Identification, Characterization and Recent Advances in Pancreatic Cancer
Clinical Dialogues™ in Pancreatic Cancer
Identification, Characterization and Recent Advances in Pancreatic Cancer
James Farrell, MD
Interventional Endoscopy and Pancreatic Diseases
Section of Digestive Diseases
Yale University School of Medicine
New Haven, Connecticut
|Anil K. Rustgi, MD
T. Grier Miller Professor of Medicine and Genetics
Chief, Division of Gastroenterology
University of Pennsylvania, School of Medicine
|Jill Lacy, MD|
Department of Medicine
Yale School of Medicine
New Haven, Connecticut
Farrell: My name is James Farrell. I am the director of the Center for Pancreatic Disease at Yale University. I would like to welcome you all to this edition of Clinical Dialogues in Pancreatic Cancer. This series has been developed to provide clinicians with the most up-to-date information. Pancreatic cancer is a small incidence malignancy. The majority of community oncology providers will see few patients with this disease annually. Hence, it is our goal to bring together leading clinicians and researchers from around the country to provide expert perspective in the latest developments across the spectrum of this disease and keeping the viewers of PartnersinPancreaticCancer.com informed and educated. Just 7 years from now, pancreatic cancer is projected to become this country’s second leading cancer killer surpassed only by lung cancer and claiming approximately 48,000 lives a year. Pancreatic cancer is currently the fourth most common cause of cancer mortality in the United States with a 5-year survival rate for most patients with resectable tumors ranging from 15-20%. However, most patients presenting with distant metastasis are not resectable and it has a 5-year survival rate of closer to 0%. So, the best chance for survival is early detection when tumors can be treated with surgical resection. However, pancreatic cancer typically develops with few symptoms. When symptoms do develop, a characteristic pattern of painless jaundice is often recognized, but commonly, atypical patterns of symptoms including weight loss, abdominal pain, and malaise lead to delays in diagnosis. Confounding the difficulties of challenging assessment in early diagnosis is a therapeutic armamentarium that until very recently has remained unchanged for 40 years. In today’s activity, we will be covering two spectrums of this disease. The first area we will cover is the identification and characterization of patients and their families who are at increased risk for pancreatic cancer and look at the latest research being undertaken in this area. We will then look at the recent advances in the treatment of metastatic pancreatic cancer and how these new advances in treatment are being used in the clinical practice setting. I am very fortunate today to be joined by Dr. Jill Lacy. Dr. Lacy is an associate professor of medicine in the section of medical oncology at Yale School of Medicine and with over 20 years of experience as a practicing medical oncologist, especially in the field of pancreatic cancer. We are also joined by Dr. Anil Rustgi from the University of Pennsylvania Perelman School of Medicine. Dr. Rustgi is chief for the Division of Gastroenterology and director of the Center for Molecular Studies in Digestive and Liver Diseases. Thank you both for participating in this activity, and Dr. Rustgi, I would like to begin with asking you just a few questions regarding your latest research and the latest research in general in this particular area. What is our current understanding of the environmental risk factors, for example, for pancreatic cancer?
Rustgi: Thanks Dr. Farrell, and to the organizers as well, nice to meet you Dr. Lacy. In the nearly 40,000 cases of pancreatic cancer that occur annually in United States, about 5-10% have some genetic predisposition, so-called familial or hereditary, we will get to that later. So, the vast majority of pancreatic cancer cases occur seemingly sporadically or randomly, but there is an age dependence. So, the mean age of pancreatic cancer is around 67. Things that influence the initiation and development and progression of pancreatic cancer from an environmental viewpoint may be linked to dietary and lifestyle factors. So, a variety of studies over time looking at populations of people as well as animal studies and cell culture studies do indicate that a high-fat diet is a risk factor, cigarette smoking as well as alcohol, and certainly, any of these factors may cooperate to enhance the risk toward pancreatic cancer. They may act either additively or in some individuals perhaps synergistically. What we lack is the ability to predict in whom pancreatic cancer may develop, even if there has been chronic exposure to these three factors, but clearly, these three factors are critical in the initiation and development of pancreatic cancer.
Farrell: Great. So, you have mentioned about familial risk of pancreatic cancer. Can you elaborate a little bit more about that? What belies or underlies the familial risks associated with pancreatic cancer?
Rustgi: Yes. To that end, then as I mentioned, about 5-10% of pancreatic cancer cases have some familial basis and it is estimated that it is highly penetrant. In other words, if someone has a genetic predisposition, then it is likely to manifest itself in pancreatic cancer and the penetrance is estimated to be 80%, and what is very important is to appreciate in a given patient with pancreatic cancer if he or she has a family history of pancreatic cancer in first-degree relatives, but even second- and third-degree relatives because that may unearth or unravel clues as to the possible genetic predisposition, and within that then, there are certain hereditary syndromes that are appreciated and recognized for which genetic testing is available in at-risk individuals in a family with pancreatic cancer. So, a subset of familial pancreatic cancer has defined a genetic basis for which genetic testing is available, and that is a heterogenous group of syndromes. However, as of now, the vast majority of familial pancreatic cancer, we do not know what the underlying genetic defect or gene mutation is, and it in turn, is likely a panoply of different genetic disorders, and for sure, current and future studies will continue to reveal new insights.
Farrell: In 2014, Dr. Rustgi, what advice do we give to patients and their families who consider themselves maybe at risk for a familial type of pancreatic cancer and what types of genetic testing would you recommend for someone who finds himself in that situation?
Rustgi: It is very important to ascertain family history by the patient and family members and for sure through the provider, physician, or otherwise, and armed with the information from the family history, then it is important for the patient and family to seek counseling through the disciplines of gastroenterology and GI oncology to see if the family history may fit a pattern of behavior that is consistent with a familial or hereditary basis of pancreatic cancer. The one that is appreciated the most and for which there has been published the most is a mutation in the gene BRCA2. BRCA1 and BRCA2 are genes that are important in normal DNA repair and maintaining the integrity of our genome, and they are most famous in being recognized as being mutated and responsible for probably about 30% of hereditary breast and ovarian cancer syndrome, but a number of studies have shown that individuals with BRCA2 mutation are at increased risk for other cancers including pancreatic cancer. There is a slight increased risk for pancreatic cancer in BRCA1 mutation but not to the same extent as BRCA2. So, if one has a family history in which there is a concordance of breast cancer, ovarian cancer, or pancreatic cancer, and especially in certain ethnic backgrounds, in particular of Ashkenazi Jewish descent, that should trigger suspicion for the possibility of BRCA2 mutation. That is one. The second one is rare even in this context and that is what is called familial atypical mole and multiple melanoma or FAMM for short syndrome in which there is a segregation or cosegregation of numerous atypical moles throughout the body, multiple melanomas including in a given family member, and it is associated with pancreatic cancer. Individuals are typically in their 20s and 30s. They can be older and that is due to a mutation in the gene called p16 which is very important as a regulator of cell cycle of progression. The third one is called Peutz-Jeghers syndrome. This is seen in adolescents where they are inclined to have large polyps in the small intestine and/or colon. It is due to a mutation in a gene called STK11. It is a negative regulator of cell growth, and as these patients live longer, they are at increased risk for a variety of cancers including pancreatic cancer. The fourth one that is a little bit controversial is an inherited form of colon cancer called Lynch syndrome and one study in particular suggest an increased risk of pancreatic cancer. And then the final one that is known or been described is very early onset condition before the age of 30 in which patients have recurrent pancreatitis or inflammation of the pancreas and that progresses to chronic pancreatitis and fibrosis or scarring of the pancreas tissue, which then triggers a substantial risk for pancreatic cancer over a lifetime. In fact, if you look in the non-genetic or sporadic pancreatic cancer, chronic pancreatitis is the biggest risk factor for pancreatic cancer. So, there seems to be an overlap here, and the gene for hereditary pancreatitis is known. It is called cationic trypsinogen abbreviated as PRSS1, but then, there is a whole host of other familial forms of pancreatic cancer in which we do not know what the responsible gene is or genes are, and hopefully, through various technologies, that information will avail itself. So, bottom line, family history is key, seek advice through a gastroenterologist as well as GI oncologist, with the genetic counselors, that is absolutely pivotal and then see if that family history fits a certain pattern that may be eligible for a genetic testing and then that can influence clinical screening as well.
Farrell: Taking a step back from the issue of familial-related pancreatic cancer, when looking at patients who may be concerned that they have it , are presenting with some of the symptoms and we are used to ordering CAT scans and MRI scans as well as other invasive types of imaging studies such as ERCP or endoscopic ultrasound. What is new in terms of the diagnosis of pancreatic cancer, be it at an early stage or even at a more advanced stage?
Rustgi: Well, many centers like ours do enroll patients at risk for pancreatic cancer based upon what we just discussed and some type of screening strategy. There is no absolute consensus in this country let alone across the world on what imaging modality should be used and the frequency with which they should be used, as well as what agent to start. That being said, from a noninvasive viewpoint, most centers will use magnetic resonance imaging or MRI coupled with dye injection to outline the pancreatic ductal tree and the biliary tree, MRCP for short. This is either complemented or substituted by endoscopic ultrasound, and typically, people will recommend doing this on an annual basis. So, that is from known clinical modalities, and either one can be done as an outpatient setting, and what one is looking for is the possibility of some abnormality in the pancreatic tissue structure which might then require biopsy or fine-needle aspiration under endoscopic ultrasound to evaluate cells under the microscope by the pathologist and do some secondary analyses. That being said, in terms of something that is available as a blood test, there really is not, and it is a gap in the field, unfortunately. There is a biomarker called CA19-9 which is helpful if someone already has pancreatic cancer or might be helpful if someone has chronic pancreatitis and is on the launching pad so to speak to pancreatic cancer, but it does suffer from relatively poor sensitivity and specificity. There is intense research to use a variety of platforms to try to detect circulating cells that can be linked back to early precancerous pancreatic lesions or early stage pancreatic cancers, and the idea is that these precancerous lesions or the early stage cancerous lesions are shedding cells into the circulation or the blood, and then they can be captured through various platforms, and one can quantitate the number of cells and one can interrogate these cells to see what may be abnormal in terms of gene mutations. So, it is a very exciting field and one is hopeful that this may then be extended to patients at risk for pancreatic cancer and thus early detection and risk stratification, as well as patients who are being treated for pancreatic cancer. One might imagine the number of circulating tumor cells is up, one intervenes with therapy or combinatorial therapeutics, and then the number of circulating tumor cells go down. I think there is much hope through the technology that circulating tumor cells might manifest itself as a diagnostic biomarker in the future for pancreatic cancer.
Farrell: Finally, Dr. Rustgi, you are a leader in the area of pancreatic cancer research. What are your thoughts about evolving areas in pancreatic cancer research that hold promise both from the early diagnostic perspective but also from the treatment perspective knowing that unfortunately in 2014 still a vast majority of patients present at an advanced stage? What is your vision for the future in terms of new developments in areas of pancreatic cancer research?
Rustgi: I think we still have to be cognizant of the fact that as of now, the only chance for cure remains surgery, and even then, it is not inconceivable that patients have micrometastatic disease not detectable by conventional imaging strategies, and therefore, is that impacting adversely on the 5-year survival that you outlined in the beginning. Early detection in patients at risk and early detection in patients who are symptomatic still remains pivotal in trying to drive patients to surgery when feasible, to enhance chances or a meaningful chance for a prolonged survival. The other end of the spectrum would be therapy and I will obviously defer to Dr. Lacy and her expertise, in exploiting knowledge of the microenvironment within which the pancreatic cells or tumor cells exist. So, one can target specific pathways or molecules within the tumor cell, but the tumor cell is coexisting and coopting neighboring cells such as supporting cells like fibroblasts which secrete growth factors and cytokines might there be something targeted there. In particular now there is a great deal of emphasis on immunotherapy and can one either enhance the body’s ability for immune surveillance or suppress cells that are immunosuppressive and interfering with the body’s ability for proper immune surveillance. And can we then extend this to a combination of therapeutics where we are targeting tumor cells, immune cells, and other types of cells to extend what we have already in terms of conventional adjuvant therapy. I think that is also an exciting area as well looking now and into the future.
Farrell: Thank you very much Dr. Rustgi. I would like now to turn our attention to Dr. Lacy. Would you answer a few questions for our listeners on the topic of recent advances in the treatment of metastatic pancreatic cancer? Firstly, can you tell us about any recent advances in the treatment of pancreatic cancer that have changed practice?
Lacy: Sure, and I would like to start by thanking you Dr. Farrell and the organizers for inviting me to participate in this discussion today. So, there have been two very significant advances in the treatment of metastatic pancreas cancer in the last 3 to 4 years, and these have been practice changing -- first the emergence of the FOLFIRINOX regimen and then more recently the gemcitabine and nab-paclitaxel regimen. Most medical oncologists are familiar with these regimens, but I thought it would be useful to just summarize the key findings. Now, in terms of the historical perspective, since 1996, gemcitabine as a single agent has been the cornerstone for the treatment of metastatic pancreas cancer, and although it is a drug that is well tolerated and actually provided clinical benefit response relative to 5-FU in the original trial back in the late 1990s that led to its approval, its activity, at best was modest with median survivals always hovering in the range of 6 to 7 months and response rates less than 10%. So, in 2010, we heard about a significant breakthrough. This was the presentation of the PRODIGE/ACCORD trial at ASCO. This was a randomized Phase III trial conducted in France comparing standard gemcitabine in the standard dose and schedule with the four-drug regimen FOLFIRINOX. The key eligibility in this trial included metastatic and measurable untreated pancreas cancer. There was an age cutoff of less than 76, and patients had to have a good performance status of ECOG 01 and a near normal bilirubin. Over 340 patients were enrolled to this study. In terms of efficacy, the results were impressive, and the study did meet its primary endpoint of survival benefit with an unprecedented median survival of 11.1 months for FOLFIRINOX compared to the usual 6.8 months for gemcitabine, and in addition, FOLFIRINOX was superior in terms of other efficacy endpoints -- progression-free survival and response. There was an impressive response rate of over 30% compared with less than 10% for gemcitabine. The toxicities of FOLFIRINOX were expected and not insignificant. In terms of grade 3 and 4 toxicity, nearly half the patients experienced neutropenia, 24% fatigue, 13% diarrhea, and 9% sensory peripheral neuropathy. But despite the toxicities, the quality of life in the FOLFIRINOX arm was superior to the gemcitabine arm. The investigators included a quality of life analysis, and FOLFIRINOX significantly delayed the time to degradation of quality of life relative to gemcitabine. So, in context, this really was the first major achievement in the treatment of metastatic pancreas cancer since 1996, with an unprecedented magnitude of benefit. And over the next few years FOLFIRINOX emerged as a new standard of care in good performance, patients, with the cautionary note being that FOLFIRNOX was studied in selected patients under the age of 76 with the good performance status and near normal bilirubin. Then fast forward to 2013 and we heard about yet another significant advance again in the treatment of metastatic pancreas cancer. This was the MPACT study, MPACT was a very large randomized global phase III trial comparing the standard of care, gemcitabine monotherapy, in a standard dosing schedule, against the same dose and schedule of gemcitabine with the addition of nab-paclitaxel at 125 mg/m2 weekly. The eligibility criteria were similar to the PRODIGE trial except there was no age cutoff (and 10% of the patients were over the age of 75) and they allowed patients with performance status of KPS 70 to enroll in the study. Again, in terms of efficacy, this study did meet its primary endpoint of improvement in survival with the median survival of 8.5 months with gemcitabine/nab-paclitaxel versus 6.7 months with gemcitabine alone, with a nice hazard ratio of 0.72. In addition there was an improvement in progression-free survival, and a response rate of 23% with the combination versus 7% with gemcitabine monotherapy. The toxicities of the combination were as expected -- primarily myelosuppression with about a 40% incidence of grade 3 or 4 neutropenia and 13% thrombopenia, but also grade 3 or 4 fatigue in 17% of patients and sensory peripheral neuropathy in the same percentage. So, the impact of MPACT was that this was the first study to demonstrate that the addition of any drug to gemcitabine yielded a meaningful increase in survival. This regimen has rapidly moved into both academic centers and community practices as another excellent option for the treatment of metastatic pancreatic cancer. Now, the investigators did not conduct a quality of life analysis in this study, so we do not have that information. So, in summary, after years of many negative studies with gemcitabine‑based doublets, we now have FOLFIRINOX, and we have gemcitabine with nab-paclitaxel for the first-line treatment of metastatic pancreatic cancer. These studies, I think, truly do represent major treatment advances in this disease and have changed our practice with respect to the initial treatment of metastatic pancreas cancer.
Farrell: You have described two regimens for the treatment of metastatic pancreatic cancer, the FOLFIRINOX and the gemcitabine with nab-paclitaxel. How do you choose which regimen to use when initiating treatment in the patient with metastatic pancreatic cancer?
Lacy: That is a tough question. Both regimens, as we know from these randomized trials, are superior to gemcitabine monotherapy, but we have been unable to identify any predictive biomarkers to date that guide us in terms of which regimen to choose for an individual patient. A number of biomarkers have been explored, including SPARC, hENT1, ERCC, and TS, but nothing has been validated thus far. We do not think a randomized trial will ever be done comparing these regimens, so what we are left with is cross-trial comparison, which is risky, but can be informative. This type of analysis does suggest that perhaps FOLFIRINOX may be somewhat more active than gemcitabine/nab-paclitaxel in metastatic pancreas cancer. If you look at these two randomized trials, the demographics and disease characteristics are very similar, although 10% of the patients in the MPACT study were over the age of 75, and a higher percentage of patients in the PRODIGE FOLFIRINOX trial had ECOG performance status of 0. But if you look at the control arms in these two studies - the patients who received gemcitabine alone - the results were virtually identical in terms of efficacy as well as toxicity. So that suggests that the patient populations in these two studies were quite similar. Then when you look at the experimental arms in the two studies, the median survival, progression-free survival, and response rate were all better with FOLFIRINOX -- 32% versus 23% response rate and survival of 11.1 versus 8.5 months. Since there was no quality of life analysis in the MPACT trial, we cannot comment on that. Importantly, in terms of toxicity, FOLFIRINOX appears to be more toxic than gemcitabine/nab-paclitaxel, with more grade 3/4 neutropenia, a higher rate of growth factor usage, more grade 3/4 diarrhea not surprisingly (6% versus 13%), and a little more fatigue, although we saw more neuropathy with the gemcitabine/nab-paclitaxel regimen. So to summarize, in the absence of predictive biomarkers, treatment really does need to be individualized. So when evaluating a patient with newly diagnosed metastatic pancreatic cancer, we assess age, performance status, comorbidities, and laboratory parameters. FOLFIRINOX, I think, remains a standard of care for fit patients with a good performance status under the age of 76, but for elderly patients with borderline performance status or comorbidities, I think one would tend to go with gemcitabine and nab-paclitaxel. But I would emphasize that the treatment decision should be individualized in the absence of predictive biomarkers or participation in the clinical trial.
Farrell: I would like to change gear just a little bit. We heard from Dr. Rustgi earlier on about the advancements and understanding of the pathogenesis and development of both early stage and late stage pancreatic cancer. With all this new information, I am beginning to wonder is there are any role for biologic or targeted agents in the treatment of pancreatic cancer?
Lacy: Sure. So, there have been many phase III clinical trials that have been conducted and completed with gemcitabine plus or minus a targeted or a biologic agent, and I would say to date those studies have largely been disappointing. However, I would add that few of these completed studies incorporated predictive biomarkers and enrolled unselected patients. At present, there is only one FDA-approved targeted drug for pancreas cancer, and that is erlotinib. The approval of erlotinib was based on the Canadian PA3 trial, published in 2007. The randomization in this phase III study was gemcitabine plus placebo versus gemcitabine plus erlotinib. Notably, this study was conducted before we knew about the predictive value of KRAS analysis, so there was no preplanned KRAS analysis. Although the study was statistically positive for survival benefit with addition of erlotinib to gemcitabine, the improvement in survival was only about 10 days. At 1 year, there was a higher percentage of patients alive 23% versus 17%. So the efficacy of erlotinib in combination with gemcitabine is modest, and that is not surprising. We know that more than 90% of pancreas cancers harbor KRAS mutations, and we know now that this confers resistance to erlotinib. The investigators did try to retrospectively look at KRAS status and outcome. They were unable to show that the KRAS status or EGFR copy number was predictive, the caveat being that the number of KRAS wild-type patients was very small, so I do not think we can draw definitive conclusions. Subsequent to this study, there was a randomized trial targeting EGFR with cetuximab with gemcitabine and that was also negative. There were a number of trials targeting the VEGF receptor pathway using gemcitabine plus or minus the targeted drug - bevacizumab, axitinib, aflibercept, or sorafenib - and those were all negative studies. Then more recently studies of gemcitabine with or without Hedgehog inhibitors were disappointing as well. Right now, erlotinib is the only FDA-approved targeted agent for pancreas cancer; it is not a very effective drug in most patients, and thus we are uncertain as to how and when to use erlotinib in the absence of a predictive biomarker.
Farrell: You had mentioned earlier on about how FOLFIRINOX and the gemcitabine and nab-paclitaxel drugs have been practice-changing developments in the treatment of metastatic pancreatic cancer, but yet, pancreatic cancer remains a lethal disease, and so, are there any investigational agents or ongoing clinical trials that show promise and may potentially impact practice in the near future?
Lacy: Yes, fortunately, I think we are making real progress. There are number of novel approaches that are being pursued. Dr. Rustgi alluded to some of these already, and these promising novel approaches are trying to exploit what we know about the unique biology of pancreas cancer including the role of the stroma. I have already touched upon studies with agents targeting signal transduction pathway intermediates, and as I mentioned, thus far those studies have been disappointing. But that work continues and we know that we need to do genomic analysis and biomarker-driven studies if we are going to move forward with those types of targeted agents.
I would like to focus now on some other novel strategies, and all of these are in clinical trials, some completed. These strategies would include (1) immunotherapeutics, (2) targeting inflammation, (3) targeting the stroma, and then (4) some new interesting chemotherapeutic agents. I will take these approaches one at a time - starting with immunotherapeutics. There has been a longstanding interest, going back many years, in using vaccine strategies in an effort to recruit the immune system to attack pancreas cancer. I think after some false starts we may finally be getting close. This year at ASCO, we heard about an interesting study from Johns Hopkins. This is a study where the investigators compared a single vaccine against a combination of two vaccines. This was a randomized phase II trial in previously treated patients, all with metastatic pancreas cancer, and the randomization was to a single vaccine, GVAX, versus GVAX plus a second vaccine, CRS-207. GVAX is a lethally irradiated allogeneic pancreatic cancer cell vaccine that has been modified to express GM-CSF and is generally given with Cytoxan to inhibit the immunosuppressive regulatory T-cells. CRS-207 is a live-attenuated listeria engineered to express mesophil and which is a tumor-associated antigen, and it is an interesting vaccine in that, it appears to boost both the innate and the adaptive immune responses. The results from this randomized phase II study were positive for survival for the combination of GVAX plus CRS-2007 in all patients, and in those patients who had two prior lines of therapy, a tough population. The median survival with the vaccine combination was 5.7 months versus 3.9 months for GVAX alone. Although the survival benefit was less than two months, the hazard ratio was impressive, and I think certainly these data are intriguing and hypothesis generating, and further studies are planned. So, going forward, they are going to look at the combination of GVAX plus CRS-207, and compare that to standard salvage chemotherapy as well as to the listeria CRS-207 vaccine alone. How about the immune checkpoint inhibitors? We have seen very impressive results with this class of agents in melanoma, lung cancer, and bladder cancer. So, these studies are in progress in pancreas cancer. We do not yet, I think, have any meaningful early returns to know whether this class of drugs will be of benefit in this disease, and so we are eagerly awaiting some of those results. We may well need to combine a vaccine strategy with these immune checkpoint inhibitors in order to evoke the kind of immune response that we are going to need to see efficacy in this disease.
Another interesting area of investigation is targeting the inflammatory response that is associated with pancreas cancer. The rationale for this strategy arises from a few observations. First of all, in preclinical models of pancreas cancer, inflammatory cytokine signaling does appear to be important not only in disease initiation but also in progression. We also know that the majority of the patients with advanced pancreas cancer have both laboratory and clinical evidence of systemic inflammation -- weight loss, decreased muscle mass, poor performance status, and it has been observed that the patients who have an elevated C-reactive protein, a marker of systemic inflammation, have a worse prognosis. Given this rationale for disrupting systemic inflammation, we heard about an interesting randomized double-blind Phase II study this year at ASCO, the RECAP study, looking at ruxolitinib versus placebo in combination with capecitabine in both arms in patients with metastatic pancreas cancer. Ruxolitinib is a JAK1 and JAK2 inhibitor that blocks the stat transcription factor pathway and inflammatory cytokines. It is an approved drug for myelofibrosis where it has been shown to reduce levels of inflammatory cytokines and improve symptoms from inflammation. The RECAP study was a one-to-one randomization to ruxolitinib plus capecitabine versus placebo plus capecitabine; in terms of efficacy, the primary endpoint was overall survival, but they did have a planned predefined subgroup analysis including C-reactive protein levels. In the entire study population, it was a negative study. But when they looked at the patient population with elevated C-reactive protein levels, there was a strong efficacy signal. The hazard ratio was robust at 0.5, and the survival at 6 months was 42% with ruxolitinib versus 11% for placebo. So, this is exciting as well, and shows evidence of survival benefit in those patients with evidence of systemic inflammation. Going forward a confirmatory randomized phase III trial looking at ruxolitinib versus placebo in combination with capecitabine in patients with prior therapy is getting underway.
We have heard about targeting the stroma from Dr. Rustgi, and there is great interest in attacking the stroma as a therapeutic strategy in this disease. I will mention just one biologic agent that is under investigation as a stroma-targeting agent -- that is PEGylated Recombinant Human Hyaluronidase or PEGPH20. In preclinical pancreas cancer models, this biologic has been shown to degrade hyaluronic acid, which is a major component of the stroma, thereby reducing tumor interstitial fluid pressure, altering the vasculature, allowing better drug delivery to the tumor, and enhancing cytotoxic efficacy. This biologic has already been evaluated in a phase I study in combination with gemcitabine, and there were no safety signals, so investigators are now moving forward with randomized phase II trials, one with gemcitabine and nab-paclitaxel plus or minus PEGPH20, and the other with FOLFIRINOX plus or minus PEGPH20. I think these are interesting studies, and certainly, we are going to stay tuned and see what we learn from this approach.
Then, finally just to end with traditional chemotherapeutic drugs, we heard from Dr. Rustgi that a small percentage of patients of pancreas cancer have germ-line mutations in BRCA2, and we know that the PARP inhibitors as a class of drugs are promising agents in BRCA2-deficient tumors. We have preclinical data again in BRCA-deficient pancreatic cancer cell lines that supports this observation, and so, there are a number of trials now for patients with BRCA2-deficient pancreas cancer looking at PARP inhibitors, both veliparib and olaparib. I think this may certainly be an interesting pathway forward for that small subset of patients that have BRCA2-deficient pancreas cancer. Then we learned about some very promising results earlier this year with an old drug in a new formulation. This agent, MM-398, is irinotecan encapsulated in nanoliposomes, and we heard about the results of the NAPOLI-1 trial. This was a global randomized phase III trial comparing MM-398 with 5-FU/leucovorin versus MM-398 monotherapy versus the control arm of 5-FU/leucovorin in gemcitabine-refractory metastatic pancreas cancer, a very tough patient population. This was a positive study with the combination of MM-398 with 5-FU leucovorin. There was just survival benefit of 1.9 months, from 4.2 to 6.1 months, a significant benefit. I think this is encouraging, and this drug will likely be moving forward, and we will want to learn how best to use it in the treatment of the pancreas cancer.
So, we have made significant advances in our understanding of the biology of pancreas cancer, and many novel drugs and biologics are now in the pipeline as a result of those advances. I am hopeful that we will see a number of promising novel treatments for pancreas cancer move into the clinic to benefit patients over the next few years.
Farrell: We have heard about practice-changing events and then promising novel therapies for metastatic pancreatic cancer. To wrap things up, I am curious about whether there are any recent advances or important ongoing clinical trial for patients who present and have resectable disease without any evidence of metastatic disease, who we normally think as predominantly surgically managed patients. Are there any recent advances or ongoing clinical trials for that subgroup of patients?
Lacy: Yes, absolutely. As you know, the 5-year survival for patients who have resectable pancreas cancer is only about 20%. At present, the current standard of care is surgery followed by 6 months of adjuvant chemotherapy with either gemcitabine or 5-FU leucovorin -- they appeared to be equivalent, so we need better therapies to increase the cure rate of those patients who are able to undergo surgery. The big question is whether these more active regimens FOLFIRINOX or gemcitabine with nab-paclitaxel that we are using in the metastatic setting will increase the cure rate if they are used in the adjuvant setting - either neoadjuvantly or adjuvantly. Right now, there are two very important trials ongoing looking at this question. One is PRODIGE/ACCORD trial. This is an adjuvant trial in patients with resective pancreas cancer. The randomization is the standard gemcitabine monotherapy compared to FOLFIRINOX, and that study is underway. In addition, the APACT study is up and running, and that is a comparison of gemcitabine versus gemcitabine and nab-paclitaxel in patients who have undergone resection. These are two critically important studies. It will be a few years before we have the answer, but we are certainly very hopeful that these more active regimens in the metastatic setting will impact on patients who have had surgery and increased the cure rate from what it is at present which is about 20%.
Farrell: I would like to thank Dr. Lacy of Yale University and Dr. Rustgi from the University of Pennsylvania for both a wonderful and informative discussion.
Rustgi: Can I make one additional point, Dr. Farrell?
Rustgi: And that is Dr. Lacy mentioned the disappointing outcomes at least in the phase II trial with hedgehog inhibition in humans, although in mouse studies, it was shown to be extremely helpful and promote enhanced delivery of gemcitabine in the recent paper which was published, which might help explain why there was initial poor outcome in humans, and that is that in mice when sonic hedgehog, the ligand for the hedgehog pathway is deleted. The sonic hedgehog-deficient tumors have reduced or diminished stroma. Surprisingly and ironically, these tumors were much more aggressive and were much more undifferentiated and with increased vascularity and so, the notion then would be perhaps in a subset of pancreatic cancers that are undifferentiated which to my knowledge is about 10% of all pancreatic ductal adenocarcinomas. These individuals might then be amenable if one carries this finding out the combination of hedgehog inhibitor with angiogenesis inhibitor, so for instance to the VEGF receptor blocking antibody. So, that is something that might emerge as well from a conceptual framework in the near future.
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