Treatment with KRAS inhibitors may help mitigate a common driver of genetic alteration across a majority of pancreatic cancers.
Michael J. Pishvaian, MD, PhD, director of Gastrointestinal, Developmental Therapeutics, and Clinical Research Programs, and associate professor of Oncology at Johns Hopkins School of Medicine, spoke with CancerNetwork® about treatments being assessed for gastrointestinal cancers that he believes may impact the field if approved.
Pishvaian began by highlighting the phase 3 MOUNTAINEER-03 trial (NCT3043313), which assessed tucatinib (Tukysa) plus trastuzumab (Herceptin) in patients with HER2-amplified colorectal cancer.1 He expressed that the trial displayed an overall response rate of approximately 50% and was used to support the regimen’s use in later lines of therapy. Furthermore, he explained that the phase 2 SGNTUC-019 basket trial (NCT04579380) was actively assessing tucatinib plus trastuzumab as a frontline therapy in patients with HER2-amplified disease.2
He then expressed that there is a need for KRAS inhibition in the pancreatic cancer field, given that KRAS is the driver of genetic alteration in most pancreatic cancers. To that end, he cited the phase 3 RASolute trial (NCT06625320), an ongoing study that compared KRAS inhibition to standard-of-care chemotherapy in patients with previously treated metastatic pancreatic ductal adenocarcinoma.3 Pishvaian suggested that KRAS inhibition has already shown enhanced survival among this patient group and that he hopes KRAS inhibition receives FDA approval in the near future to expand its use to a greater number of patients with pancreatic cancer.
Transcript:
Looking in the crystal ball, but hopefully, a realistic crystal ball, staying in the biomarker space, there is a drug combination that got FDA approval for later lines of therapy [in] colorectal cancer a couple of years ago, the combination of tucatinib and trastuzumab. It was in the [phase 3 MOUNTAINEER-03] study, and what they showed was that that combination had about a 50% response rate in HER2-amplified colorectal cancer, with some of the patients living significantly longer than would otherwise be expected.
Seattle Genetics––now Pfizer––is running an active [phase 2 trial] looking at chemotherapy plus tucatinib-trastuzumab as [frontline] therapy for patients with metastatic colorectal cancer that is HER2-amplified comparing it with chemotherapy [alone]. I am not a betting man, [and] I have no intimate knowledge of the study ... but I would be hopeful that [the study] might be positive and could present yet another biomarker subgroup that we have carved out for first-line therapy for patients with metastatic colorectal cancer.
In the world of pancreatic cancer, the drug class that we are all waiting for desperately is the KRAS inhibitors ... [there are] about 18 different compounds out there, probably more–– the numbers are growing––that are showing tremendous promise, because it is targeting KRAS, which is the driving genetic alteration in the vast majority of pancreatic cancers, as well as several other key cancer types as well. True to our hope, these KRAS inhibitors are leading to a significant response rate and a significant prolongation of survival, at least compared with historical controls. The average survival for a patient with, for example, pancreatic cancer with chemotherapy is about 6 months in the second-line setting. These drugs are now achieving survival rates that are [at 1 year] and growing, and I say growing because patients are still actively on the study.
There is a pivotal study called the [phase 3 RASolute 302] trial, which compares one of these KRAS inhibitors to standard-of-care chemotherapy [in patients with previously treated metastatic pancreatic ductal adenocarcinoma]. The study is accruing like gangbusters, including at Johns Hopkins and many other centers, and it should complete accrual hopefully by the end of the summer. Those of us who want patients to get access to these drugs, we are hoping that this drug is going to [receive FDA approval], maybe by the end of this year [or] early 2026 so that we can start prescribing it to virtually all of our [patients with] pancreatic cancer.