Conversely, if someone starts on a gemcitabine-based regimen such as gemcitabine and nab-paclitaxel, we will then switch them second-line to a regimen that contains fluoropyrimidine and a platinum agent, such as FOLFOX, capecitabine plus oxaliplatin; or maybe if they are very robust, they could receive FOLFIRINOX in that second-line setting. Then, beyond that we are a little bit grabbing for straws in that we do not have any hard data to guide us, and certainly clinical trials should be the main emphasis of how we direct these patients following progression on standard chemotherapy.

Drugs Under FDA Review

Now, I want to just spend a few minutes talking about some of the interesting drugs that are coming down the pike that may ultimately be realized in practice if some of the ongoing studies turn out positive results. I will mention a few and then in the later part of this talk, my colleague, Dr. Saab will talk a bit more about immunotherapy-based approaches that certainly are on everyone’s mind. The one drug that is currently under FDA review right now for possible approval in the second-line setting, post gemcitabine, is the drug called MM-398 which is a nanoliposomal formulation of irinotecan. This drug was evaluated in the context of a phase 3 trial called the NAPOLI-1 study, in which patients with metastatic pancreatic cancer following progression on a gemcitabine-based regimen were randomized to receive this agent MM-398 by itself, MM-398 in combination with 5-FU/leucovorin, or, as the control arm, 5-FU/leucovorin by itself. The study as reported last year demonstrated that the combination of MM-398 with 5-FU/leucovorin was statistically significantly superior to 5-FU/leucovorin (the control arm) in terms of overall survival and progression-free survival. These results have led to this drug now being under FDA review for approval in that second-line setting. Certainly for patients who have received FOLFIRINOX frontline, I would not necessarily think about using MM-398 as it is a different formulation of irinotecan, with better pharmacokinetics and biodistribution but not necessarily one that I would use for patients who had already received prior irinotecan. There is another drug called evofosfamide or TH-302 which is the prodrug of a cytotoxic alkylating agent, the idea here being that it is converted into its active form under hypoxic conditions. A large phase 3 trial called the MAESTRO trial evaluated patients with metastatic or locally advanced pancreatic cancer, comparing gemcitabine to gemcitabine plus TH-302, and we are waiting the results of that study. So those are a couple of the novel cytotoxic agents that may ultimately be incorporated into practice in the first- or second-line setting.

Stromal Depleting Agents

I want to mention another category of agents called stromal depleting agents. One that has gotten a lot of attention recently is a compound called PEGPH20. This is a recombinant human hyaluronidase, the idea being that hyaluronic acid is a main stromal component of pancreatic tumors. In this stroma, there is a desmoplastic or fibrotic reaction that often envelopes pancreatic cancers and is thought to be a physical barrier that may limit the penetration of chemotherapy agents. So, there has been a lot of interest in drugs that might be able to modify or deplete the tumor stroma, and PEGPH20 is one of them. There is some very nice preclinical data supporting this idea that this agent could deplete pancreatic tumor-associated stroma, and it has now been evaluated in a randomized phase 2 study. As presented at the 2015 ASCO meeting, patients with high levels of hyaluronic acid (HA) in their tumors had response rates and progression-free survivals that look to be substantially improved when this PEGPH20 agent was added to gemcitabine and nab-paclitaxel, compared to patients receiving just chemotherapy by itself. So, the intent here is that this is going to lead to a much larger phase 3 study evaluating this combination in the frontline setting.

In terms of targeted agents or molecularly targeted agents, these have by and large been disappointing up to this point. I mentioned erlotinib, an EGFR inhibitor, which is approved for use in the United States, but it is really used very infrequently. Certainly, KRAS and agents that target KRAS effector pathways are an area of intense interest. I want to bring your attention one other targeted agent called ruxolitinib, which is a JAK/STAT inhibitor already approved for use in the context of myelofibrosis. The idea here is that this agent may actually be important in patients in whom high levels of systemic inflammation is contributing to their disease, and may be contributing a lot to the cachexia and anorexia and wasting associated with pancreatic cancer. So, a study that was presented at the 2014 ASCO meeting, called the RECAP trial, evaluated ruxolitinib in combination with capecitabine for patients who had progressed on gemcitabine-based chemotherapy. When compared to capecitabine plus placebo in the subset of patients who had high levels of C-reactive protein, (so again, indicating a high level of systemic inflammation), there was a significant improvement in 6-month survival rate. This has now led to a couple of large registrational trials, the JANUS-1 and -2 studies, evaluating ruxolitinib plus capecitabine in the second-line setting for pancreatic cancer.

So, I touched upon briefly on some agents coming down the pike in terms of cytotoxic agents, stromal depleting agents, and molecularly targeted therapies. I am now going to transition here to my colleague, Dr. Saab, who is going to talk a little bit more about immunotherapies in pancreatic cancer and what we might expect in this area.

Immunotherapeutic Approaches in Pancreas Cancer

Dr. Tanios Bekaii-Saab: Great. Thank you Andrew. So, to follow up on the continuing development of new emerging therapies in pancreatic cancer and moving from molecular targeted therapies and looking at the role of immunotherapeutic approaches in pancreas cancer and their future in the treatment of pancreas cancer, vaccine approaches are being tested in various stages and phase III data will be available soon. Why is it important or why is it an important consideration to think about immune therapies in pancreatic cancer? Is there anything different about pancreatic cancer? Like most cancers, the concept of immune-targeted therapy in pancreatic cancer is attractive. Pancreas cancer is an interesting disease since it establishes a barrier to block and evade immune response, so it hides from the immune system, but that does not mean that pancreas cancer or pancreatic cancer cells are not immunogenic. They are actually very immunogenic. It is just that they protect themselves from the immune system through a variety of mechanisms. We will talk about that briefly, and so they are prime targets for immune therapies as long as we are able to find the right way to target these cells.

Similar to other cancers, pancreas cancer exhibits two types of immune responses. In pancreas cancer, you have the accumulation of tumor-associated macrophages (TAMs) which tend to inhibit T-cell responses through a variety of mechanisms. TAMs are available in the stroma at high levels and inhibit T-cell response and therefore are immunosuppressive as such. There are a variety of ways to target TAMs and suppress their activity and many of these strategies are under development, these include targeting indoleamine dioxygenase (IDO) inhibitors, singly or in combination with vaccines for example. There are also the colony-stimulating factor-1 receptor TAMs to help improve the response to chemotherapy, at least theoretically. Additionally, pancreas cancer is associated with an adaptive immune response. Pancreatic cancer cells express several cancer-associated antigens, and as such are very immunogenic and recognizable by T-cells. However, the main limiting factor is the density of the surrounding stroma and its immunosuppressive elements including the complete absence of NK cells, the overrepresentation of Tregs (T regulatory cells) and the presence of tumor-associated macrophages. Pancreas cancer is characterized by the presence of a desmoplastic reaction with stroma and fibroblastic components occupying more than half of the tumor tissue. Cross-talk between pancreatic cancer cells and stellate cells promotes further detriment, progression and immunosuppression. These limitations create a number of opportunities to target the immune system and somewhat take advantage of this immunosuppressive effect through the disruption of cancer cell-stroma interactions in pancreas cancer.

There are multiple ways to target the immunosuppressive environment through various strategies including checkpoint inhibitors such as anti-PD-1 and anti-CLA4 antibodies, cancer vaccines, combinations of vaccines and PD-1 inhibitors and FAK inhibitors. FAK inhibitors can potentially affect fibroblast and stellate cell proliferation to help disrupt the stromal influence on pancreas cancer cells and expose them to the immune system. A variety of these strategies are already being looked at in a number of early phase clinical trials. As mentioned above, cancer vaccines in pancreatic cancer are being developed very aggressively, given the early promising results from smaller studies. As you recall, there was a very interesting phase II randomized study that assessed the combination of GVAX and the listeria vaccine CRS-207 with low-dose cyclophosphamide that has led to further development of this strategy in follow-up trials. Another vaccine of great interest is Algenpantucel-L that is being looked at in a phase 3 study of chemotherapy or chemotherapy and radiation in surgically resected pancreatic cancer patients. The study is complete, and the analysis is underway, and we expect some results by the end of the year. This study was based on the promising results of a phase 2 study of roughly 70 patients.

Another immunotherapy area of great interest in pancreas cancer is the concept of oncolytic (cancer-killing) viral therapy such as T-VEC (talimogene laherparepvec) and Reolysin. These viruses specifically target and theoretically replicate in cancer cells to achieve cancer cell kill. We recently conducted a randomized study with Reolysin, a cold virus that has a presumed oncolytic effect on cancer cells, and specifically pancreatic cancer cells given the KRAS activation dependence of this virus. Despite some initial enthusiasm, the virus did not seem to add any benefit to chemotherapy in pancreas cancer, including in the KRAS selected group. Other viruses may hold more promise, including herpes or measles viruses.

How about the potential for PD-1 inhibitors in pancreas cancer and other T-cell directed strategies that aim at harnessing the power of these T-cells? As I previously mentioned, pancreatic cancer cells are immunogenic. The question is how to expose them to the immune system and the power of T-cells, given all the immunosuppressive elements in the surrounding stroma. Multiple strategies are currently under development to introduce these checkpoint inhibitors such as CART-cells anti-CTLA-4, PD-1, or combination of thereof following an “immunogenic blast” using complex chemotherapy or radiation therapeutic strategies. More aggressive cytotoxic approaches induce a higher likelihood of response and a higher likelihood of breaking down more cancer to help induce an “immunogenic blast.” This may or may not help harness the power of the cytotoxic T-cells. Additional strategies include introducing immune re-sensitizing strategies through the use of vaccines and oncolytic viruses to sensitize these cells to the effect of PD-1 inhibitors.

Finally, to conclude this discussion with immunotherapy, a quick word about Bruton’s tyrosine kinase inhibitor such as ibrutinib. Ibrutinib may have an antifibrotic effect in pancreas cancer as observed in preclinical studies. This means that theoretically they could break down the stroma, allowing for immune cells to find their way to the cancer cell. Ibrutinib and other BTK inhibitors have also been shown to enhance the activity of PD-L1 blockade. A number of studies are underway to evaluate the role of BTK inhibitors in combination with PD-1 inhibitors. The hope here is that this strategy will enhance targeting cancer cells through a 2-prong approach by allowing stromal depletion and increase cancer kill.

This in brief summarizes some of the advances and promises of immunotherapies in advanced and metastatic pancreatic cancers. So, I will open this back to Dr. Ko perhaps to start the discussion regarding key points on the state-of-the-art treatment of pancreas cancer today and the promise of future strategies.

Panel Discussion and Key Pearls for Community Oncologists

Dr. Andrew H. Ko: Sure. I want to keep this practical for the audience, how do you decide about your choice for first-line treatment of metastatic pancreatic cancer?

Dr. Tanios Bekaii-Saab: Certainly, as you summarized it, we have achieved important advances in the treatment of advanced pancreas cancer. Selecting first-line chemotherapy regimens is primarily based on availability of clinical trials, but absent of clinical trials, these will depend on the presence of a multitude of effective second-line options. We favor a sequential approach rather than a “kitchen sink” approach; meaning that FOLFIRINOX has fallen out of favor as a first-line regimen in our practice to be limited to early stage cancer (such as borderline resectable, and locally advanced disease) only. Patients in first-line receive a modified version of the doublet gemcitabine and nab-paclitaxel, with the hopes to apply salvage therapy when this line fails. Options include 5-FU and oxaliplatin (FOLFOX) or 5-FU and irinotecan (FOLFIRI –favored). We are anxiously awaiting MM-398 to be approved to be integrated into our standard pathway.

Dr. Andrew H. Ko: That is very interesting and I think highlights some institutional practices and differences. At our institution, outside the context of a clinical trial, I still do use FOLFIRINOX for patients who are very robust or younger and in particularly good shape; and then will reserve gemcitabine and nab paclitaxel as the second line. I think certainly nationally we are seeing trends with an upsurge in use of gemcitabine and nab-paclitaxel as first-line therapy. There has been a lot of question about whether these two regimens are ever going to be compared directly head-to-head. I think it is unlikely that there is going to be a driving force to lead a big study of that sort. So, we are left a little bit guessing or extrapolating or doing these sort of cross-study comparisons. But I think you bring up a good point about our ability now to sequence through multiple lines of treatment, that is sort of an issue that we are now facing as people live longer with this disease.

A question that often comes up is, “These regimens that we have for use for patients with metastatic disease, does it make sense to consider them in earlier stage settings, like the adjuvant setting?” So, you have a patient who has undergone successful surgery of pancreatic cancer, but we know the risk of relapse is very high, and maybe our instinct is that more has to be better. Since gemcitabine and nab-paclitaxel and FOLFIRINOX are better than gemcitabine in the metastatic setting, should we think about using them instead of gemcitabine as postoperative adjuvant treatment? I want to sound a note of caution there, mainly because I think we have learned time and time again that more is not necessarily better, and regimens that seem to have some impact in the metastatic setting when looked at in the adjuvant or earlier stage settings have not realized any improvement. There are ongoing studies right now to address this question: a big trial called the APACT trial is comparing gemcitabine and nab-paclitaxel with gemcitabine alone in the adjuvant setting, while in France, there is a gemcitabine versus FOLFIRINOX trial. So, hopefully, in the next few years we will really know whether these regimens are appropriate for use in the earlier stage setting.

For now, I tend to limit the use of this regimen to patients with more advanced or metastatic disease. The one exception is in patients who have borderline resectable pancreatic cancer, who you might be able to ultimately take to surgery but because their tumor is encroaching on or partially involving the superior mesenteric artery or superior mesenteric vein or portal vein, you want to try to cytoreduce them to increase the likelihood of an R0 resection. In this situation where we do not know what the best approach to use is, I have found that with a regimen such as FOLFIRINOX in this neoadjuvant or preoperative setting for borderline resectable disease, we can actually see very, very nice responses and get these patients successfully to surgery.

I think that time is fairly limited, so I want to conclude this session by just highlighting maybe the main pearls for the audience. Tanios, I will give you the chance to go up first. We have talked a lot about novel agents coming down the pike, including immunotherapies and other agents, and we certainly hope those will be realized in practice one day. But right now, if you have a key take-home message you wanted to share to this audience, what would it be?

Dr. Tanios Bekaii-Saab: I think the key pearl is really the changing landscape in one of the most desperate diseases, where we actually have gotten to the point where we can talk about options in first and second line, and possibly beyond. It is a great time to take care of pancreatic cancer patients, especially as we look at the landscape of what to come. I think this is a very exciting time. We are making a difference and we will see further improvements in the outcome of our patients.

Dr. Andrew H. Ko: Thank you. I agree with your sentiments. I would also say, though, in terms of where we still have to go, just the fact that there is a lot of talk about precision medicine and precision oncology these days, that this is one area where we are still a little bit behind the eight ball in terms of treatment of pancreatic cancer. I mentioned earlier about predictive biomarkers – or the lack thereof – in pancreatic cancer, so that we know if we should be using this regimen or this drug or not. Thankfully, some of the studies that we have highlighted before do incorporate biomarkers, whether it be C-reactive protein for ruxolitinib or hyaluronic acid expression for PEGPH20. As it stands today, we really are still lacking biomarkers that can guide us, so for studies going forward, I think we really should emphasize incorporation of companion biomarker testing so that we can be a little bit smarter in how we treat this disease. I think we will wrap things up there, and want to thank everyone for their attention.


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