Pancreatic Cancer Field Pushes Forward Following Pivotal Trial Readouts

Jordan D. Berlin, MD

Unprecedented findings from the phase III PRODIGE 24/CCTG PA.6 trial brought great hope to the field of locally advanced, resectable pancreatic cancer. However, topline findings from the phase III APACT trial were less than encouraging, leaving physicians unsure of where to place certain agents, explained Jordan D. Berlin, MD.

Prior to the readout of PRODIGE 24/CCTG PA.6, overall survival (OS) for patients with resectable pancreatic cancer had hovered around 24 to 28 months. Following its results, modified FOLFIRINOX became the standard of care in this setting, having resulted in an OS of 54.5 months.¹

Yet the combination of gemcitabine and nab-paclitaxel (Abraxane), a commonly used regimen in the metastatic setting, failed to improve disease-free survival (DFS) versus gemcitabine alone in patients with surgically resected pancreatic adenocarcinoma, according to topline results of APACT.² However, the combination demonstrated a statistically significant improvement in OS, which served as one of the secondary endpoints.

Moreover, radiation therapy, though a compelling modality, has yet to demonstrate a survival benefit in this setting, said Berlin.

Although systemic therapy has been a focus in the field, certain targets may provide additional insight into the disease that may unleash more potent, and importantly targeted approaches that may be able to infiltrate the stroma.

“There are other potential targets in pancreas cancer,” said Berlin. “This disease is not without targets...we're going to start teasing out the weaknesses of various parts of pancreas cancer.”

OncLive: Could you discuss the neoadjuvant and adjuvant landscape in locally advanced pancreatic cancer?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Berlin, Ingram Professor of Cancer Research, professor of medicine, VICC associate director for clinical research strategy, director, Phase I Program, gastrointestinal malignancies, clinical trials, Department of Medicine, Vanderbilt University Medical Center, shed light on current and future directions in the field of locally advanced pancreatic cancer.Berlin: The standard of care for resectable disease remains adjuvant therapy, though there has been a shift toward neoadjuvant therapy in clinical trials. As for adjuvant therapy, the most recent data from the [PRODIGE 24/CCTG PA.6 trial] showed that modified FOLFIRINOX should be the standard of care in patients younger than the age of 80, with an excellent performance status. With this regimen, the dose of irinotecan is reduced, and the 5-flurouracil bolus is dropped. There are no other standards for that group of patients. For patients who aren't in as good shape, gemcitabine monotherapy or gemcitabine/capecitabine are also reasonable options.

The combination of nab-paclitaxel and gemcitabine was not found to improve DFS in the phase III APACT trial. Where does that leave the combination in this space?

What ongoing trials have you been following?

Neoadjuvant therapy is probably best to use in patients with locally advanced and or borderline resectable disease. Although we say [these patients are] locally advanced, [these cases almost] never go to resection. Here, neoadjuvant therapy is likely the therapy of choice because you have a better chance of an R0 resection.I'm on the steering committee for the APACT trial; the combination did not meet the trial’s primary endpoint of DFS. We need to see the mature data. Hopefully, we will see it in the very near future. At the moment, gemcitabine and nab-paclitaxel is not an option for adjuvant therapy.I’m following the intergroup trials, which are looking at neoadjuvant therapy. We’re also comparing FOLFIRINOX with gemcitabine/nab-paclitaxel in locally advanced disease.

Could there be potential for immunotherapy in this setting?

What are the biggest unanswered questions and the next steps that need to be taken?

What are some potential targets?

A trial looking at neoadjuvant therapy in borderline resectable disease suggested no benefit with stereotactic radiation. Radiation is really an investigational agent in pancreas cancer. We’ve yet to demonstrate a role for radiation. Whether we like to believe it or not, many of us suspect positive margins are a good place to consider adjuvant radiation. The best thing to do is support clinical trials.No, not at the moment. We haven't figured out how to use immunotherapy in pancreas cancer. A very small group of patients with microsatellite instability-high (MSI-H) tumors may benefit from immunotherapy; that’s a reasonable approach. Beyond those patients, the use of immunotherapy off trial in any setting is not appropriate.We have to know if there is a place where radiation truly helps. As we get better systemic therapy, it's possible radiation may be of more benefit. Radiation has most likely not been helpful because our systemic therapies are weak; we need better agents. We need to know if we can do better for certain populations. In patients with DNA damage-repair defects, there are some new data in the metastatic setting. In the neoadjuvant or adjuvant setting, we may be able to bring more patients to resection.There are some patients who have HER2 amplification. Patients with DNA damage-repair defects comprise the biggest group of patients. It may be possible to figure out what to do with SMAD4; it's possible that SMAD4 may give us an indication of how the tumor might behave.

There are some [other] potential targets that may give us more knowledge about how the tumor will behave. There is a group of trials under Precision Promise that look very promising; I encourage patient enrollment on that. I also encourage next-generation sequencing, so that we can find out a patient’s mutation profile.

Is there anything you would like to highlight about Precision Promise?

What does the future of pancreatic cancer hold?

Additionally, every patient with pancreas cancer needs genetic counseling—not just genetic testing. As much as I'm a pancreas cancer specialist in oncology, I know nothing about genetic counseling. As such, my patients see a genetic counselor. The optimal time for genetic counseling is at diagnosis; the discussion about a genetic counseling referral should be part of the initial consultation.Enrollment is very important. It's going to look at whether we can target certain things, including the stroma. We have yet to figure out the stroma. We stand to learn a lot from these trials.I'm hoping we're going to start seeing some RAS inhibitors. A set of RAS inhibitors are currently being tested in the laboratory. Hopefully, we will get those to the clinic. It certainly seems to be an important target. Other targets, such as MEK, will be important as well.

References

1. Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIGE Group. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. J Clin Oncol. 2018;36(suppl 18; abstr LBA4001). doi: 10.1200/JCO.2018.36.18_suppl.LBA400.
2. Celgene Provides Update on ABRAXANE Combination Therapy in the Treatment of Metastatic Triple-Negative Breast Cancer and Pancreatic Cancer. Celgene. Published March 12, 2019. https://bit.ly/2HmHy2X. Accessed March 12, 2019.