Transcript:   Okay, we’re here at ASCO G. I. 2024 and we have Dr. Vivek Sivaya, Medical Doctor, Chief Early Phase Drug Development at the Sarah Cannon Research Institute, Nashville, Tennessee. Dr. Sivaya, thank you so much for joining us today. Thank you so much. Okay, today we’ll be discussing durable efficacy of sulprocatinib in patients with RAT Fusion Plus solid tumors with a focus on GI tumors, the Libretto 001, a study featured here at ASCO GI 2024.
So, Dr. Sabaya, could you provide an overview of the Libretto 001
study? The LIBERATO 001 study is a Phase I II study of cell percatenib and Rett altered cancers that include Rett fusion positive non small cell lung cancer, Rett fusion positive thyroid cancer, Rett mutant medullary thyroid cancer, and beyond non small cell lung cancer and thyroid cancer, most importantly, it had an all comer tissue agnostic basket cohort of Rett fusion positive solid tumors that include Rett Uh, cancers like pancreatic cancer, GI cancer, celibate cancer, and multiple row cancers.
Okay, could you discuss the significance of the observed durable anti tumor activity of selprocatenib in patients with RET fusion plus cancers, particularly in GI histologies like pancreatic and colorectal tumors, would typically, uh, have limited, uh, treatment options with, uh, poor outcomes.
Thank you so much for the question.
So selprocatinib is a highly potent and selective red inhibitor that is approved for redfusion positive non small cell lung cancer, redfusion positive thyroid cancer, and red mutant medullary thyroid cancer. Redfusions are seen beyond non small cell lung cancer and thyroid cancer in multiple tumor types.
Although less than 1 percent in difficult to treat GI tumors like pancreatic cancer and colorectal cancer among many other cancers. One of the main challenges of red fusion positive cancers in multiple GI solid tumors is, you know, they do not have any treatment options. Again, the LIBERATO 001 trial, uh, showed that red fusions are actionable beyond non small cell lung cancer and thyroid cancer with durable efficacy and safety.
multiple tumor types. Most importantly, in difficult to treat cancers like pancreatic cancer, the response rate was over 50%. And in colorectal cancer, the response rate was over 30%. Again, these are very promising responses. In fact, based on the early data from the LIBERATO 001 study, the drug selporcatinib, highly potent selective rate inhibitor, was FDA approved.
Uh, it received an accelerated approval. in a tissue agnostic matter known as red fusion positive solid tumors. So this, uh, ASCOGI meeting, we presented the updated data set that includes more patients with red fusion positive solid tumors and, uh, you know, also showing more safety data and more efficacy data.
Excellent. Okay, given the encouraging results with, uh, selprocatenib in this study, what are the potential implications for the use of comprehensive genomic profiling to identify actionable oncogenic drivers such as RAT fusions across various tumor types?
Thank you so much for that question. So we are now in the era of tissue agnostic precision medicine.
Again, cancer, as we all know, is a genomic disease. Every patient with cancer deserves a diagnosis that includes comprehensive genomic testing. 2017 was a watershed moment because Pembrolizumab and immunotherapy received tissue agnostic approval, meaning it was approved based on a biomarker across multiple solid tumors.
For MSI high and DMMR positive cancer, the first targeted therapy to be approved subsequently in 2018 was retinol NTRK fusion positive cancers. Subsequently, another drug called Entrectinib was also approved in all Entrectinib positive cancers. And, you know, Pembrolizumab immunotherapy got, again, a tissue agnostic indication in all tumor mutation burdened high cancers.
B RAF V600E is also a tissue agnostic target. Again, Dabrafenib, Tremitinib received a tissue agnostic. Indication across multiple cancers that include, uh, difficult to treat cancers like glioblastoma and anaplastic thyroid cancer and cholangiococcinoma, among others. RET positive cancers, RET fusion positive cancers are seen in multiple tumor types.
Again, this was also, uh, achieved an FDA approval based on the LIBERATO 01 study. So, again, you know, RET fusions and ENTREC fusions are needles in haystacks. And to identify these patients, we need comprehensive genomic testing. Again, we are not going to be testing for red fusions but we’re going to be testing patients in a comprehensive manner for all these alterations so that our patients can benefit from these novel immunotherapies and targeted therapies.
All
right. Are there any specific considerations or challenges when treating patients with RET fusion plus solid tumors in terms of selecting the appropriate therapy and managing potential adverse events, especially in the context of supracathinibs, uh, safety profile?
Thank you so much. So again, uh, now we have data in more than 500 patients from.
Red fusion positive non small cell lung cancer, red fusion positive thyroid cancer, red mutant medullary thyroid cancer, and red fusion positive multiple solid tumors. So, what are the adverse events? One of the adverse events that we see most commonly is dry mouth, that we see a lot with these patients.
Another side effect that we see is increased liver functions. ALT and AST, aspartate and alanine amino transferase elevations. Uh, we see, uh, in, in these patients. In such cases, what we do is we do dose, dose reduction. Or, you know, if it’s, uh, uh, you know, above, above two or three times the upper limit of normal, we hold the drug and resume the drug at a low, low dose level and slowly dose escalate.
Again, it’s important for us to make sure that we have a baseline liver function study in these patients so that we can expectantly monitor. Another side effect that we see is acuity prolongation. So for that, we need to do a baseline EKG to make sure that their QT interval is within normal limits. And we also need to monitor for QT prolongation.
Also, most importantly, make sure that we optimize the concurrent medications. You know, we don’t add in other concurrent medications that increase the QTC prolongation. Most importantly, you know, this selective RET inhibitor in most patients is, uh, reasonably well tolerated and, you know, we’ve seen dramatic, uh, reductions and tumor shrinkage in several patients with multiple types as long as the tumors are driven by RET.
So the key message here is in order for patients to benefit from selective RET inhibitor therapy, we need to identify These patients who have altered biomarker with red fusions. So we cannot guess we need to do NGS. So comprehensive genomic testing is required for all patients with cancer with the diagnosis of cancer so so that they can benefit from these novel targeted therapies and our immunotherapies.
Thank you so much. All right.
Well, this has been an interview with Vivek Subbiah, medical doctor, chief early phase drug development at the Sarah Cannon Research Institute in Nashville, Tennessee. Dr. Subbiah, thank you so much for taking the time to join us
today. Thank you.