Shedding Light on the Challenging Pancreatic Cancer Paradigm

Vaibhav Sahai, MBBS

Although pancreatic cancer has lagged behind other tumor types in terms of recent therapeutic progress, early genomic testing may help identify actionable targets in patients, said Vaibhav Sahai, MBBS.

There are currently no FDA approved chemotherapy-free immunotherapy or targeted regimens in this space, but over one-quarter of patients with metastatic pancreatic cancer harbor a genetic alteration, added Sahai, who is an assistant professor of medicine at the University of Michigan.

“I discuss genomic testing with all of my patients,” said Sahai. “I specifically consider doing this when I have patients who are candidates for clinical trials, as there is no approved [targeted] therapy [available] today.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Sahai shed light on ongoing research in metastatic pancreatic cancer and discussed the role of genomic profiling in the space.

OncLive: Have there been any recent advances made in the frontline setting of metastatic pancreatic cancer?

Sahai: Unfortunately, there have not been any recent updates for these patients that have led to any FDA approved therapies. In 2011, we heard FOLFIRINOX was approved as a first-line therapy for metastatic pancreatic cancer. In 2013, gemcitabine plus nab-paclitaxel was also approved [based on results from] a global trial. Since then, we have not had any FDA-approved therapies, but there are certainly several exciting phase III trials that are ongoing both in the United States and globally.

What are some drawbacks to the current standards of care?

The current standards are only inclusive of chemotherapy. Unfortunately, we have not had any immunotherapy or targeted therapy agents approved for this cancer. There are also several adverse events (AEs) that we commonly associate with chemotherapy that I believe limit all patients' abilities to not only tolerate those drugs, but remain on them long-term.

What are some of the key takeaways from the phase II PRODIGE 35-PANOPTIMOX study?

PRODIGE 35-PANOPTIMOX was a European trial in which investigators tried to identify whether we should stop therapy after 6 months, switch to maintenance therapy, or do switch maintenance therapy. This study looked at overall survival and toxicity profile for these regimens to answer the question. Although it's a small study—it's not a phase III trial—the biggest takeaway is that intermittent chemotherapy with FOLFIRINOX for 6 months followed by evaluation or a break every few months with scans versus maintenance therapy with 5-fluorouracil (5-FU), is similar in terms of survival. However, the switch maintenance therapy led to inferior survival and higher toxicity rate, so it definitely should not be considered.

Another key trial in this space was NAPOLI-1. What were the implications of this research?

After progression on frontline therapies, there is finally an FDA approved regimen called NAPOLI-1, which emerged from this [phase III] trial. The regimen is a combination of 5-FU, leucovorin, and liposomal irinotecan (Onivyde); it's given every 2 weeks and is relatively well tolerated. This regimen has also shown an improvement in survival when compared with 5-FU and leucovorin alone. This presents a unique opportunity for patients who have not received irinotecan to receive therapy after failing the frontline regimen.

What are some sequencing strategies to consider?

For frontline therapy, about 50% of the population gets started on gemcitabine plus nab-paclitaxel, and the other 50% gets started on FOLFIRINOX. After progression on this initial regimen, patients are frequently asked to switch to the alternative. Therefore, the biggest question in our mind is whether the sequencing really matters. Should we start all of our patients on one of these regimens and then switch to the other, or vice-versa?

There are no known targeted therapies or immunotherapies in this space, but very recently, there was a maintenance trial in a small cohort of BRCA1/2-positive patients in which olaparib (Lynparza) was given. This was done after at least 4 months of FOLFIRINOX or platinum-based chemotherapy. We've seen a press release that the study was positive, and the data will be released at the 2019 ASCO Annual Meeting. We are eager to see these data.

Since there is a lack of effective therapies in this space, what is the role of genomic profiling?

We have to consider this as a research modality to some degree. There are data out there showing that 27% of patients with metastatic pancreatic cancer may actually have a targetable mutation; however, only 3% of these patients are paired with a therapeutic option. I discuss with patients that there is a less than 10% likelihood of us finding a targetable mutation that we can then subsequently identify and put them on a drug for.

It is not an option for all patients, but it's really important for us, as physicians, to identify the appropriate candidates. Some of the actionable mutations that appear in pancreatic cancer are BRCA1/2, PALB2, RET, microsatellite instability-high status, and high tumor mutational burden. NTRK is another one with an FDA-approved therapy.