Chemo Selection in Metastatic Pancreatic Cancer Continues to Evolve With KRAS-Targeted Therapies on the Horizon

As targeted therapies such as daraxonrasib (RMC-6236) and other KRAS inhibitors are evaluated in clinical trials, frontline treatment selection for patients with advanced pancreatic ductal adenocarcinoma (PDAC) require considerations of patient and disease factors to inform chemotherapy selection, according to Jennifer B. Valerin, MD, PhD, who also noted that clinical trial enrollment remains a critical option in the frontline setting.

In an interview with OncLive^®, Valerin broke down current approaches for frontline chemotherapy selection for patients with PDAC; how she approaches selecting a standard-of-care (SOC) approach vs a clinical trial for a given patient; and how targeted therapies such as daraxonrasib are already affecting the pancreatic cancer field.

Valerin is an assistant professor in the Division of Hematology/Oncology of the Department of Medicine at the University of California Irvine (UCI) School of Medicine.

OncLive: What are some of the considerations when selecting between approved regimens in the frontline setting for patients with advanced PDAC?

Valerin: By the book, if we're talking about what's currently FDA approved, the main choices that we typically have are chemotherapy-based. In patients whose performance status is not as great, we usually give single-agent gemcitabine, or if patients have a better performance status, we usually choose between triplet therapy, which would be 5-fluorouracil [5-FU], irinotecan, and oxaliplatin, or gemcitabine [plus] nab-paclitaxel [Abraxane].

However, being a pancreatic cancer doctor, and knowing that, at least at the present moment, our 5-year survival is only approximately 13%, my go-to is always a clinical trial. At UCI and at other institutions, we have several different available studies in the first-line, including KRAS inhibitors or other agents. [A clinical trial] is usually the thing that I choose in order to serve a patient and hopefully keep patients off chemotherapy if we can, or at least provide rational combinations to patients to have better outcomes.

What are the patient goals and other factors you use to determine if patients are ideal candidates to enroll in a clinical trial?

A lot of these trials are biomarker-driven, so for the most part, it is SOC to do next-generation sequencing [NGS] for these patients. Frequently, we'll do that through liquid biopsy, just because the turnaround time is closer to 10 days, and you don't want to be waiting 4 to 6 weeks to get a full NGS panel on a patient who has a biopsy. Most of the time, I place patients on a study based on whether they qualify for that study and if they have the target of the agent. Additionally, I think about the patient's performance status. Are they fit enough to go on to a clinical trial? Knowing what some of the [adverse] effects associated with the various different studies [is also helpful]. Then I'll make a determination [based on those factors].

For example, right now we have a [phase 2/3] study [NCT06989437] looking at patients with [pancreatic cancer] and cancer cachexia [to help determine] if [cachexia] is a big component. It's common for patients to come to me and say that they've lost 50 pounds prior to the diagnosis, so [ponsegromab] might be an agent that I would put the patient on.

However, universally, I'm usually offering patients more than what we have for SOC, because, unfortunately, we know where SOC is going to get these patients. Additionally, non-chemotherapy options are great for patients because it preserves the rest of their organ function, even though we know that all of these things are not curative. Eventually, these patients are going to end up on chemotherapy, but if we can give them options that are non-chemotherapy to prolong their life, then that's usually the selection. A lot of these studies, especially with the KRAS inhibitors, because they have such great responses—the disease control rate we think is somewhere around 85% to 90%—we know that at least their disease will remain stable or shrink, and it kind of resets the clock for these patients.

For the patients who do ultimately proceed with SOC chemotherapy in the first-line setting, what are the factors that drive regimen selection?

There's a lot of debate right now about the benefit of NALIRIFOX [irinotecan liposome (Onivyde) plus oxaliplatin, 5-FU, and leucovorin] over FOLFIRINOX [leucovorin, 5-FU, irinotecan, and oxaliplatin]. The thing that we've seen that's most important is a little bit higher of a response rate [with NALIRIFOX]. Even in some patients, who, for example, aren't necessarily metastatic but are locally advanced, and we are still trying to get that 20% or so to surgery, then I absolutely reach for NALIRIFOX. It makes it a little bit difficult in patients who have metastatic [disease], because there's also data based on the [phase 3] NAPOLI-3 study [NCT04083235], that you can actually re-challenge patients in the second line with liposomal irinotecan.¹

Since [pancreatic cancer] is not like other cancers where we have 10 options for these patients, you have to be strategic about who you're placing on what [treatment] at different time points of their disease. Going back to liposomal irinotecan, we don't really know whether somebody who has already seen regular irinotecan will have added benefit [with the liposomal formulation]. Again, that comes to the art of oncology, [where we try to make] the best decision for patients, thinking of both the short- and long-term goals.

What role do you ultimately see daraxonrasib and other targeted therapies playing in the treatment paradigm?

What I see [targeted therapy] as is like kind of resetting the clock. [Recently,] I had a patient who had already had surgery, had already been treated in the adjuvant setting, and then in the first-line metastatic setting, I put him onto a KRAS inhibitor—it wasn't with daraxonrasib, but another KRAS inhibitor. This patient had been on [treatment] for approximately 9 or 10 months, and then eventually, unfortunately, progressed like most or all patients will. He's in clinic on chemotherapy, and we've finally hit a sweet spot where he's tolerated the medications well.

However, he was just so upset with me the other day in clinic because he said he was living his life [while receiving the KRAS inhibitor], doing all the things that he wanted to do. He was just taking a pill, and even just from a quality-of-life standpoint, that was important. I do still firmly believe, even if he progressed, at least we gave him some quality time over that short period of time in order for him to be able to get other additional therapies, whereas, a large portion of patients with pancreatic cancer are not going to even make it to the second- or third-line. That's why [targeted therapies] do influence the trajectory, regardless of whether they're going to provide a cure.

Given all the research and time poured into developing improved treatment options for patients with pancreatic cancer, what has the emergence of KRAS inhibitors and their potential effect on the field meant for you and colleagues?

I came into this field about 20 years ago, because my aunt was diagnosed with pancreatic cancer. I was with her from when she was diagnosed until the day that she died, and I remembered frantically looking on ClinicalTrials.gov for solutions for her, and she just never qualified. The first patient who I ever treated on a KRAS inhibitor [was] actually with daraxonrasib on the [phase 1/2] second-line study [NCT05379985] that was just recently published.² That patient was on all sorts of pain medications. She was in bad shape, and she likely would have passed away within a couple of months. Within the first 10 days that she came to me, she told me just haphazardly that she started to forget taking her pain medication, and the hairs on my arm raised. A single tear dripped down my face, and she said, 'Are you crying, Dr. Valerin?' I told her, 'You have no idea how important this is,' because I saw a change that I had never seen in any other patient who I had treated before. I knew that this was a huge breakthrough, and there's so much joy and elation with that, because for a long time treating this disease, you can feel like just a glorified hospice doctor. In patients who have metastatic disease, only approximately 3% will actually survive 5 years. This has been such a huge breakthrough and a great feeling.

This is a stepping stone for us. We're going to come up with more rational therapies, consider combination with other targeted therapies, and consider immunotherapy for these patients—whatever we can do to push the envelope, even if it's slowly notching up the survival. What I foresee us doing in the future is using [targeted therapy] in the neoadjuvant setting for patients who we want to go to surgery, or in the locally advanced setting to convert more than the 20% of patients [who are eventually able to undergo surgery]. That's where we're going to make the biggest impact, and all of those things are coming down the pipeline. I'm just excited to see what happens.

References

1. Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023;402(10409):1272-1281. doi:10.1016/S0140-6736(23)01366-1
2. Wolpin B, Park W, Garrido-Laguna I, et al. Dara­xon­rasib in previously treated advanced RAS-mutated pancreatic cancer. N Engl J Med. 2026;394(18):1790-1802. doi:10.1056/NEJMoa2505783