Molecular Testing Helps First-Line Treatment Landscape Evolve in Pancreatic Cancer

Tanios S. Bekaii-Saab, MD

Along with helping select a preferred chemotherapy regimen for a select group of patients, molecular testing has helped shape treatment decisions in advanced pancreatic cancer, according to Tanios S. Bekaii-Saab, MD, who added that the continued development of RAS inhibitors could increase the importance of genetic testing for this patient population.

“The future for pancreatic cancer is looking much brighter than the past. Five to 7 years ago, pancreatic cancer was considered a desert for targeting,” Bekaii-Saab said in an interview with OncLive^®. “Today, it's more target-rich. [This testing has given us] a better understanding of how to use some of the chemotherapy [strategies], some strategies to target RAS and other alterations, and how to take advantage of the small proportion of patients who could be candidates for immune-oncology [IO]–based therapy."

In the interview, Bekaii-Saab outlined factors for selecting a chemotherapy regimen in the frontline setting for patients with advanced pancreatic cancer, underscored the importance of molecular testing for this patient population, and explained how targeted therapies could play a bigger role in this paradigm.

Bekaii-Saab currently serves as the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research, chair and consultant in the Division of Hematology and Medical Oncology at Mayo Clinic, and co-leader of Advanced Clinical and Translational Science at Mayo Clinic Cancer Center in Phoenix, Arizona.

OncLive: What are the current treatment considerations in the first line for advanced pancreatic cancer?

Bekaai-Saab: The landscape for treating pancreatic cancer in the first-line [setting] has become a bit more complicated. We're still limited by options—primarily cytotoxic therapy—except for [patients with] microsatellite instability–high tumors, where pembrolizumab [Keytruda] or another IO-based therapy would be the standard, and that's only approximately 4.5% of the patients or less. For all other patients, the only deciding factor on what [other treatment options] to use [outside of chemotherapy] is the presence of BRCA1/2 or PALB2 mutations, which are present in approximately 2% to 3% [of patients] at the germline level and approximately another 2% [of patients] at the somatic level.

When we think about the landscape of genetic alterations in the first-line [setting], we do favor a platinum-based regimen when there are BRCA1/2 or PALB2 mutations, and that [regimen] can be FOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin]; however, [data from a phase 2 trial (NCT01585805)] from Eileen O'Reilly, MD, [of Memorial Sloan Kettering Cancer Center], [showed that] gemcitabine plus cisplatin is a preferred regimen to go with [for patients harboring BRCA1/2 or PALB2 mutations].

For the other 95% [of patients], we're currently looking at 3 options: NALIRIFOX [irinotecan liposome (Onivyde), oxaliplatin, 5-fluorouracil (5-FU), and leucovorin], FOLFIRINOX, and gemcitabine plus nab-paclitaxel [Abraxane].

Have triplet regimens proven to be more effective than doublets?

We have 2 triplet [chemotherapy regimens with NALIRIFOX and FOLFIRINOX] and then a doublet [regimen with] gemcitabine plus nab-paclitaxel. The answer for the longest time was that it's better to use a triplet because it's more aggressive, and this is an aggressive cancer. However, we have data from 2 studies—one from Japan called [the phase 2] JCOG1407 trial [jRCTs031180085], and another one called [the phase 2] PASS-01 trial [NCT04469556]—that suggest that gemcitabine plus nab-paclitaxel may do just as well or out-perform FOLFIRINOX, which was surprising.

In Japan, gemcitabine plus nab-paclitaxel is now the standard over FOLFIRINOX. PASS-01 was interesting because it excluded patients with BRCA1/2 mutations. Therefore, those patients who were highly sensitive to platinum were excluded, and it showed that gemcitabine plus nab-paclitaxel is at least as good, maybe a little bit better [than FOLFIRINOX]. [Those results] complicated the landscape a little bit, and now the thought is, [these 2 regimens] seem to be about the same.

Then NALIRIFOX entered. The [phase 3] NAPOLI 3 study [NCT04083235] looked at gemcitabine plus nab-paclitaxel vs NALIRIFOX. NALIRI [refers to] the liposomal formulation of irinotecan used in this combination [along with] a lower dose of oxaliplatin. [Prior data] suggested that it's safer to [decrease the dose of oxaliplatin] and not sacrifice outcomes.

[In NAPOLI 3, NALIRIFOX] was better than gemcitabine plus nab-paclitaxel, and that threw a wrench into the whole thinking that [these chemotherapy regimens] are similar. Now we have a study that shows a triplet is better than gemcitabine plus nab-paclitaxel.

A lot of folks will say there shouldn't be much of a difference [between] NALIRIFOX and FOLFIRINOX. The problem is that we've never compared them, and I suspect they'll never be compared head-to-head. At the same time, we have 2 studies with FOLFIRINOX and gemcitabine plus nab-paclitaxel that were negative in the sense that they didn't show superiority [for one of the regimens], and now we have another study with NALIRIFOX that did show superiority vs gemcitabine plus nab-paclitaxel.

In your eyes, have data from NAPOLI 3 made NALIRIFOX a preferred regimen?

That's a tough question. I have moved more and more toward considering NALIRIFOX; however, I haven't universally moved to it because it does have its own [unique] toxicities. It is better regarding neuropathy, but it is a little bit worse in terms of gastrointestinal toxicities, which can be tough on some older patients and even some younger patients.

In my practice, I universally use biweekly gemcitabine plus nab-paclitaxel instead of the weekly regimen. [Based on] at least most published experience, the biweekly regimen performs historically as well as the weekly regimen.

In the first-line landscape, [where] we do germline testing and somatic human profiling on everyone, if there is evidence of BRCA1/2 or PALB2 [mutation], I'm moving to gemcitabine plus cisplatin [with] the biweekly regimen. At some point, I may consider a PARP inhibitor for maintenance; however, for many patients, I have been shying away from that strategy. With biweekly gemcitabine plus cisplatin, you can extend their life, and for the complete responders, I have [seen] some good responses where I have been able to give them a holiday from any treatment.

For the rest of the patients, [frontline treatment] decisions are more] individualized. A good number of patients are still receiving biweekly gemcitabine plus nab-paclitaxel; for others, I'm starting to use more and more NALIRIFOX, and a few [still receive] FOLFIRINOX.

What roles do germline testing and somatic tumor profiling play in the treatment-selection process?

Universally, every patient [with advanced-stage pancreatic cancer] who comes to our clinic now undergoes both germline testing and somatic tumor profiling. [This testing] is important because there are a number of targets identified as important to assess in pancreatic cancer and others.

One of those [mutations] that had been considered undruggable for the longest time is RAS. RAS mutations [are] omnipresent in pancreatic cancer, where approximately 90% to 93% of patients have RAS mutations. The remaining 7% of patients are also are target rich, [where they could have alterations such as] NRG1 fusions, BRAF mutations, or HER2 mutations. [There are] other fusions, like ROS1 and NTRK fusions, that are relevant for other targeted strategies.

It's incredibly important to have this genetic profile when we think about RAS mutations. We started working with KRAS G12Cmutations and have a couple of agents that were approved for other indications, but [are also included] in the NCCN Guidelines for pancreatic cancer. I worked very closely with an agent called adagrasib [Krazati]. There's also another agent called sotorasib [Lumakras], and we've seen, at least in my experience with adagrasib and from the published data, some interesting responses for many patients. However, KRAS G12Cends up being mutated in less than 1% of all patients. Most patients will have either a KRAS G12D or G12V mutation.

There are agents being developed [specifically] targeting KRAS G12D or G12V. There are also agents being developed that target all RAS [mutations] instead of targeting only one and are making their way into the second-line [setting]. There's [the phase 1 RMC-6236-001 trial (NCT05379985)] that's looking at a compound called RMC-6236, which is a pan-RASagent.

[There are other] strategies that are looking at moving KRAS G12D–targeted agents and pan–RAS–targeted agents even further into the first-line [setting], along with exploratory studies [looking at] combinations with chemotherapy.