Beyond Chemotherapy: Targeting RAS in Metastatic Pancreatic Cancer

Shubham Pant, MD, discusses treatment considerations for a patient with KRAS G12D–mutated metastatic pancreatic adenocarcinoma following progression on first-line chemotherapy.

In this video, he highlights the importance of clinical trial enrollment and explores emerging pan-RAS and KRAS G12D–targeted therapies as potential options. He also examines how advances in RAS inhibition may reshape the treatment landscape for pancreatic cancer.

Transcript: 

Hi, I'm Dr. Shubham Pant. I'm a professor of GI Medical Oncology at MD Anderson Cancer Center in Houston, Texas. I'm going to talk about a case of metastatic pancreatic adenocarcinoma. 

This is a case of a 62-year-old man who presented with metastatic adenocarcinoma of the pancreatic body with biopsy-confirmed liver metastases. The patient started first-line chemotherapy with gemcitabine and nab-paclitaxel. 

Initially with his first few scans, he had stability, but restaging scans showed increasing liver lesions. And there was also a dominant liver lesion growing from 1.2 centimeters to 4.2 centimeters. In addition, he had a rise in his CA-99 from 103 to 8530. The ECOG is 1, liver enzymes and other labs are within normal limits. Somatic NGS identified a KRAS G12D mutation with a TP53 mutation. 

Our question is, given this patient's progression on first-line chemotherapy and his KRAS G12D mutation, what is the most appropriate next step in management? A, switch to second-line FOLFIRINOX; B, continue gemcitabine nab-paclitaxel at a reduced dose; C, enroll in a clinical trial of a pan-RAS inhibitor; or D, refer directly to hospice given the aggressive disease biology. And the answer, which would be the most appropriate, I think would be C, try to enroll in a clinical trial of a pan-RAS inhibitor. And I'll tell you why. 

First of all, we should always look for clinical trials for our patients, any appropriate clinical trials that they can get on, because with chemotherapy, again, the survival is about 6 months in second-line metastatic pancreatic cancer. 

Now, recently, we've had some data come out about pan-RAS inhibitors, which is not yet FDA approved. This data came out at ASCO, which was on a pan-RAS inhibitor called daraxonrasib in a phase 3 trial called RASolute 302. On this trial, patients were randomized to daraxonrasib versus any standard of care chemotherapy, which was the investigator's choice. Daraxonrasib almost doubled the survival in this setting. 

Right now, it's under consideration with the FDA for approval. We've seen these pan-RAS inhibitors really shift the therapy for patients with pancreatic cancer. 

As a reminder, 90% of patients with pancreatic cancer have a RAS mutation.  In this case, our most appropriate would be to try to find a clinical trial of a pan-RAS inhibitor or for a KRAS G12D inhibitor. Both are very appropriate. That would be our choice because these new targeted therapies are truly changing the landscape of pancreatic cancer. 

I hope you like that question and that explanation. Thank you so much for listening.