Andrew Hendifar, MD, on Developing Targeted Approaches in Pancreatic Cancers

Findings from a retrospective case series analysis on real-world outcomes with targeted and standard therapies in RAF altered pancreatic cancer indicated that further examination of RAF-directed therapies is warranted in this population, according to Andrew Hendifar, MD.

Of the 81 patients with RAF family–mutated pancreatic cancer who were included in this case series, 21.0% had a BRAF V600/Exon 15 mutations without any confounding drivers, 30.9% had BRAF or RAF1 fusions, 22.2% had Exon 11 mutations, and 25.9% had atypical RAF variants or multiple oncogenic drivers. Of the 3 patients in the V600E-mutant subgroup who were treated with BRAF, MEK, or ERK inhibitors, all derived clinical benefit, as well as those with fusions (n = 4/6) and Exon 11 mutations (n = 2/6). No patients with confounding drivers achieved benefit (n = 0/3).

“We do know that there is this distinct group of patients with BRAF-mutated pancreas cancer in retrospective cohorts who have responded to targeted therapy,” Hendifar explained in an interview with CancerNetwork® Pancreatic Cancer Awareness Month. “For pancreas cancer, that's a big deal.”

In the discussion, Hendifar, the medical director of pancreas cancer at Cedars Sinai Medical Center, emphasized that although only a small subgroup of patients currently stand to benefit from a targeted approach, the number of patients is growing and the approach remains important.

Could speak to the rationale behind assessing real-world outcomes with targeted and standard therapies in patients with pancreatic cancer and RAF alterations?

We were involved in a nationwide project to do next-generation sequencing for patients with pancreatic ductal adenocarcinoma in what is known as a Know Your Tumor Program. It was done with Perthera and the Pancreatic Cancer Action Network [PanCAN]. When we started sequencing patients, it was probably at a time where it wasn't necessarily being reimbursed, it was kind of experimental and PanCAN, agreed to foot the bill. We went full speed ahead with this effort, and a lot of the things we were getting were those that were expected, which was KRAS-mutated pancreas cancer. We started to see a signal in a small group of patients [who] had KRAS wild-type tumors. Within that group of KRAS wild-type tumors, the biggest collection of tumors happens to have BRAF alterations. That's when our interest was piqued, and we started to collect these patients to try to understand what was going on.

Based on that information from the Know Your Tumor paper, we found that there are basically more or less 4 different types of groups of BRAF alterations. Some of those are V600E, fusion abnormalities, insertion deletions, and there are other types as well. These can be classified in different ways, especially by BRAF scientists. Armed with that information, we really knew what we were looking for. We went around the country to all these major medical centers, and we asked for them to collect all their retrospective data for those [who] had these data available. We were able to collect a lot of information from a lot of great medical centers, and then we compiled this information together for BRAF-altered pancreas cancer. What we found was that, not only is this a distinct subtype of pancreas cancer, but we don't have enough information to really say that there are clinical differences in the presentation or the outcome, or the disease itself.

What about these results are significant for pancreas cancer space?

It really establishes that a targeted therapy approach in KRAS wild-type tumors can be beneficial for our patients. Going forward, we're going to be doing prospective work in this cohort of patients. It's a rare group, which is the only caveat, but we will be collecting data prospectively. We have a clinical trial for V600E-mutated pancreatic cancer that's enrolling now nationally. We want to establish this as an approach for our patients. We want to bring molecular sequencing and testing into the mainstream, and we want to have an NCCN-approved targeted regimen outside of olaparib (Lynparza) for BRCA-mutated germline patients. These are some of the first steps that we're making [towards] a personalized approach for pancreas cancer. At the current time, I have to concede that the majority of patients aren't eligible for a personalized therapeutic approach, but we should not forget those who might be, and we should pursue that as much as we can.

Was there anything that you found to be significant in relation \ to clinical outcomes for the patients who were analyzed?

The novel things that we did find were that BRAF mutations occur almost exclusively in those [who] are KRAS wild-type. That's an important principle in V600E mutations, fusion abnormalities, as well as indels, and insertion deletions, we seem to be able to find some activity. We saw activity in those cohorts, and definitely the kind of activity that would warrant further prospective studies.

What were some of the limitations of this study’s retrospective design and how might future prospective studies poentially address this in the future?

That's a great point. The limitations of the retrospective design are that we basically are cherry picking patients because what's memorable to most practitioners are patients [who] have done well, and patients [who] have met certain criteria. Those patients’ data tend to be collected more than other types of patients. Other potential biases are that the group of patients are not homogenous. They received BRAF-directed therapy at different stages in their cancer treatment, and not necessarily in a uniform way. These biases add up so that it's hard to say definitively that the therapies are actually able to improve outcomes in these patients. However, in a prospective design, those limitations can be addressed quite effectively. We can really say that in a refractory patient population, these therapies have value.

Where should future research efforts be focused from here?

Right now, there's the ongoing [phase 2] BrafPanc clinical trial (NCT04390243) through [Academic and Community Cancer Research United], which is a national clinical research organization. Right now, we have 7 sites open nationally, [and] we have already 3 patients enrolled. This is a prospective trial looking at binimetinib (Mektovi) and encorafenib (Braftovi) for patients with V600E-mutated pancreatic cancer who have progressed on 1 line of therapy.

There are other studies, though, that are looking at second generation BRAF inhibitors, specifically those in classes type 1 and type 2. Again, this is a different classification and it's hard to know how these classifications translate across tumor types, but anyone who's looking at BRAF inhibition should consider [patients with] pancreatic cancer as a cohort in their trials. I think that has a lot of promise for these patients, and it's something that needs to be explored further.

What should the field know about the current state of precision medicine for patients with pancreatic cancer?

What is interesting about precision medicine for pancreas cancer is that the deeper we dig, we are finding little kernels of truth and importance here. We are certainly dividing off these patients into slices. The slices are small, but they are accumulating. We have NRG fusions being targeted in pancreas cancer, we have [microsatellite instability]–high being targeted in pancreas cancer, [and] BRAF abnormalities. There are many more that I'm not even mentioning. Slowly but surely a targeted approach does have importance in this disease and specifically in the KRAS wild-type population. In those KRAS wild-type tumors, we have to be vigilant in order to find the drivers and to target them appropriately.

Reference

Hendifar A, Blais EM, Wolpin B, et al. Retrospective case series analysis of RAF family alterations in pancreatic cancer: real-world outcomes from targeted and standard therapies. JCO Precis Oncol. 2021;5:1325-1338. doi:10.1200/PO.20.00494

For additional interviews with leaders in the treatment of pancreatic cancer, see other CancerNetwork® interviews conducted for pancreatic cancer awareness month:

Using Genetic Predispositions to Determine the Likelihood of Being Diagnosed With Pancreatic Cancer”