Exploring Targeted Therapy Options in GI Oncology

Kristin Barber, FNP-BC, AOCNP, discusses ongoing phase 1 trials aimed at targeting mutations along the MAP kinase pathway.

Despite advances in precision oncology and genomic sequencing, gastrointestinal (GI) cancers still have limited targeted therapy options.

Oncology Nursing News® recently spoke with Kristin Barber, FNP-BC, AOCNP, Huntsman Cancer Institute, about understanding the MAP kinase signaling pathway and some of the ongoing trials targeting MAP Kinase pathway mutations in GI oncology. Barber discussed some of the ongoing phase 1 trials she is participating in and how she hopes the results of these trials could change patient outcomes following targeted treatment.

Researchers know that KRAS is often displayed or mutated in a lot of GI malignancies: 90% of pancreatic cancers, 50% of colon cancers, 30% of cholangiocarcinoma, and 5% to 10% of upper GI cancers have a KRAS mutation, explained Barber.

“Previously, this mutation has been undruggable, but this is now changing,” she shared. “There was an FDA approval of a KRAS G12C inhibitor that's most commonly seen in lung cancer. We have a KRAS G12D mutation that we often see more common in pancreatic cancer. That one has not been targeted yet, but it's exciting to see that we are finally approaching these targeted therapies.”

The MAP Kinase Pathway

The MAP kinase pathway is a signaling pathway, Barber explained. “The way it works is you get external stimuli from growth factors outside of the cell. And then these growth factors will stimulate the signal through the nucleus. And then this signal is propagated downstream by phosphorylation and is what is responsible for cell survival and proliferation.”

The genetic mutations that alter the functions of these protein kinases ultimately lead to oncogenesis and promotion of cell migration and metastasis.The protein kinases involved in the pathway are RAS, RAF, MEK and ERK.

“[With] the RAS proteins, the one I talk about most commonly is the KRAS protein. We also have HRAS and NRAS and these activate the proteins in the RAF pathway,” she explained. “So, our RAF mutations are family mutations, there are ARAF, BRAF and CRAF. The most common one is the BRAF mutation that we're familiar with in both melanoma and then also in colorectal cancer. And then the RAF mutations will phosphorylate the MEK so MEK1 and MEK2 and then the MEK proteins will activate for ERK1 and ERK2.”

Trials to look for: Targeting the MAP kinase pathway and KRAS mutations

Huntsman Institute, Barber’s institution, is currently hosting some phase 1 clinical trials aimed at targeting specific mutations along the pathway. Two of these trials involve SHP2 inhibitors, a new class of drugs being evaluated both as a monotherapy and in combination with MEK inhibitors for GI cancers or cancers that have mutations in this MAP kinase pathway.

“The SHP2 inhibitor is ubiquitously expressed in cells that regulate cells survival and proliferation,” said Barber. “And then activated in that RAS, RAF, MEK, and ERK pathway. So, we found that in vivo and invitro SHP2 inhibition has impaired the proliferation of the KRAS-mutant cancer cells.”

One ongoing trial at her institution is studying the first-in-human study of the SHP2 inhibitor BBP-398 (formerly known as IACS-15509) in patients with advanced solid tumors (NCT04528836).1 Another trial is assessing SHP2 inhibitors in combination with MEK inhibitors (NCT04720976).2

“We also have phase 1 trials with the chemotherapy backbone or FOLFIRI added to the MEK inhibitor binimetinib [Mektovi]. We are evaluating patients who have patients with advanced RAS (HRAS, NRAS, or KRAS)-positive metastatic colorectal cancer (CRC) with a combination to the MEK inhibitor, MEK162, and mFOLFIRI (NCT02613650),” Barber added.3

“We are hopeful that this is going to combat some of the resistance pathways or mutations and prolong the efficacy of the FOLFIRI chemotherapy,” she explained.

Other trials of note include the Utah trial,4 which will assess ulixertinib (BVD-523) and hydroxychloroquine in patients with advanced MAPK-mutated gastrointestinal adenocarcinomas (NCT04145297), as well as a phase 1 trial examining the safety and tolerability of the MEK inhibitor, trametinib, plus hydroxychloroquine in patients with advanced pancreatic cancer (NCT03825289).5

Managing Safety

Barber noted that the SHP2 inhibitors are associated with the adverse events (AEs) typically observed in GI oncology treatments, such as diarrhea, nausea, vomiting, and cytopenia. Investigators have also seen anemia, thrombocytopenia, and neutropenia with this class of medications.

The MEK inhibitors, as well as the MEK/FOLFIRI combination are linked to AEs such as rash, dermatitis, as well as ocular toxicities like retinal vein occlusion or fluid behind the eyes.

Exciting Trial Updates

While the SHP2 inhibitor trials are still in their early stages, Barber shared that the mFOLFIRI/MEK162 combination has yielded some promising results. “These patients are patients who have progressed on FOLFIRI, but we put them on the combo regimen,and they have overcome someof the resistance and stabilize their disease for some time before requiring a next line of therapy. So, I think that's the longest trial we've had open and we've seen some success.”

“The last point I would leave us on is with these different driver mutations that we're identifying,” Barber concluded. “[We’re intending to] really use these different therapies to target the clones when they progress and then find out based on the pressure, the chemotherapy was given, really what is driving the resistance or the progression?

“So, I think using more circulating tumor DNA, following HER2, JRAS, BRAF, as well as both finding and tailoring the treatment on and off, depending on the resistance, is the direction where we're going to go.”

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