Targeted Therapies Remain Central to Ongoing Research in Pancreatic Cancer

During an X (Twitter) takeover of the OncLive^® social media account in honor of Pancreatic Cancer Awareness Month, Suneel Kamath, MD, highlighted the ongoing push to integrate more targeted therapies, particularly RAS inhibitors, into the pancreatic cancer treatment paradigm.

Following the social media takeover, Kamath sat down with OncLive in an interview to detail the intricacies of the pancreatic cancer treatment landscape. He discussed the integration of next-generation sequencing (NGS) into practice, ongoing work with RAS inhibitors, and other potential targeted therapies that could impact the treatment space. Kamath is an assistant professor of medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Ohio.

Want to hear more from Dr Kamath? Check out our previous article, in which he discusses the evolution of this disease.

OncLive: How has the incidence of pancreatic cancer evolved in recent years?

Kamath: In pancreatic cancer, we are seeing [increases in] young-onset [incidences of this disease], especially for the youngest patients in the 15-to-34-year age range. Sadly, we have seen multiple teenagers develop this cancer. We still need to investigate more into why that's happening. This is not just something [that is occurring] in colorectal cancer [CRC]; we are seeing it in pancreatic cancer as well, and for whatever reason, it seems to be affecting women more so than men in that earliest age group. We have a lot to learn about that, but this is an important thing for people to be aware of.

That idea that people can be too young to develop cancer is not true. Therefore, I hope we in the medical community remain aware and have a high suspicion [about the possibility of cancer], even in the younger person, because early detection and diagnosis can make all the difference.

In the X Takeover, you mentioned the agent RMC-9805. What is important to note about the trials evaluating this agent?

This is a drug to keep an eye on in the future. It's further along than many other [novel RAS inhibitors] in the pancreas cancer space, and it [represents] an interesting way to target RAS. What Revolution Medicines has done with this drug—and a few others that are also developing—is largely targeting the RAS mutation when it's in its 'on' or activated position. The thinking is that one potential resistance mechanism [for RAS inhibitors] is the tumor learning to turn the mutation into the 'off' position, but it may still be active. [RMC-9805] is [intended to] lock the RAS mutation into that 'on' position and then inhibit it, preventing that resistance mechanism. [RMC-9805] is [a selective] KRAS G12D inhibitor, which is the most common [KRAS mutation in patients with pancreatic cancer, appearing in] approximately 40% of patients.

The early data for this were promising. There were [data for] 40 patients with pancreatic cancer presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in October.[Investigators] looked at the original 40 patients; 12 had responses, [translating to] a 30% overall response rate [ORR], which is good. If you think about a phase 1 population with pancreatic cancer, [where] patients have had multiple lines of therapy and have highly resistant disease, [these are good outcomes]. Anything ORR that starts with a '3' in that setting stands out. Also, the [sample size] was pretty decent for a phase 1 study. It is not [common] that you'll get phase 1 trials with that [large of a population of] patients. Additionally, the disease control rate was 80%; only 8 patients had a best response of progressive disease, which is good.

[RMC-9805] is in phase 1 [testing], but we are excited to see what this drug might be able to do in phase 2 and 3 trials. We are also excited to bring it earlier in the [treatment] journey. All of these patients [treated in the phase 1 trial] had at least 2 prior lines of therapy, so [these responses] were in the third-line and beyond; I would expect a higher ORR and greater activity if you [gave RMC-9805] up-front or in the second-line setting.

This agent also had a pretty good toxicity profile. It seems like there were a lot of gastrointestinal [GI] adverse effects [AEs] including nausea, diarrhea, and rash, but [most were] low grade at 1 or 2, with very few grade 3 or higher AEs. There was also no treatment-related discontinuation.

What is the importance of targeted therapy and NGS for patients with pancreatic cancer?

NGS testing is important in this disease. Although current actionable mutations [with approved therapies] are relatively uncommon, the therapies that we have for those are quite effective. The great thing is [some targeted therapies] have tissue-agnostic approvals, such as BRAF-targeted therapy, RET-targeted therapy, and microsatellite instability–high tumors; the NRG1 fusion is not targetable just yet with an FDA-approved therapy, but we're expecting [zenocutuzumab (MCLA-128)] will probably get approved sometime within the next year. We know that most [patients with pancreatic cancer] are going to [harbor] RAS mutations, which is good to know. If you didn't find a RAS mutation, you want to make sure you're looking for other targets.

With KRAS and the other [alterations] out there, like MTAP deletions and PTEN loss, we have to keep finding these alterations and understanding which ones are associated with tumor biology. That's how we find new therapies. If we know something is there, we know to start working on pharmacology for that particular target.

A lot of patients with pancreatic cancer are, unfortunately, still getting fine needle aspirations [FNAs] of their tumors. You're often not able to get NGS testing off of those. You're either faced with rebiopsying something if you can, or [getting a] liquid biopsy. [Liquid biopsies] are a nice backup to get NGS testing from the blood without subjecting someone to another biopsy. I try to get both circulating tumor DNA via liquid biopsy and a tissue-based NGS in everybody at least once, to make sure that we've looked for any possible actionable mutation.

Talk with your GI oncologists about their practice patterns. If you suspect pancreatic cancer, get a fine-needle biopsy instead of an FNA. At Cleveland Clinic, fortunately, we have been doing that for quite some time, and it's been a huge help to us. We can often get NGS testing now; that's something we can do as medical oncologists to make sure there's sufficient tissue to do this testing.

Reference

Revolution Medicines presents initial data from RMC-9805 monotherapy study in patients with advanced pancreatic ductal adenocarcinoma. News release. Revolution Medicines, Inc. October 25, 2024. Accessed October 28, 2024. https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-initial-data-rmc-9805-monotherapy