Biomarker Testing, Targeted Agents May Impact RAS+ Pancreatic Cancer Care

Shubham Pant, MD, MBBS

The University of Texas MD Anderson Cancer Center

Gastrointestinal Editorial Advisory Board Member for ONCOLOGY

Once considered an “undruggable” target, research focused on the RAS mutation has opened the door for new therapeutic strategies that may have an impact on the lives of patients with pancreatic cancer, according to Shubham Pant, MD, MBBS.

In a conversation with CancerNetwork^® ahead of the 15th Annual Ruesch Center Symposium, Pant, a professor in the Department of Gastrointestinal Medical Oncology with a joint appointment in the Department of Investigational Cancer Therapeutics (Phase I Center) at The University of Texas MD Anderson Cancer Center, and gastrointestinal editorial advisory board member for ONCOLOGY, spoke about his presentation highlighting ongoing initiatives and potential next steps in RAS-mutated pancreatic cancer research.¹

Pant emphasized the use of next-generation sequencing and mutation testing among most patients with advanced pancreatic cancer, which may inform treatment strategies involving targeted therapy agents. Regarding potential advancements in novel treatment modalities, he described how pan-RAS inhibitors such as RMC-6236 and RAS-directed vaccination may improve outcomes across this population.

“What I hope my colleagues take away [from the presentation] is that there’s a lot of hope in the future,” Pant stated. “Pancreatic cancer, normally, has been a tough and devastating disease. Survival has not budged a lot; it has done a bit, but not a lot, only in single digits in the last decades. I truly think this is the moment in which we’re getting newer therapeutics that can have an impact on our patients’ lives. I hope they take away some hope from this presentation.”

CancerNetwork: What was the basis for this research focused on RAS mutations in pancreatic cancer at this year’s Ruesch Center Symposium?

Pant: I’m excited about the Ruesch Symposium this year. About a decade back, we did not have anything to target RAS mutations, and the RAS mutation was called undruggable. However, we first had the KRAS G12C inhibitors, which were mostly in lung and colorectal cancer. Now we have other inhibitors called pan-RAS inhibitors that can target pancreatic cancer. It’s an exciting time in this field.

How important is it to conduct biomarker testing among patients with pancreatic cancer? What do current testing strategies entail?

It’s important. I think all patients with metastatic pancreatic cancer or advanced pancreatic cancer should undergo mutation testing or next-generation sequencing testing. The important thing is that [after] you find these RAS mutations, you can look for clinical trials for your patients. Some patients also have other mutations like BRCA1/2, which there’s an approved drug for that called olaparib [Lynparza]. They can also have KRAS wild type [disease]. Then there are other fusions that patients with pancreatic cancer can have, like RET fusions, microsatellite instability–high [disease], and NTRK fusions. The thing is, if you don’t look, you won’t find them. You need to look. I would say the majority of the patients [with advanced disease], if possible, should get this next-generation sequencing.

What are some currently available treatment regimens for patients with RAS-mutated disease? How effective are they in treating this patient population?

For RAS-mutated disease, we don’t have any approved agents as of now. We do have a lot of RAS inhibitors, which are in clinical trials. One RAS inhibitor is called RMC-6236, it’s something called a RAS(ON) inhibitor. It inhibits RAS in its ON phase, and that has now quickly gone to a randomized phase 3 trial called RASolute 302 [NCT06625320] in the second line setting in pancreatic cancer vs standard of care.² We’re hoping to see advances quickly in this disease.

What we’re seeing with these pan-RAS inhibitors, specifically RMC-6236, has response rates in the second line setting of up to 30%, which is an improvement over our classic chemotherapy, which is [approximately] 10% to 15%.³ We’re also seeing an improvement in progression-free survival. In a single-arm study, results that were reported showed a progression-free survival north of 8 months. Normally, the progression-free survival, with regular chemotherapy, is [approximately] 3.1 months. Hopefully, we’ll find out what happens in a randomized setting. This was a single-arm study, but they were encouraging data.

What are the next steps for research related to RAS mutations in the pancreatic cancer field?

This is an exciting time for research with RAS. Another thing I’m going to talk about [during my presentation] is RAS-directed vaccines. Patients who have early pancreatic cancer post-resection and post-adjuvant chemotherapy can still have a 50% to 70% chance of the cancer coming back.With this new wave of RAS-directed vaccines, we’re trying to decrease the chances of the cancer coming back. That would signify a true cure for these patients; their cancer doesn’t come back. I’m going to discuss a little bit about this new and exciting phase of drug development in pancreatic cancer [during my presentation].

References

1. Pant S. Targeting the RAS mutation in pancreatic cancer. Presented at the 15th Annual Ruesch Center Symposium; November 21-23, 2024; Washington, DC.
2. Phase 3 study of RMC-6236 in patients with previously treated metastatic pancreatic ductal adenocarcinoma (PDAC) (RASolute 302). ClinicalTrials.gov. Updated November 18, 2024. Accessed November 26, 2024. https://tinyurl.com/3hhw5rr8
3. Revolution Medicines presents updated data from RMC-6236 monotherapy study in patients with advanced pancreatic ductal adenocarcinoma. News release. Revolution Medicines, Inc. October 23, 2024. Accessed November 26, 2024. https://tinyurl.com/mtx57rs4