Progress Made in Pancreatic Cancer Allows for Personalized Approaches

Syma Iqbal, MD

Although pancreatic cancer has been a historically difficult disease to treat, the emergence of novel combinations have allowed for more patients to receive later lines of therapy, and recent advances have inspired a shift to more personalized treatment approaches to improve outcomes, according to Syma Iqbal, MD.

“Unfortunately, pancreatic cancer remains a very difficult disease to treat. Although we've made progress over the past several years, it has been very incremental. We have broadened our cytotoxic armamentarium, and for the first time, we've been able to tailor therapy based on the genetic profile of the tumor itself,” said Iqbal. “Hopefully, as we move forward in treating this disease, not only will we expand our ability to offer perhaps better and more tolerable cytotoxics, but actually profile these tumors, so we are targeting therapy and treating patients individually to improve their outcomes.”

In an interview with OncLive, Iqbal, an assistant professor in the Division of Oncology, assistant program director of the Oncology Department's Fellowship Program at Keck Medicine, and co-director of the Liver Cancer Program at the University of Southern California, discusses the strategies used for the first-line treatment of patients with pancreatic cancer, options for later-line settings, and research efforts being made with targeted therapies.

OncLive: Could you speak to the PRODIGE 35-PANOPTIMOX study? What should be taken away from this work?

Iqbal: The randomized, phase 2 PRODIGE 35-PANOPTIMOX study evaluated maintenance therapy with the use of FOLFIRINOX, which is our standard-of-care regimen in the treatment of patients with metastatic pancreatic cancer. This was a 3-arm study that made a comparison between FOLFIRINOX versus FOLFIRINOX followed by an approach where patients were given maintenance treatment with leucovorin [plus 5-fluorouracil (5-FU)] to see if an improvement in quality of life [could be achieved]. Although the third arm of the study examined sequential treatment with gemcitabine and FOLFIRI.3, the results of this arm were not favorable. The primary outcome of the study that is most relevant to us is that patients who received continuous FOLFIRINOX versus FOLFIRINOX for 8 cycles followed by maintenance 5-FU/leucovorin had similar outcomes. This allows our patients to have a break from the cytotoxics that offer the most adverse effects (AEs).

This will now, hopefully, move forward into a randomized phase 3 trial. I believe this is something that we already do, based on the OPTIMOX data [from] colorectal cancer in many patients who are receiving oxaliplatin-based regimens because of the toxicity related to the neuropathy. This study offers us some support to continue [to use that approach in] this patient population. Obviously, we'll await phase 3 data, but this is good data that allows us to continue to do what many of us had already been doing [in clinical practice].

What is currently being done for patients who progress on standard-of-care frontline regimens?

Our standard-of-care frontline regimens are either gemcitabine plus nab-paclitaxel or FOLFIRINOX. For the patients who have progressed on gemcitabine-based regimens, several trials have looked at a few combinations in the second-line setting. This includes 5-FU/oxaliplatin, 5-FU/irinotecan, as well as 5-FU/liposomal irinotecan (Onivyde). Basically, all 3 of these studies have shown us that 5-FU combinations following progression on gemcitabine offer some efficacy in this patient population.

What has been interesting is that over the past several years, there has been some thought that perhaps patients with pancreatic cancer don't really make it to second-line therapy because of the nature of this disease. However, we're seeing that patients are able to receive second-line treatments and do maintain performance status. Second-line regimens are very important in this group of patients. [It’s important to remember that] if you're using an nab-paclitaxel–based combination in the first-line setting, [you can see] overlapping toxicities related to neuropathy [if you use] FOLFOX in the second-line setting. Therefore, we may be limited and want to pursue either [liposomal irinotecan] or an irinotecan-based regimen [in the second line] to avoid the residual overlapping toxicity that patients may still have from their first-line treatment.

Could you expand on the NAPOLI-1 trial with liposomal irinotecan following prior gemcitabine-based therapy?

NAPOLI-1 is an older, second-line study that explored options for patients who progressed on a gemcitabine-based regimen. The trial specifically looked at single agents in the second line such as liposomal irinotecan versus 5-FU/leucovorin versus the combination [of the 2] once safety was established with the single agents. The combination appeared to be well tolerated and offered greater efficacy, so it exists as a second-line option for these patients who have progressed on gemcitabine-based regimens. A nice benefit of this regimen is that it doesn't have the overlapping toxicity related to neuropathy that is seen with gemcitabine combinations that patients may have received with front-line nab-paclitaxel.In terms of safety, themost commonly reported grade 3 toxicities with the 5-FU/leucovorin and liposomal irinotecan[KR4] combination were diarrhea and neutropenia. However overall, it was thought to be a well-tolerated regimen.

A phase 3 trial is now evaluating first-line liposomal irinotecan plus 5-FU/leucovorin plus oxaliplatin or nab-paclitaxel plus gemcitabine so we’ll see if the addition of liposomal irinotecan offers benefit over our standard regimen.

What are some areas of research that are generating excitement right now?

One of important things that has come up is the evaluation of BRCA in our patients. The POLO trial was presented during the 2020 ASCO Virtual Scientific Program, and it evaluated patients with BRCA1/2-positive disease, which account for approximately 4%-7% of our entire population. Patients received a platinum-based regimen for about 4 months and then were randomized to placebo versus olaparib (Lynparza). Results showed that patients who received olaparib had an improvement in progression-free survival. No difference in overall survival was observed, but this potentially offers patients a break from chemotherapy. This is the first time a tailored regimen has shown activity in pancreatic cancer.

Although some quality-of-life (QOL) measures were evaluated, we didn’t necessarily observe a difference in QOL despite what we had predicted. However, this study has allowed us to tailor chemotherapy based on patients who have these BRCA mutations. In fact, this has been incorporated into our National Comprehensive Cancer Network [KR5] guidelines, as all patients should be screened for these mutations to allow for therapy [to be tailored] accordingly.

Another very interesting part of treatment now is evaluation of microsatellite instability (MSI); this is actually a broad evaluation, not necessarily specific to pancreatic cancer; however, we know that the use of checkpoint inhibitors in patients with MSI-high tumors allows for a significant response to therapy, even in the refractory setting. As such, this should be a part of our profiling up front in this patient population.

How does the feasibility of genomic stratification influence the design of targeted therapies, such as maintenance olaparib?

Across tumor types, and for the first time in pancreatic cancer, we're seeing genomic evaluations identifying targetable markers, and it's impacting our treatments. The POLO trial determined that in patients with BRCA-positive disease [and we see that] across the board in our MSI-H patients and in those with mismatched repair deficiency. Our goal for the future is that we will have other potentially targetable mutations. At this point, most of us do next-generation sequencing on all of our patients as they present up front; this not only allows for standard-of-care therapeutics, but it also potentially allows for participation on clinical trials as potential targetable mutations can help us match patients to various studies.

One of the difficulties faced with pancreatic cancer is that oftentimes we have a small biopsy specimen. The nature of these biopsies is that oftentimes they don't leave us with [much tissue] to work with; as such, profiling can be difficult.

With so many options available in the space, how do you approach sequencing?

A few years ago, ASCO put out guidelines on how to approach [the treatment of] patients with pancreatic cancer. Now that we have options, [a lot of the decision making] depends on the patient's performance status. Performance status is a factor that determines how we should move forward with therapy. Generally, if you have a patient with a very good performance status, who you feel will be able to tolerate a significant regimen, then you will offer them a FOLFIRINOX-based therapy. The original trials were done on patients who were under the age of 75.

If you have patients who have more of a borderline performance status, or patients who don't want to deal with the pump and potential AEs from chemotherapy, or patients who you feel aren't going to tolerate a FOLFIRINOX-based combination, then that patient would be a candidate for gemcitabine and nab-paclitaxel. In the IMPACT trial, for example, patients had performance statuses of 0-1, but it was 1+, approaching 2, as they used Karnofsky performance status. If you have a patient who has more of a borderline performance status, a single agent, likely gemcitabine, would be a reasonable [option].

We stratify our patients now based on their motivation for chemotherapy, but more so based on their performance status in terms of what they may be able to tolerate with the support that they have.

Is there anything that you would like to add?

Over the past several years, many improvements have been made in pancreatic cancer treatment. Some of the most exciting advances have been focused on tailoring therapy for patients. Although we’ve only achieved success in a small number of patients, it's a huge step forward. As we continue to move forward, the most important thing is having patients participate in clinical trials so that we can continue to [learn more about the disease]. In pancreatic cancer, we still see very low participation in clinical studies—less than 5%. We're making progress, but there's a lot [more work that is needed]. We should be encouraging our patients to participate on clinical trials so we can keep moving forward.