Chung Captures Key Advances Across Pancreatic Cancer Paradigm

Vincent Chung, MD

In the early-stage setting for pancreatic cancer, the use of neoadjuvant chemotherapy may result in better disease control and higher rates of R0 resection, explained Vincent Chung, MD, whereas in the metastatic setting, the focus has shifted to sequencing chemotherapy regimens, thereby optimizing tolerability and time on therapy.

“We're making a lot of progress in the treatment of pancreatic cancer. This was originally thought of as a deadly disease, and now, we're curing patients with pancreatic cancer,” said Chung. “That's really exciting. A lot of the trials that have been coming out recently have been able to show survival of around 4 years as opposed to 1 or 2 years.”

OncLive: What agents are improving survival for this patient population?

In an interview during the OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Chung, an associate clinical professor in the Department of Medical Oncology and Therapeutics Research, and director of the Phase I Program at City of Hope, discussed the therapeutic landscape of early-stage and advanced pancreatic cancer.Chung: Thierry Conroy, MD, of the Institut de Cancerologie de Lorraine, presented data from the PRODIGE 24/CCTG PA.6 trial at the 2018 ASCO Annual Meeting. This was a phase III trial that was done in France and Canada, in which patients were randomized to receive either FOLFIRINOX or gemcitabine following surgical resection. FOLFIRINOX is a tough regimen. In the stage IV setting, FOLFIRINOX had much higher response rates compared with gemcitabine; that was the rationale for taking it into the adjuvant setting. In the trial, patients who received FOLFIRINOX had a median overall survival (OS) of 54.4 months and 35 months with gemcitabine.

What are some questions that still need to be answered in this setting?

Prior to this, there was the combination of gemcitabine and capecitabine, which was tested in the ASPECT-4 trial. Patients who received the combination had a median OS of about 28 months. Going from 28 months to 54.4 months is a really huge leap forward.We still need to wait for the results of the APACT trial, which randomized patients to receive either gemcitabine and nab-paclitaxel (Abraxane) or gemcitabine alone. Hopefully, that trial will present within the next year. My feeling is that this will probably be a positive trial, although we probably won't see as long of survival as we see with FOLFIRINOX. We're probably going to be faced with a choice of 2 different regimens in the future in which we'll have to decide which patients will be able to tolerate the chemotherapy in the adjuvant setting.

What is the chance of a cure in this setting?

How beneficial is neoadjuvant chemotherapy in patients with pancreatic cancer?

You also spoke on metastatic disease. What are your thoughts on SM-88?

Could ibrutinib (Imbruvica) still have a role in the field following the negative results with gemcitabine and nab-paclitaxel?

What are the biggest challenges faced in the metastatic setting?

Another question that's still out there is, “What is the role of radiation therapy?” Radiation therapy is very controversial because [prior studies] really didn't show any benefit with radiation therapy. I do think there are select patients who benefit from radiation therapy because it helps with local control. The challenge is trying to select those patients; that's where we need more studies to figure out who the right patient is.In the early-stage setting, we need to think about how we are going to get more patients to surgical resection. Unfortunately, only about 20% of cases can go to surgical resection, and only about 20% of those patients live out to 5 years. If we can get more patients to surgical resection, we can hopefully cure more patients. The approach is shifting because we're starting to move chemotherapy to the neoadjuvant setting. In the future, we're going to be moving more toward all neoadjuvant therapy, [similar to how we are] in other cancers.There are different reasons for giving neoadjuvant chemotherapy. For pancreatic cancer, it's really because even with surgical resection, 75% of patients will recur within 2 years; that really indicates that this is a systemic disease. There are micrometastases that the surgeons cannot see. Even if they go in and do an R0 resection with negative margins, patients will still recur within 2 years. If we can give full-dose chemotherapy upfront, it is going to control that systemic disease and potentially downstage the tumor, thereby increasing the chances of getting to R0 in surgery. Then, we will start seeing more people cured.It's a very interesting agent, acting upon the Warburg effect by trying to induce cell apoptosis and repurposing other drugs. We're still accruing patients to the SM-88 trial, so it will be very exciting [to see how that plays out]. Also, that trial allowed not only patients in their second-line of therapy, but those in their third-line of therapy and beyond—as long as they met the eligibility criteria. It was exciting to see a clinical trial that allowed multiple prior lines of chemotherapy.It'll depend on patient selection; that's something that we really need to look into. It is a very interesting drug. Ibrutinib affects the mast cells and may change the microenvironment. We need to do a little bit more research to see where we're going to go with that.Pancreatic cancer, unfortunately, causes many complications in and of itself. People have thromboembolic events, biliary infection, and cachexia. They have many problems that they're trying to manage with just the cancer alone. When we give chemotherapy, we have to think about how they will tolerate the chemotherapy if they're already symptomatic from their disease.

Do you have a preferred sequence of chemotherapy?

If we give them FOLFIRINOX and they have nausea, vomiting, neutropenia, and diarrhea, it makes it difficult for patients to have a good quality of life. For patients with metastatic disease, we need to think about how we're going to manage the toxicities of the chemotherapy and how we are going to sequence our chemotherapies so that they can stay on therapy for a longer period of time; that's what is really going to impact survival.It really has to do with managing the toxicities. For instance, I will give a lot of my patients gemcitabine and nab-paclitaxel to start off with. Even though the nab-paclitaxel causes a lot of neuropathy, it tends to be more reversible. After you stop nab-paclitaxel, the neuropathy will go down over the course of the next month to less than grade 1 for most patients.

The advantage with that is once you have signs of progression, you can go onto second-line nanoliposomal irinotecan and 5-fluorouracil, which you are able to get good disease control with. You’re also getting further away from the neurotoxicity seen with nab-paclitaxel.

What is the biggest trend from the 2019 ASCO GI Cancer Symposium in pancreatic cancer?

When you get to the third-line setting, you can think about incorporating oxaliplatin into the regimen. Unfortunately, with oxaliplatin, the neuropathy tends to be more irreversible. For patients with really good performance status who receive modified FOLFIRINOX in the first-line setting, I typically drop the oxaliplatin as we start to see more neuropathy. I don't want that neuropathy to be permanent. If it causes a lot of problems where patients have difficulty buttoning their shirts and doing activities, they’re not going to tolerate gemcitabine and nab-paclitaxel afterwards.The most exciting study that came out of the 2019 ASCO GI Cancer Symposium was the COMPASS trial. The COMPASS trial was a prospective trial that was done in Canada where patients who were undergoing first-line therapy underwent tumor tissue biopsy and sequencing.

They did RNA sequencing as well as patient-derived organoids, results of which were received an average of 39 days later. When the patient progressed on their first-line therapy, they could get a targeted therapy tailored to what their genomic profile was. I thought that was really exciting because we're seeing that pancreatic cancer is no longer a single disease. We're now seeing that there are many different subtypes of pancreatic cancer and those different subtypes have different survival [outcomes] as well as potentially different treatment options. It’s a really exciting time in pancreatic cancer.