Dr Shubham Pant Highlights Progress and Promise in Pancreatic Cancer Treatment

Pancreatic cancer remains one of the most aggressive and challenging malignancies to treat, with limited effective options and historically poor outcomes. While chemotherapy is the predominant approach by current treatment standards, recent advances in targeted and precision therapies are beginning to shift the landscape. During Baptist Health Miami Cancer Institute’s fourth annual Precision Oncology Symposium, Shubham Pant, MD, reflected on these strides in pancreatic cancer treatment across approved regimens and an expanding pipeline of investigational agents.

Ahead of the symposium, Dr Pant, professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, shared with Targeted Oncology some of the most promising agents gaining ground—from RAS inhibitors to therapies targeting MTAP and claudin expression—and underscored the value of next-generation sequencing to guide patients toward this growing breadth of personalized options.

Targeted Oncology: How would you characterize the current treatment landscape of pancreatic cancer?

Shubham Pant, MD: The current treatment of pancreatic cancer is mostly chemotherapy-based. We recently had a phase 3 trial of NALIRIFOX [NAPOLI 3; NCT04083235] which is compared [with] gemcitabine and [nab-paclitaxel]. Patients [receiving] NALIRIFOX had a 2-month overall survival benefit [vs] gemcitabine and nab-paclitaxel. This was a global trial. But now, we are looking beyond chemotherapy in a way — we are looking at KRAS inhibitors and other inhibitors called MTAP and targeting claudin in pancreatic cancer.

Regarding KRAS inhibitors, there has been some progress with KRAS G12C inhibitors; however, this only represents a small proportion of patients. What other RAS-targeted therapies are currently on the horizon?

I'm talking about all of them in this symposium. We're talking about the pan-RAS inhibitors; the one… which has data is a drug called daraxonrasib or RMC-6236. We recently wrapped up the phase 3 trial in second-line pancreatic cancer [RASolute 302; NCT06625320] in which patients received chemotherapy, which is investigator’s choice vs daraxonrasib. Th[ose] data [are] awaited; hopefully we'll get it sometime this year.

I'm also going to discuss KRAS G12D-targeted agents, which is 40% of patients with pancreatic cancer. The drugs I'm going to discuss are RMC-9805, or zoldonrasib, which is a small-molecule oral agent... it's a RAS(ON) agent. Then I'm also going to discuss another molecule by a company called Incyte [INCB161734], which is an ON/OFF inhibitor, and then also discuss PROTAC inhibitor[s] which degrade a protein… also in clinical trials. Multiple KRAS G12D agents are out there, and those clinical trials have been reported. Really exciting times.

In terms of the challenges in treating pancreatic cancer, many attribute resistance to the dense stroma of tumors. Are you seeing promise in some of these agents with regard to penetrating this stroma?

So desmoplastic stroma, it's something that we discussed ad nauseam before, but we are seeing good responses with even single-agent pan-RAS inhibitors. So maybe these RAS inhibitors are really disrupting the desmoplastic stroma and getting to the tumor cells, and that's what we are seeing. So hopefully, we found a way to… really attack the cancer cells after breaking through the desmoplastic stroma.

What are your big takeaways or advice for those in the community who are treating these patients?

My big takeaway is that they should do the next-generation sequencing on patients with pancreatic cancer, because though chemotherapy is a standard of care right now, that's changing rapidly, and we have a number of clinical trials available for our patients… We have RAS inhibitors. We also have PRMT5 inhibitors target[ing] MTAP deletion, which we can find on next-gen sequencing. And then we also have clinical trials [for agents] targeting claudin, which is actually a target [where] there's an approval in gastric cancer. We're looking at different claudin antibody–drug conjugates for patients with pancreatic cancer also, because patients [with pancreatic cancer] also express claudin in a large number.