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The Changing Landscape of Pancreatic Cancer Treatment

Insights From: Tony Saab, MD, Mayo Clinic; Davendra Sohal, MD, MPH, Cleveland Clinic
Published: Tuesday, Feb 19, 2019



Transcript: 

Davendra Sohal, MD, MPH:
We’ve certainly made a lot of progress in advanced pancreatic cancer over the last 5 to 7 years or so. It started with FOLFIRINOX, the triple-drug regimen of 5-fluorouracil, irinotecan [hydrochloride, leucovorin calcium], and oxaliplatin, for treatment and was followed by gemcitabine and nab [albumin-bound] paclitaxel combination. So those have improved our outcomes that we see in the clinic. It used to be barely 6 months with gemcitabine alone, and now we are approaching a median overall survival of close to 1 year with these aggressive regimens. And these have also opened up avenues for treatment advancements in the adjuvant and neoadjuvant settings as well.

Tanios Bekaii-Saab, MD: Things have changed quite meaningfully and significantly over the last, I’d say, 10 to 20 years in pancreatic cancer. In fact, over the last 2 decades, we’ve seen significant improvement in a disease where the 5-year overall survival rate for all stages was less than 4%. We’re getting close to the double digits. We’re not there; we’re about 8% to 9% and every year improving. Now, that may not seem like a lot because we’re still not doing as well as we should with respect to other cancers, but this is doubling, more than doubling, the 5-year survival rate. And most of it has happened over the last 4 to 5 years.

The year 2018 was a good year, mostly for the early stage pancreatic cancers where we’re starting to learn a little bit more about these strategies regarding neoadjuvant therapy, intensifying adjuvant therapy. Survival in the adjuvant, in the early stage setting, is now close to 50 to 60 months, whereby for the longest time it wouldn’t budge beyond 20 to 25 months. And a lot of it has to do not just with how well we’re doing before and after surgery, but it also has to do with the salvage component. We have more options, you know, with nab-paclitaxel, with nonliposome, irinotecan, with FOLFIRINOX. A lot of these salvage strategies have also helped improve significant survival.

The other component is, of course, we’re understanding a little bit better the whole genetic and genomic landscape around pancreatic cancer. And we’re starting slowly but surely, in very small subsets of patients who understand what makes sense and what doesn’t make sense and how we target them better. We’re still away from getting where we want to be, but I think we’re on the right track.

I think that train that left the station awhile ago and has accelerated through 2018 will continue accelerating through 2019. We expect more data about perioperative treatment on the earlier stages. We also expect 2 major studies, phase III studies, to close down in early 2019 or late 2019. We may not have results before the end of the year or by 2020, but there will be 2 major achievements, 2 large studies in pancreatic cancer—1 with a stem cell inhibitor, napabucasin, and the other one with a PEGPH20 [pegylated recombinant human hyaluronidase PH20]. They are large phase III studies, and we’ll also see a lot of movement around the whole question of what PARP [poly (ADP-ribose) polymerase] inhibitors add in terms of value to pancreatic cancer. Specifically, 1 study, a large study, the POLO trial, will hopefully report in 2019 and will help us understand the role of maintenance following FOLFIRINOX in patients with BRCA, so BRCA1 and BRCA2 mutations.

So I think, you know, we will see, I suspect, we will see some movement forward by the end of 2019 and hopefully by early 2020.

Davendra Sohal, MD, MPH: The natural history and biology of advanced pancreatic cancer and pancreatic cancer in general have been helped greatly with next-generation sequencing using genomic methods and molecular techniques. So we are learning quite a lot. We are learning about the biology and the natural evolution of pancreatic cancer, how there’s a lag time between the initiation of disease in the pancreas to the clinical evidence of disease in the patient. We are learning about the genomic makeup of the tumor. There are some actionable alterations that have emerged: microsatellite instability, for example; the deficient DNA repair pathways, for example; actionable fusions such as NTRK, etc.
But still, unfortunately, this constitutes only about 1% to 2% of all cases of pancreatic cancer. We still have a long way to go in terms of finding molecular targets that are actionable in terms of making a clinical difference for patients.

We certainly need a lot more in terms of predictive biomarkers in pancreatic cancer. Right now there’s nothing—there’s nothing prognostic or predictive, really. Nothing that changes a patient’s management for us. As I mentioned, microsatellite instability, deficient DNA repairs, some targetable fusions, molecular fusions in pancreatic tumors are potentially meaningful biomarkers where we can select treatments based on these. But again, these are single digit, 1% to 2% of all patients. For most patients, we sorely need either a blood-based, or a tissue-based, or a genomic-based biomarker to be able to better predict who should get what.


Transcript Edited for Clarity
 
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Transcript: 

Davendra Sohal, MD, MPH:
We’ve certainly made a lot of progress in advanced pancreatic cancer over the last 5 to 7 years or so. It started with FOLFIRINOX, the triple-drug regimen of 5-fluorouracil, irinotecan [hydrochloride, leucovorin calcium], and oxaliplatin, for treatment and was followed by gemcitabine and nab [albumin-bound] paclitaxel combination. So those have improved our outcomes that we see in the clinic. It used to be barely 6 months with gemcitabine alone, and now we are approaching a median overall survival of close to 1 year with these aggressive regimens. And these have also opened up avenues for treatment advancements in the adjuvant and neoadjuvant settings as well.

Tanios Bekaii-Saab, MD: Things have changed quite meaningfully and significantly over the last, I’d say, 10 to 20 years in pancreatic cancer. In fact, over the last 2 decades, we’ve seen significant improvement in a disease where the 5-year overall survival rate for all stages was less than 4%. We’re getting close to the double digits. We’re not there; we’re about 8% to 9% and every year improving. Now, that may not seem like a lot because we’re still not doing as well as we should with respect to other cancers, but this is doubling, more than doubling, the 5-year survival rate. And most of it has happened over the last 4 to 5 years.

The year 2018 was a good year, mostly for the early stage pancreatic cancers where we’re starting to learn a little bit more about these strategies regarding neoadjuvant therapy, intensifying adjuvant therapy. Survival in the adjuvant, in the early stage setting, is now close to 50 to 60 months, whereby for the longest time it wouldn’t budge beyond 20 to 25 months. And a lot of it has to do not just with how well we’re doing before and after surgery, but it also has to do with the salvage component. We have more options, you know, with nab-paclitaxel, with nonliposome, irinotecan, with FOLFIRINOX. A lot of these salvage strategies have also helped improve significant survival.

The other component is, of course, we’re understanding a little bit better the whole genetic and genomic landscape around pancreatic cancer. And we’re starting slowly but surely, in very small subsets of patients who understand what makes sense and what doesn’t make sense and how we target them better. We’re still away from getting where we want to be, but I think we’re on the right track.

I think that train that left the station awhile ago and has accelerated through 2018 will continue accelerating through 2019. We expect more data about perioperative treatment on the earlier stages. We also expect 2 major studies, phase III studies, to close down in early 2019 or late 2019. We may not have results before the end of the year or by 2020, but there will be 2 major achievements, 2 large studies in pancreatic cancer—1 with a stem cell inhibitor, napabucasin, and the other one with a PEGPH20 [pegylated recombinant human hyaluronidase PH20]. They are large phase III studies, and we’ll also see a lot of movement around the whole question of what PARP [poly (ADP-ribose) polymerase] inhibitors add in terms of value to pancreatic cancer. Specifically, 1 study, a large study, the POLO trial, will hopefully report in 2019 and will help us understand the role of maintenance following FOLFIRINOX in patients with BRCA, so BRCA1 and BRCA2 mutations.

So I think, you know, we will see, I suspect, we will see some movement forward by the end of 2019 and hopefully by early 2020.

Davendra Sohal, MD, MPH: The natural history and biology of advanced pancreatic cancer and pancreatic cancer in general have been helped greatly with next-generation sequencing using genomic methods and molecular techniques. So we are learning quite a lot. We are learning about the biology and the natural evolution of pancreatic cancer, how there’s a lag time between the initiation of disease in the pancreas to the clinical evidence of disease in the patient. We are learning about the genomic makeup of the tumor. There are some actionable alterations that have emerged: microsatellite instability, for example; the deficient DNA repair pathways, for example; actionable fusions such as NTRK, etc.
But still, unfortunately, this constitutes only about 1% to 2% of all cases of pancreatic cancer. We still have a long way to go in terms of finding molecular targets that are actionable in terms of making a clinical difference for patients.

We certainly need a lot more in terms of predictive biomarkers in pancreatic cancer. Right now there’s nothing—there’s nothing prognostic or predictive, really. Nothing that changes a patient’s management for us. As I mentioned, microsatellite instability, deficient DNA repairs, some targetable fusions, molecular fusions in pancreatic tumors are potentially meaningful biomarkers where we can select treatments based on these. But again, these are single digit, 1% to 2% of all patients. For most patients, we sorely need either a blood-based, or a tissue-based, or a genomic-based biomarker to be able to better predict who should get what.


Transcript Edited for Clarity
 
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