26 Jan CTO Jonathan Cartu Research – Bekaii-Saab Sheds Light on Furthering Biomarker-Driven Treatment …
Tanios Bekaii-Saab, MD
While earlier efforts of precision medicine focused on basket trials, Tanios S. Bekaii-Saab, MD, explained that it’s time for the field of oncology to move on to umbrella trial designs that can better target an individual cancer.
In a breakout session during the 2020 Gastrointestinal Cancers Symposium, Bekaii-Saab, medical oncologist, and medical director of the Cancer Clinical Research Office, vice chair and section chief of Medical Oncology in the Department of Internal Medicine, at Mayo Clinic, presented on basket trials and umbrella trials in biliary cancer, adding that umbrella trials can provide a new proof-of-concept.
“We do these umbrella protocols where we develop a proof-of-concept for FGFR, IDH, HER2, or other targets for biliary cancer, and depending on the alteration we find, the patient will be matched to a treatment,” said Bekaii-Saab. “That’s enriching for the disease and enriching for the target.”
Another method for ensuring that patients receive a drug that matches their particular disease characteristics is biomarker testing. According to Bekaii-Saab, every patient with a gastrointestinal (GI) malignancy should be screened for genetic alterations with next-generation sequencing.
However, biomarker testing is not without challenges, Bekaii-Saab explained. Responses seen with a targeted therapy in one disease does not necessarily translate to other diseases, he said, adding that ongoing research is looking into better understanding these differences.
In an interview during the 2020 Gastrointestinal Cancers Symposium, Bekaii-Saab examined the effectiveness of umbrella trials and their importance in aiding precision medicine in GI oncology.
OncLive: Can you provide an overview of your presentation at the 2020 Gastrointestinal Cancers Symposium?
Bekaii-Saab: The way we look at these targets in synchrony has been done in two different ways; we have the basket trials and umbrella trials. Basket trials are those trials that take 1 target, 1 drug, and whatever disease that has the target, and the patient is entered into that arm. The new generation of trials is the umbrella trials, in which there is 1 target, a disease-specific entity that is being tested, and other targets that belong to the same disease. The umbrella trial is a disease-centric mechanism with multiple targets, whereas the basket trials are target-centric, multi-arm studies with a target that is tumor-agnostic.
What are the pros and cons of basket trials and umbrella trials?
With the basket trials, there is a good proof-of-concept about whether an agent works with a specific target, regardless of histology. The problem is that there are very few targets matched with agents that seem to fit the bill; these agents would be PD-1 and NTRK inhibitors, and also agents that [work in MSI-H tumors].
Most targets behave differently in a specific disease. One example is BRAF V600E. In melanoma, BRAF V600E seems to have a good response to single-agent BRAF inhibitors, but it doesn’t work the same when we use it as a target in colorectal cancer. The response rate goes from more than 50% to 5%, and [these are] short-lived responses. This is just one example, but there are a lot of targets that [don’t have the same activity in GI cancers as they do in other cancers].
It doesn’t make a lot of sense to continue down the path of tumor-agnostic drug development. It’s better to move our efforts into a disease-specific setting, and that is what the umbrella trials are.
Which GI malignancies have a greater need for umbrella trials?
It becomes urgent to focus on disease-specific trials when we are thinking about rare diseases, such as biliary tract cancer, where you’re pulling from a lot of different studies with few patients, or from a basket trial with multiple targets. Then, you get a dilution effect from the patients with biliary tract cancer who enroll. It’s like looking for a needle in a haystack, and it makes it difficult to make sense of the results. You may miss some good targets or good agents that may work in that specific setting; that is not a good way to develop agents anymore.
With biliary tract cancer, and others such as pancreatic and colorectal cancer, we want to move to a disease-specific setting. We do these umbrella protocols where we develop a proof-of-concept trial for FGFR, IDH, HER2, or other targets for biliary cancer. Depending on the alteration we find, the patient will be matched to a treatment. This enriches for the disease and enriches for the target.
What steps being taken to move this adoption of umbrella trials forward?