O'Reilly Discusses Status of Immunotherapy Research in Pancreas Cancer

Eileen O'Reilly, MD

As an immune-resistant disease, pancreas cancer has raised several challenges as investigators explore immunotherapy regimens to treat this patient population. While pancreas cancer has not demonstrated the same signal for immunotherapy as other diseases, several ongoing trials are investigating potential strategies that could help overcome this immune resistance, including combining immune agents together.

“That's what the current strategies in the clinic are all about. Can we reverse this inherent immune resistance, and can we make pancreas cancer an immune-responsive disease? I think people are optimistic — and I certainly am – that we will figure this out for pancreas cancer,” said Eileen M. O’Reilly, MD, associate director for Clinical Research, David M. Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center.

OncLive: At the World GI meeting, you gave a presentation on whether progress is being made with immunotherapy in pancreatic cancer. Can you give an overview of that talk?

During the World Congress on Gastrointestinal Cancers, O’Reilly spoke on the progress being made with immune therapies in pancreatic cancer, which she says is an area that is currently in flux. In an interview with OncLive, O’Reilly discussed her presentation, as well as some of the treatment strategies currently being examined in the field.The topic for discussion here is what is happening with immunotherapy in pancreas cancer. I would say this is an area of flux. Pancreas cancer is traditionally considered to be an immune-resistant disease. It's characterized by the stroma, which is hostile. There's a lack of effector T cells, a lot of myeloid-derived suppressor cells, and really a dearth of the key immune effector cells and T-regulatory cells, so this may be part of the reason why we haven't seen the major signal in pancreas cancer with single-agent checkpoints compared to other diseases. However, there are a lot of strategies being pursued. A key question is if you can make pancreas cancer immune responsive. A strategy to do that is to combine immune agents together. We have some signal-seeking studies underway in the second-line setting to combine immune agents with chemotherapy.

For example, the Parker consortium is looking at combining gemcitabine/nab-paclitaxel and nivolumab (Opdivo) with CD40. There is pretty good preclinical data for that combination. Other examples of immune therapy and chemotherapy are a phase III trial that is about to mature looking at FOLFOX and pegylated interleukin-10, again, altering the immune microenvironment. This study will complete recruitment probably late this year or early next year. Hopefully, we will have data next year.

Another area of interest is CSF1R targeting. Some data were presented at the SITC meeting last year for a cohort of patients with advanced heavily pretreated pancreatic cancer who had received a CSF1R inhibitor and nivolumab. There were a notable number of responses and durable responses in 5 patients. This is resulting in that combination being developed further with chemotherapy in the second-line setting in pancreas cancer. I think there is more to come on that topic.

What are some agents showing promise right now in early phase studies?

Another point to keep in mind is that there is a subset of patients with mismatch repair deficiency in pancreas cancer. It's small, probably about 1%. For that group of patients, immunotherapy with single-agent checkpoints may have a role. We are still learning where strategies with adoptive T-cells have a role in pancreas cancer. I would say it's an exciting time, but we still have to prove that there is a signal for immune therapy for the average patient with this disease. There is more to come.Agents that are being evaluated in early phase settings in pancreas cancer, such as PEGPH20, include modulation of the stroma. That agent is in frontline testing in a randomized phase III study in a biomarker-selected population of patients with elevated levels of hyaluronan. Patients receive either gemcitabine/nab-paclitaxel plus PEGPH20 or gemcitabine/nab-paclitaxel alone. That is based on phase I and II data, suggesting that the approach may have value in that setting. We have to temper that a little bit with some data in a different setting in metastatic disease, and using a different cytotoxic combination where there wasn't an obvious signal. In fact, the signal may have been detrimental. There's more to be elucidated from that trial. I think we are looking forward to seeing the maturation of the phase III.

What are some challenges with using immunotherapy in pancreatic cancer?

Stroma modulation is an important area. The area of DNA damage repair and homologous targeting is also an important area in pancreas cancer. A strict population would be patients who have germline mutations in BRCA-1 or BRCA-2, or PALB2. Those patients do appear to preferentially benefit from platinum-based therapies. PARP inhibitors are being adjudicated as a maintenance value in a phase III trial, so we are hoping next year we may have data on the use of olaparib (Lynparza) in this setting in pancreas cancer. That is another important group. We are trying to understand beyond germline BRCA-1 and BRCA-2 and PALB2 if there are other patients with defects and either somatic homologous recombination deficiency (HRD) genes, or germline-mutated HRD genes. For example, patients with ATM or CHEK2. Are they also individuals that may benefit from DNA repair strategies, or even combination of DNA repair strategies and other agents? That's another promising avenue of research in pancreas cancer at the current time.Challenges for using immunotherapy are the fact that pancreas cancer in general is considered not to be an immune-responsive disease, which is partly related to the microenvironment. It's related to the immune-suppressive nature of that environment, so a lot of myeloid-deprived suppressor cells, T-regulatory cells, and lack of effector T-cells. All of those components are thought to confirm immune resistance; it's considered cold.

Are there any pancreas cancer studies that were presented at the 2018 ASCO meeting that are practice-changing?

One of my colleagues shows a nice picture of a melanoma cell and a pancreas cancer epithelial cell, where in the melanoma cell, the T cells are stuck on the malignant cell, and in the pancreas cell, there are some T-cells there, but they are discordant from where the malignant cell actually is. This speaks to the fact that some are there, but even the ones that are there don't do a good job in terms of affecting immune leverage. That's what the current strategies in the clinic are all about. Can we reverse this inherent immune resistance, and can we make pancreas cancer an immune-responsive disease? I think people are optimistic — and I certainly am – that we will figure this out for pancreas cancer.An important study from ASCO is the PRODIGE 24 trial in the adjuvant setting. This was a study conducted in fit people, ECOG 0 to 1, who underwent resection of pancreas cancer and were well enough to be randomized to either a modified version of FOLFIRINOX or gemcitabine within 12 weeks of their surgery. The FOLFIRINOX regimen was modified to reduce the bolus 5-FU and reduce the irinotecan dose. This helped with the tolerability, but the signal was very important. The disease-free survival, relapse-free survival, and overall survival (OS) were all significantly improved with compelling hazard ratios. The OS was 54.4 months for the FOLFIRINOX group versus 35 months in the patients treated with gemcitabine. I'll make the point again that this was very selective. The gemcitabine arm tells us that, because this is significantly better than other gemcitabine control arms in other trials. Not only did the patients have a good performance status, they had to have a CA 19-9 level less than 180 at the time of study enrollment, and they had to be less than 79 years of age.

Can you discuss the results from the PREOPANC-1 study?

Nonetheless, this is probably the biggest signal we've ever seen in pancreas cancer. Hopefully, that translates, and more people are living longer and more patients are cured. These are exciting data and I would say absolutely practice-changing in the clinic for that person who is well enough to tolerate the rigorous of that treatment's intensity. The PREOPANC trial was a Dutch trial. It was a perioperative study, so the experimental arm received gemcitabine for a cycle, then gemcitabine with radiation, then went to surgery, and then received additional gemcitabine. The control arm was surgery first, followed by adjuvant gemcitabine. This trial was in both resectable and borderline resectable patients. The trial trended for a signal in favor of neoadjuvant therapy. Numerically, the values were very different to the FOLFIRINOX trial, so median survival for the experimental arm was about 17 months and it was about 13 months for the traditional upfront adjuvant arm.

Are there any other recent studies in pancreas cancer that you are excited about?

Again, this is a more real world-based evaluation on an intent-to-treat basis, so you're taking patients at the time of diagnosis as opposed to the very selected patient who is able to get through surgery, recover, and be well enough for FOLFIRINOX. You can't compare these 2 studies, but the way I think about it is that it provides more support for the hypothesis that neoadjuvant therapy in resectable pancreas cancer is an important theme and we are probably ready now in North America to begin to think about a randomized study of neoadjuvant versus adjuvant, or if we should continue to focus on the development of neoadjuvant therapy.I would mention one other trial from ASCO which looked at this question of maintenance therapy — deescalating treatment after a patient’s disease has been debulked and stabilized on standard therapy. Data would suggest, for example, for patients who receive FOLFIRINOX, dropping oxaliplatin and then reintroducing it at the time of progression is a reasonable thing to do and doesn't appear to disimprove survival. As you would expect, there's more neuropathy in that since patients did have more oxaliplatin exposure. That's a theme that resonates with what we know in colorectal cancer and how we hope to increasingly be able to treat patients with pancreas cancer. These therapies are tough and they're cumulatively debilitating for patients in terms of fatigue, myelosuppression, neuropathy, etc. Being able to deintensify therapy and offer patients not a break in the full sense of the word, but maybe an improved quality of life for a period of time, hopefully will have a value for a subset of patients.