New Paradigm Emerging in Advanced Pancreatic Cancer

Johanna Bendell, MD

The majority of patients with pancreatic adenocarcinoma are diagnosed with late-stage, unresectable tumors, a setting in which combination chemotherapy remains the mainstay. Although progress has been slow, new drugs have become available, important research questions are being addressed, and treatment strategies are continuing to evolve.

The take-home message from a recent OncLive Peer Exchange® roundtable entitled “Progress and Promise in Advanced Pancreatic Cancer” is that the established way of viewing this disease has been largely supplanted by approaches currently available and that there are encouraging signs of progress from new strategies in development.

First-Line Choices

“Who would have ever thought we’d have treatment options to discuss for patients with pancreas cancer?” said Johanna Bendell, MD, who served as moderator for the discussion. “There will be controversy about what to use when but finally we’re able to sequence. We’ve probably doubled survival for patients with metastatic disease over the last couple of years. So that’s very impressive, and hopefully we’ll be translating that into curing more patients.”Before thinking about what therapy to recommend for a newly diagnosed patient, Philip A. Philip, MD, PhD, considers the psychological impact of the diagnosis.

Philip A. Philip, MD, PhD

“The most important thing, in my opinion, is to stabilize the patient physically and mentally,” he said, adding that this includes addressing pain control and managing biliary obstruction if necessary. Instead of moving directly into an established treatment, however, Philip considers enrolling the patient in an appropriate clinical trial. Since clinical trials offer standard treatments plus an experimental agent, patients would not be deprived of active treatment, he noted.

When it comes to selecting a frontline systemic regimen, panelists debated the relative merits of two choices: the combination of gemcitabine and nab-paclitaxel (Abraxane) or FOLFIRINOX (leucovorin, fluorouracil [5-FU], irinotecan, oxaliplatin). Factors that Philip considers in choosing between the two regimens include patient performance status, which helps him determine how aggressive to be; organ function, particularly the liver; and age. He said there is a lack of evidence about FOLFIRINOX for patients over the age of 74 or 75 years of age.

Thomas A. Abrams, MD

The major trials evaluating the two regimens differed in patient selection, explained Thomas A. Abrams, MD. In the PRODIGE trial,¹ FOLFIRINOX was given to patients from France who, for the most part, had a slightly better performance status than who received gemcitabine/nab-paclitaxel in the MPACT study.² The control arms of the major trials of both regimens used gemcitabine.

The median overall survival (OS) of patients who received FOLFIRINOX during the trial was 11.1 months while the median OS for those who were treated with gemcitabine/nab-paclitaxel in the MPACT trial was 8.5 months. FOLFIRINOX patients experienced slightly more toxicity including neutropenia and diarrhea. FOLFIRINOX might be a little bit more effective and have a better response rate, said Abrams, but he cautioned that cross-trial comparison is “fraught with landmines.”

Caio Rocha Lima, MD

New Sequencing Option

George P. Kim, MD, said the patient’s wishes concerning the potential for toxicity of therapy should be taken into consideration. He also said that clinicians often believe that FOLFIRINOX should be administered to patients with good performance status and gemcitabine monotherapy for those with poor status but, in fact, gemcitabine/ nab-paclitaxel can be effective in both populations.Another consideration in first-line treatment should be sequencing options in the event of disease progression, noted Caio Rocha Lima, MD. In October 2015, the FDA approved second-line liposomal irinotecan (MM-398; Onivyde) in combination with 5-FU for patients with pancreatic cancer following progression on a gemcitabine-based regimen. Rocha Lima said there is now phase III trial evidence for both first- and second-line therapies that use gemcitabine and that he considers that data to diminish the risk of toxicities. “We are moving to a new paradigm,” said Rocha Lima.

Philip agreed that the concept of using the gemcitabine/ nab-paclitaxel doublet upfront instead of the FOLFIRINOX triplet allows for sequencing more tolerable treatments and is being done in other digestive system malignancies such as gastric and colon cancers.

He noted, however, that FOLFIRINOX is not being used in practice as it was in the pivotal clinical trial. Other panelists agreed that they modify dosing by reducing different components or altering the schedule of administration.

Discussing MM-398, Kim explained that it is essentially a nanoparticle liposomal form of irinotecan. The NAPOLI study,³ which enrolled 417 patients, concluded that for patients previously treated with gemcitabine-based therapy, MM-398 with 5-FU and leucovorin provides superior survival to 5-FU and leucovorin alone (6.1 months versus 4.2 months; 95% CI, 0.41-0.80; P = .0009).

Although the safety profile is considered manageable, MM-398 is associated with GI toxicity, particularly diarrhea, and myelosuppression including neutropenia that requires growth factor support, said Rocha Lima.

Kim said he considers sequencing with particular care and is using more gemcitabine/nab-paclitaxel now that MM-398 has been approved.

Abrams pointed out that knowing there is an approved second-line regimen that might have been considered for first-line therapy cannot help but color the way he thinks about treatment.

As a result, with an individual patient for whom there is clinical equipoise on whether the first-line treatment should be FOLFIRINOX or gemcitabine/ nab-paclitaxel, the fact that there’s an approved effective regimen in the second -line steers him closer to gemcitabine/nab-paclitaxel for first line. Yet, he would continue to select FOLFIRINOX if he suspects an individual patient might achieve an explosively positive response from it.

Philip then noted that because findings of studies of FOLFOX [leucovorin, fluorouracil, oxaliplatin] are not consistent, the sequence he frequently prefers involves using gemcitabine/ nab-paclitaxel in the front line, and then in the second line he chooses a regimen like that used in the NAPOLI-1 trial. He likes this sequence because it is based on evidence and because it removes the risk of exacerbation of neuropathy.

Philip said that more patients treated at major cancer centers go on to second- and third-line treatments than those treated in the community. He emphasized the importance of focusing on quality of life, for some patients may not achieve great benefit from additional aggressive treatment. In contrast, Rocha Lima noted that for many patients quality of life does not drop because of toxicity but because of cancer progression. Therefore, he initiates second-line treatment without permitting a long break in treatment and is very cautious about acceding to patients’ requests to take a break from therapy.

Abrams emphasized the importance of providing excellent supportive care. He noted that the ability to moderate symptoms may impact the extent to which a patient is willing to continue with chemotherapy and thus, ultimately, how the patient will respond to therapy.

George P. Kim, MD

He urged oncologists to support a continuum of care and to recognize that it is artificial to distinguish between palliative care and therapeutic intervention, as these are two sides of the same coin.

Surgical Intervention

Ensure that nurse practitioners and chemotherapy nurses provide strong supportive care, Kim urged.The panel also focused on surgical intervention for patients with pancreatic cancer. After reviewing films with a skilled radiologist to be sure the CT scan is up to standard for both the pancreas and surrounding blood vessels, Rocha Lima categorizes patients. He identifies those who are resectable, those who are borderline resectable, and those who are clearly unresectable. For those who are resectable, he frequently gives neoadjuvant treatment prior to surgery.

This approach may tell him about the biology of the disease and may help avoid unnecessary surgeries. Although this approach is not supported by solid evidence, it seems likely that many borderline resectable patients can become resectable if treated with systemic chemotherapy first, Rocha Lima said.

Immunotherapy

Philip and Abrams both start with neoadjuvant chemotherapy for borderline resectable disease. While he thinks it is reasonable to use nab-paclitaxel/ gemcitabine in that borderline population, Kim suspects that most clinicians are using FOLFIRINOX.Hopes have been high that immunotherapy would benefit patients with pancreatic cancer but efforts to advance two leading programs have proved disappointing.

Rocha Lima discussed the vaccine algenpantucel- L, which demonstrated favorable OS and disease-free survival outcomes in a phase II trial when combined with chemotherapy and chemoradiation. Abrams, who participated in the study, said he was very excited by the drug.

Another promising approach involved GVAX,⁴ which incorporates two pancreatic cell lines overexpressing GM-CSF, Kim explained. Adding CRS-207, which leads to the expression of mesothelin, further improved survival in second-line in early studies.

However, both agents faltered in later-stage testing, according to results disclosed in May after the Peer Exchange session was filmed. Algenpantucel- L failed to improve survival over standard of care (chemotherapy with or without radiation) in the phase III IMPRESS trial, and developer NewLink Genetics said it would focus on other therapies.

Moving Forward

Within days, the developer of a combination CRS-207/GVAX vaccine announced that the regimen had failed to outperform either CRS-207 or chemotherapy alone in the phase IIb ECLIPSE trial. Aduro Biotech said it would continue exploring the combination with and without the PD-1 inhibitor nivolumab in pancreatic cancer.The key to further strides in pancreatic cancer is participation in clinical trials, Bendell and other panelists emphasized. “It’s a huge area for research, a very exciting area with lots of clinical trials,” said Bendell.

In that vein, Kim noted that the Pancreatic Cancer Action Network has launched the Know Your Tumor program through which molecular tumor analysis is offered free of charge, according to the advocacy group’s website (www.pancan.org). Bendell noted that the group has a clinical trials matching service for patients, their families, and healthcare providers on its website.

Although maximizing current and future management strategies is vital, Philip stressed the importance of treating the whole patient.

“You can’t change the diagnosis but you can change the patient’s mental status, their comfort level, and that of their caregivers,” he said. “If you provide chemotherapy while at the same time maintaining quality of life and dignity, you can also almost ensure that the patient will continue treatment as long as the biology of their disease allows them to continue rather than stopping at an earlier point.”

Kim spoke of the need to help patients manage their symptoms such as insomnia, diarrhea, and pain, and noted that nurse practitioners and midlevel providers are important in this effort. He also stressed the need for positive thinking.

“We collectively have to get away from the negativity,” he said. “We have to keep moving forward. We’re going to see some advances, and there’s some exciting treatments out there.”

References

1. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
2. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2011;369(18):1691-1703.
3. Chen LT, Von Hoff DD, Li CP, et al. Expanded analyses of napoli-1: phase 3 study of MM-398 (nal-IRI), with or without 5-fluorouracil and leucovorin, versus 5-fluorouracil and leucovorin, in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy. J Clin Oncol. 2015;33(suppl 3; abstr 234).
4. Le DT, Wang-Gillam A, Picozzi V, et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes—expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015;33(12):1325-1333.