Tailoring Treatment Strategies in Pancreatic Cancer: Prognostic Factors that Matter

e-news_2016-05-16_oreilly_content

Written by:

Eileen M. O’Reilly, MD
Associate Director for Clinical Research
David M. Rubenstein Center for Pancreas Cancer
Memorial Sloan Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College
New York, New York

Pancreatic cancer is the deadliest of all major cancers in the United States with a five-year survival rate of just 8%. In 2016, an estimated 53,070 Americans will be diagnosed with the disease and 41,780 will die from it.1 Additionally, the number of deaths from pancreatic cancer will surpass those from breast cancer, making it the third leading cause of cancer-related death in the United States. Pancreatic cancer is projected to surpass colorectal cancer to become the second leading cause of cancer-related death around 2020.2 Treatment advances in this disease have been modest with only incremental improvements in survival, and options for patients are limited. A growing area of research that has the potential to significantly change the paradigm for this disease by improving patient selection for treatment is the use of molecular biomarkers to tailor personalized treatment strategies.


Eileen M. O’Reilly, MD, Associate Director for Clinical Research at the David M. Rubenstein Center for Pancreatic Cancer Research and Medical Oncologist was interviewed for her perspective on this topic.

Anitra Engebretson (AE): Please describe the current landscape of the use of biomarkers to direct treatment of pancreatic cancer.

Dr. O’Reilly: Considering the complex tier of biomarkers for pancreas cancer, the field is primarily investigational as opposed to being a standard of care. When we think about biomarkers, we think about characteristics of the disease itself. In a particular person with pancreatic cancer, we consider genomics, blood-based assays and tissue assays that may direct therapy.

The majority of state-of the-art treatments for pancreas cancer are unselected with regard to biomarker designation. The closest thing we might have to a biomarker that is becoming a standard is the identification of germline BRCA mutations and possibly somatic BRCA mutations as indicators for platinum-based therapies and, experimentally, PARP-inhibitors. There are many other potential biomarkers that are being investigated but are not considered standard.

Several studies have demonstrated that BRCA1/2 and other DNA-repair gene mutations occur in pancreatic cancer3,4,5 and may be susceptible to DNA-damaging agents such as platinum therapies and PARP-inhibitors.3 The Pancreatic Cancer Action Network’s Know Your Tumor® molecular profiling program recently reported that 17% (24 of 144) of patients who underwent next-generation genomic sequencing had a mutation in at least one DNA-repair gene.4

AE: Are there other known actionable mutations or biomarkers in pancreatic cancer with linked targeted treatments that are currently available?

Dr. O’Reilly: Another biomarker that has been investigated is C-reactive protein (CRP), which is measured by a blood test. Data from a Phase II study was presented at the American Society of Clinical Oncology Annual Meeting in 2014 and published in the Journal of Clinical Oncology in 20156 looking at CRP-directed therapy using ruxolitinib combined with capecitabine. Ruxolitinib is thought to target systemic inflammation, and CRP is a marker of systemic inflammation in pancreas cancer. Two Phase III trials have been undertaken. One completed recruitment and the other has been closed due to negative interim results. So, in this context and with that drug, the hypothesis may not hold up in the setting of pancreas cancer.

A Phase II study of ruxolitinib in combination with capecitabine versus capecitabine with placebo in patients with metastatic pancreatic cancer previously treated with a gemcitabine regimen showed statistically significant improved overall survival in a prespecified subgroup of patients with high CRP when treated with the investigational combination versus capecitabine alone.6 These findings were followed by the development of the JANUS-17 and JANUS-28 Phase III studies investigating this novel drug combination of ruxolitinib and capecitabine in patients previously treated with gemcitabine with high CRP levels. An interim analysis of the JANUS-1 study did not demonstrate significant enough levels of efficacy in the ruxolitinib and capecitabine arm to continue the study.9

Dr. O’Reilly continued: An example that is going to Phase III testing right now is hyaluronan (HA) as a biomarker for identification of patients that may benefit from the use of a pegylated enzyme, PEGPH20, combined with gemcitabine and nab-paclitaxel. In a randomized Phase II trial looking at the combination of gemcitabine, nab-paclitaxel, and PEGPH20 compared to gemcitabine and nab-paclitaxel, in the biomarker selected group of patients with elevated hyaluronan levels in the tumor stroma, those patients appear to do better.10 The randomized Phase III study will restrict entry to the biomarker high population and evaluate whether the addition of PEGPH20 to standard therapy is meaningful in pancreas cancer.11

An interim analysis of the Phase II study10 of the combination of PEGylated Recombinant Human Hyaluronidase (PEGPH20) with gemcitabine and nab-paclitaxel versus gemcitabine and nab-paclitaxel alone, in patients with untreated stage IV pancreatic cancer, showed improved overall response rate and progression-free survival in patients with high-HA tumors treated with the PEGPH20 combination versus those patients with high-HA tumors treated with standard treatment. These findings were followed by the development of the currently recruiting Phase III11 trial testing the combination of PEGPH20 with gemcitabine and nab-paclitaxel versus gemcitabine and nab-paclitaxel alone in patients with high-HA stage IV previously untreated pancreatic cancer.

Several studies4,5 have observed additional actionable biomarkers in patients with pancreatic cancer. According to the recently reported results of the Pancreatic Cancer Action Network’s Know Your Tumor® program, of 144 patients, 44% had molecular changes linked to a potential treatment option.4

AE: A recent paper published in Nature presented data from the Australian Pancreatic Cancer Genome Initiative12; the paper included data from some genomic analyses as well as four newly defined subtypes of pancreatic cancer. Why is this research important? What impact will it have on treatment of the disease?

Dr. O’Reilly: I think this paper is very important. It brings a new way of thinking about this disease; that pancreas cancer is as heterogeneous as any other malignancy. That notion has not been always fully appreciated, but certainly recognized in day-to-day clinical practice as there is a huge variation in outcomes, even in a disease that overall has a challenging prognosis. Trying to put some structure on that is in essence the theme of that paper in terms of identifying the four subgroups of patients with pancreas cancer.

One area that intrigues people in particular is the immunogenic subgroup, suggesting that there may be a population of patients that could be identified that may be more likely to benefit from immune therapies.

The paper reported some themes; key genes that are mutated in this disease, the pathways in which those genes are involved, and how that all interplays. It is a framework, a reference in terms of how we use this information fully.

I think we have a while to go but just beginning to think about selecting groups of patients and that we might be able to refine treatment choices for them based on where they fit – I think it is very good. It is encouraging to see this happening in this disease.

Bailey, et al., reported on the genomic analyses of 456 pancreatic cancer specimens.12 Mutations of genes tended to aggregate into several molecular pathways. Additionally, RNA-transcription analysis revealed four different subtypes of pancreatic cancer with distinct disease characteristics and survival termed squamous, pancreatic progenitor, immunogenic and aberrantly differentiated endocrine exocrine.

AE: What should current patients and treating physicians be considering with regard to accessing molecular testing and biomarker-driven treatment? Who should be considering this type of testing, and how might they access it?

Dr. O’Reilly: These are very interesting and very important questions, and there are two contexts to think about this – research and clinical practice. In the broader landscape of research, we want to learn as much as we can about the disease in every way, shape, and form. With that perspective in mind, I think we strongly encourage genomic sequencing, both somatic and germline, and consideration of a comprehensive serologic-based biomarker panel. What this means in terms of clinical practice and how we use this is a challenge.

This term “actionability” is discussed a lot. It is one thing to see in a report that a certain genomic change is present and that we have a drug available in another context that may be appropriate for that mutation or that pathway. It is another thing to know that in a setting of pancreas cancer after an individual has two lines of treatment, for example, that that genetic change and that drug are meaningful and will have an impact on the patient.

There is a little bit of dichotomy in terms of where we want to be and where we are at the moment, but I think from the research perspective, as much as we can learn we enthusiastically embrace. I think we have to be a little bit more cautious in saying that this is standard of care and that we are making decisions based on these findings for now.

Certainly, the idea of next-generation sequencing in trying to identify patients that are candidates for trials, I think that is a very important consideration. It requires a lot of thought as we know this disease has many challenges and that things can change fairly quickly. Often we are getting this information at the later stages of a patient’s illness and the opportunity to capitalize on it, if there is a way to capitalize on it, is not necessarily straightforward.

A unique resource for patients and physicians who are interested in multi-omic analysis of pancreatic tumors is the Pancreatic Cancer Action Network’s Know Your Tumor Initiative® (www.pancan.org/knowyourtumor/).4,13 The goal of this service is to make molecular profiling available to patients in diverse clinical settings across the US. A recent presentation of data shows that this type of testing is feasible4,13 and can produce actionable findings in up to 44% of patients.4

AE: Is there anything else that you would like to share on this topic?

Dr. O’Reilly: I think this is an extremely worthy area of pursuit; we just have to be a little cautious in our enthusiasm. What we hope for in the next five years is that we will, at least for a subset of patients, be able to align a treatment algorithm with some biomarker – be it via blood analysis, tissue analysis, or patient or disease characteristics – that we will make some headway into this overall theme of a more personalized approach in addressing this disease.



References

  1. Cancer Facts & Figures (2016). Accessed April 2016. http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf
  2. Pancreatic Cancer Action Network Pancreatic Cancer Facts 2016. Accessed April 2016. https://www.pancan.org/wp-content/uploads/2016/02/2016-GAA-PC-Facts.pdf
  3. Sahin IH, Lowery MA, Stadler ZK, et al. Genomic instability in pancreatic adenocarcinoma: a new step towards precision medicine and novel therapeutic approaches. Expert Rev Gastroenterol Hepatol. 2016:1-13.
  4. Rahib L, Engebretson A, Pishvaian MJ, et al. Molecular profiling of pancreatic cancer patients from a wide geographical distribution across the US. Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; 2016. Abstract nr 93.
  5. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518(7540):495-501.
  6. Hurwitz H, Uppal N, Wagner S, et al. Randomized, Double-Blind, Phase II Study of Ruxolitinib or Placebo in Combination With Capecitabine in Patients With Metastatic Pancreatic Cancer for Whom Therapy With Gemcitabine Has Failed. J Clin Oncol. 2015;33(34):4039-4047.
  7. ClinicalTrials.gov. Identifier: NCT02117479. Study of Ruxolitinib in Pancreatic Cancer Patients (Janus 1).Accessed April 2016. https://clinicaltrials.gov/ct2/show/NCT02117479
  8. ClinicalTrials.gov. Identifier: NCT02119663. A Study of Ruxolitinib in Pancreatic Cancer Patients. Accessed April 2016. https://clinicaltrials.gov/ct2/show/NCT02119663?term=janus+2&rank=1
  9. Incyte Announces Decision to Discontinue JANUS Studies of Ruxolitinib plus Capecitabine in Patients with Advanced or Metastatic Pancreatic Cancer. Business Wire. 11 February 2016. Web. Accessed April 2016.
    http://www.businesswire.com/news/home/20160211005321/en/Incyte-Announces-Decision-Discontinue-JANUS-Studies-Ruxolitinib
  10. Hingorani SR, Harris WP, Hendifar AE, et al. High response rate and PFS with PEGPH20 added to nab-paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients with high-HA tumors: Interim results of a randomized phase II study. J Clin Oncol. 2015;33:(suppl; abstr 4006).
  11. ClinicalTrials.gov. Identifier NCT02715804. A Study of PEGylated Recombinant Human Hyaluronidase in Combination With Nab-Paclitaxel Plus Gemcitabine Compared With Placebo Plus Nab-Paclitaxel and Gemcitabine in Participants With Hyaluronan-High Stage IV Previously Untreated Pancreatic Ductal Adenocarcinoma. Accessed April 2016. https://clinicaltrials.gov/ct2/show/NCT02715804?term=pegph20+pancreatic+cancer+phase+3&rank=4
  12. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531(7592):47-52.
  13. Engebretson A, Brody JR, Rahib L, et al. The Know Your Tumor (KYT) initiative: A national program of multi-omic molecular profiling (MoP) for patients (Pts) with pancreatic cancer (PDA). ASCO Annual Meeting Proceedings. 2016 Feb 1;34(4_suppl):279.

Partners in Pancreatic Cancer would like to recognize and thank Celgene Corporation
for their educational support of PartnersinPancreaticCancer.com.

©2017 MediCom Worldwide, Inc. All rights reserved