New Treatment Paradigms in Second-line Therapy for Pancreatic Cancer

ppc_tx_paradigm_2016-06-01_content

An Interview with

Tanios Bekaii-Saab, MD, FACP
Co-Leader, Gastrointestinal Cancer Program
Mayo Clinic Cancer Center
Senior Associate Consultant
Division of Hematology and Oncology
Mayo Clinic
Phoenix, Arizona

Pancreatic cancer is the deadliest of all major cancers in the United States with a five-year survival rate of just 8%.1 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. However, in October 2015, the U.S. Food and Drug Administration approved a new treatment option for patients with metastatic pancreatic cancer previously treated with a gemcitabine-based regimen,3 effectively defining a new standard-of-care in this patient population.

A Phase III randomized clinical trial of nanoliposomal irinotecan plus fluorouracil and folinic acid versus nanoliposomal irinotecan alone versus fluorouracil and folinic acid in patients with metastatic pancreatic ductal adenocarcinoma previously treated with a gemcitabine-based regimen demonstrated improved overall survival. The median overall survival in the experimental combination arm reached 6.1 months versus 4.2 months in the fluorouracil and folinic acid arm.4 These findings led to the FDA approval of the combination of nanoliposomal irinotecan, fluorouracil, and folinic acid in this patient population.

Anitra Engebretson (AE): Thank you for speaking with us, Dr. Bekaii-Saab. Can you tell us what treatments are currently available for second-line therapy in patients with advanced (metastatic) pancreatic cancer?

Dr. Tanios Bekaii-Saab: The landscape, unfortunately, is still small. The agents that are available for second-line pancreas cancer are determined by what patients receive in the first-line setting. Currently, for the majority of patients in the United States, the standard-of-care in first-line is gemcitabine and nab‑paclitaxel. The remainder of patients will receive the combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and folinic acid, known as FOLFIRINOX.

The chemotherapy combinations of FOLFIRINOX and gemcitabine plus nab‑paclitaxel are both reasonable first-line treatment options in patients with metastatic pancreatic cancer. The combination of gemcitabine and nab‑paclitaxel showed a nearly two month improvement from 6.7 to 8.5 months in median overall survival versus gemcitabine alone in the Phase III randomized trial5 that led to its FDA approval in 2013.6 FOLFIRINOX demonstrated a 4.3-month increase in median overall survival from 6.8 to 11.1 months when compared to gemcitabine in a Phase III trial conducted in France, and has been considered a standard option for untreated, metastatic pancreatic cancer patients.7

First, let’s talk about patients who receive gemcitabine and nab‑paclitaxel in the first-line setting. These patients have essentially three second-line treatment options: first, fluorouracil or capecitabine, each of which are used as single agents, and typically in patients with poor performance status or the elderly. Another option is the combination of fluorouracil, folinic acid, and oxaliplatin (FOLFOX), which was commonly used prior to the recent approval of nanoliposomal irinotecan, specifically in those patients who do not develop neuropathy from the gemcitabine and nab‑paclitaxel. The newest option is the recently approved combination of nanoliposomal irinotecan with fluorouracil and folinic acid.

When we look at FOLFOX, unfortunately, we have conflicting data from two studies. We have a European study, CONKO-003, that looked at fluorouracil with folinic acid and weekly oxaliplatin, also called the OFF regimen. This study showed an improvement in overall survival from 3.3 to 5.9 months in the group receiving the OFF regimen.8 But then another study from a Canadian group suggested that modified FOLFOX-6, which is what we typically use in the United States, did not perform any better than fluorouracil and folinic acid. These two conflicting studies bring into question the value of oxaliplatin in pancreas cancer, specifically in the second-line setting.

We now have this agent, nanoliposomal irinotecan, that was looked at in a study called NAPOLI-1.4 This Phase III study randomized patients to receive either nanoliposomal irinotecan alone, fluorouracil and folinic acid, or nanoliposomal irinotecan plus fluorouracil and folinic acid. The study showed improvement in progression-free survival, overall survival, and response rate in the patients receiving nanoliposomal irinotecan with fluorouracil and folinic acid versus fluorouracil and folinic acid alone.4 All of the efficacy parameters were improved, and the toxicities were as expected. This has now become the standard of care for patients with performance status 0-1 who received gemcitabine-based therapy, including gemcitabine and nab‑paclitaxel, in the first-line setting.

The most common Grade 3 or 4 adverse events observed in the nanoliposomal irinotecan plus fluorouracil and folinic acid group were neutropenia, diarrhea, vomiting, and fatigue.4

AE: For that smaller percentage of patients who receive FOLFIRINOX in the first-line setting, what treatments are appropriate in the second-line setting?

Dr. Bekaii-Saab: For those patients who start with FOLFIRINOX, it gets a little more complicated; we have options, but there is not actually any data to suggest a standard-of-care. In those patients, the combination nanoliposomal irinotecan regimen would not make sense, and it has not been tested in that patient population. One could suggest gemcitabine and nab‑paclitaxel as an option. The potential concern here is the possibility of overlapping toxicities. This includes specifically neurotoxicity, but sometimes lingering neutropenia and blood count issues, as well. Gemcitabine monotherapy has some data as second-line treatment following fluorouracil from the 1990s and could perhaps be a reasonable option for patients with poor performance status, especially in the presence of neurotoxicity.

Sequencing into second-line after first-line FOLFIRINOX is a little bit more difficult, as there are fewer options than when sequencing into second-line after gemcitabine and nab‑paclitaxel, which now allows the use of an established and standard regimen.

The landscape for second-line metastatic pancreas cancer has really experienced some recent development with the approval of the nanoliposomal irinotecan regimen. I think it makes sense to start reconsidering how we treat patients with metastatic pancreas cancer, and consider a sequencing approach with a gemcitabine-based regimen in the first-line, preferably being gemcitabine plus nab‑paclitaxel, followed in the second-line by nanoliposomal irinotecan plus fluorouracil and folinic acid.

That does not mean FOLFIRINOX in the first-line is not a viable option, but my personal approach and the practice of my clinic is that FOLFIRINOX is less desirable due to its increased risk of toxicity and to the limited treatment options in the second-line for those patients.

AE: You have commented a bit on toxicities with these various treatment regimens. Could you please provide a little more detail about how you take those toxicities into consideration when you’re making treatment decisions, and how they might affect which treatment is pursued in the second-line option?

Dr. Bekaii-Saab: The two regimens that are established in the first-line setting can cause quite significant toxicities, specifically neurotoxicity. Both nab‑paclitaxel and oxaliplatin will add significant neurotoxicity to the gemcitabine plus nab‑paclitaxel and FOLFIRINOX regimens, respectively. Some of this toxicity is cumulative and does actually trickle down to the second-line options.

The other issue is hematologic toxicities that may persist after the first-line. It is unusual to have lingering hematologic toxicities with the gemcitabine-based regimen, although you could see some baseline neutropenia and thrombocytopenia that may limit dose intensity in the second-line.

The second-line nanoliposomal irinotecan plus fluorouracil and folinic acid regimen has no neurotoxicity, so in patients with lingering neurotoxicity through lines of therapy, this subsequent use of nanoliposomal irinotecan would make sense, as it would not add to their toxicity. Subsequent FOLFOX or oxaliplatin would not be optimal in this setting, due to the overlapping neurotoxicity.

AE: Are there any other considerations, such as the mechanism of action of a particular drug, that you take into account, or do you primarily make the decision of which second-line option to pursue based on the patient profile, treatment history, and the potential toxicities?

Dr. Bekaii-Saab: One thing about pancreas cancer is that your options are really limited. So there are, unfortunately, not a lot of regimens available. You think about two pathways, and the second-line decision really only depends on what you use in the first-line, either gemcitabine and nab‑paclitaxel or FOLFIRINOX. Since most patients get first-line gemcitabine and nab‑paclitaxel for the reasons we discussed, the second-line options include nanoliposomal irinotecan plus fluorouracil and folinic acid in those with good performance status. For those with poor performance status, you would consider fluorouracil only or best supportive care. Frankly, it is a very straightforward equation.

In the patients who receive first-line FOLFIRINOX, it’s a little bit more difficult to justify second-line; for one, because of the lingering toxicities, and also because there is really nothing approved for treatment after FOLFIRINOX. So, we have to be creative with these patients and consider regimens that have activity in the first-line like gemcitabine and nab‑paclitaxel. But, those patients can be so beat up by the first-line FOLFIRNIOX that they can have difficulty achieving adequate dose intensity with aggressive second-line regimens, and most often they will end up on gemcitabine monotherapy.

My preference is really to consider sequencing as an optimal approach with a gemcitabine-based first-line treatment, preferably gemcitabine and nab‑paclitaxel, followed by nanoliposomal irinotecan plus fluorouracil and folinic acid in those patients with adequate performance status.

AE: What about clinical trials for this patient population? Should they be considered, and under what circumstances?

Dr. Bekaii-Saab: I think that for patients with pancreas cancer, the standard treatment remains a clinical trial. If you look at the cumulative benefit from all these lines of therapy, we have not even crossed the one-year line yet in pancreas cancer. We do have an improvement in five-year survival times, which are now up to almost 8% from 4% or 5%. So, at least from that standpoint, we are getting closer to ten percent, as a two digit five-year survival percentage.

But, we are not there yet and therefore, since it remains the most desperate cancer from that standpoint, it makes a lot of sense to continue aggressive development of new agents. There are a number of new agents, from stem cell inhibitors to vaccines to immunotherapy to modifiers of the microenvironment. There is a lot of activity going on in pancreas cancer, and I think we should definitely encourage all of our patients and all of our referring physicians to consider clinical trials first for all patients with metastatic pancreas cancer, especially when those trials are available.

In addition to online resources such as Cancer.gov and ClinicalTrials.gov, to find clinical trials for your pancreatic cancer patients, consider the Pancreatic Cancer Action Network’s Clinical Trial Finder (clinicaltrials.pancan.org), a unique, up-to-date and comprehensive pancreatic cancer-specific tool.


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. FDA approves new treatment for advanced pancreatic cancer. FDA News Release. 22 October 2015. Web. Accessed April 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm468654.htm

4. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557.

5. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab‑paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703.

6. FDA approves Abraxane for late-stage pancreatic cancer. FDA News Release. 6 September 2013. Web. Accessed April 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm367442.htm

7. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.

8. Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014;32(23):2423-2429.

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

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