OncologyTube: [00:00:00] Okay.
Okay, we’re here at ASCO GI 2024 and we have Dr. Anthony B. El-Khoueiry, MD a medical doctor, associate professor of medicine at USC Norris Comprehensive Cancer Center, USC, in Los Angeles. Dr. El Khoury, thank you so much for joining us today. Pleasure. Okay. Today we’ll be discussing Tizolizumab plus chemotherapy with or without Bevacizumab and advanced biliary tract cancer results from a randomized proof of concept phase two trial, otherwise known as the IMBRAVE151, which has been featured here at ASCO GI 2024.
So Dr. Okahiri, can you provide an overview of the IMBRAVE151 study and treatment of advanced Biliary tract cancer?
Anthony B. El-Khoueiry, MD: Yes. So the current standard for advanced biliary tract cancer is the combination of a chemotherapy backbone, gemcitabine and cisla, and combined within anti PD one like pembrolizumab or anti pd, L [00:01:00] one, like durvalumab.
That’s the current standard. So this study was. designed to augment that benefit by adding bevacizumab. The idea behind this, or the rationale, is, is that blockade of vascular endothelial growth factor of VEGF, combined with chemotherapy, can augment the anti PD 1 responses by creating an immune permissive environment.
So anti VEGF therapy can do many things that are helpful. to have an anti tumor effect. For example, they assist with recr Blocking VEGF can assist with recruiting cytotoxic T cells to the tumor, can lower the activity of some of the suppressive cells that we do not want in the tumor microenvironment, like T regulatory lymphocytes, myeloid derived suppressor cells.
So, that’s the rationale behind it. The idea that was tested through a randomized design where patients were randomized [00:02:00] one to one to get atazolizumab, bevacizumab plus chemotherapy or atazolizumab placebo plus chemotherapy. Now, despite its randomized design, this is, this study is signal seeking, so it It really had a non comparative design.
It did not have adequate power to do formal hypothesis testing. It was really designed to pick the winner by assessing or estimating the relative benefit from each experimental arm. So the primary endpoint was progression free survival. Patients to be eligible had to have advanced biliary tract cancer, good performance status, and not treated previously for advanced biliary tract cancer.
So treatment naïve. Uh, the primary. The updated hazard ratio for the primary endpoint of PFS is 0. 67 in favor of the bevacizumab arm. So, in [00:03:00] other words, there was a 33 percent reduction in the risk of progression or death with the addition of bevacizumab compared to the placebo arm. The benefit of the Bevacizumab arm seemed sustained at 6 months and 12 months.
Actually, at 12 months, the PFS rate was 33 percent in the Bevacizumab arm compared to about 15, if I recall correctly, the number for the placebo arm. As far as overall survival, there was no significant difference. It was around 14 months. Now, the study is not powered for overall survival, but we measured it anyway.
The response rate was 27 percent across both arms, no difference. But despite the absence of any difference in response rate, the median duration of response was longer in the Bevacizumab arm at 10. 3 months compared to about six months with placebo. The safety [00:04:00] Uh, no surprises is as expected for this combination.
The majority of the side effects occurred during the induction phase, which are the initial eight cycles where patients were getting the chemotherapy plus the atezolizumab and the bevacizumab or placebo. After eight cycles, patients were on maintenance atezobev or atezoplacebo and, uh, adverse events were less frequent.
When looking at important measures like grade three and four events, Uh, or adverse events leading to treatment discontinuation or treatment interruption and modification. There were no significant differences between two, both arms. So the other important data we presented yesterday. is the molecular correlates data.
The idea here is, can we figure out the subset of patients that would really benefit the most? Now, these are exploratory analyses in this study, but we did what we call transcriptomic analysis on baseline tissue from [00:05:00] 95 patients in the study and looking at RNA expression. And in that we noted that tumors with, or Patients whose tumors extract, expressed higher levels of vascular endothelial growth factor, VEGF A, had improvement in progression free survival, uh, with a significant benefit in the Bevacizumab arm, and a trend for improved overall survival in the, uh, and a trend for overall survival also in the Bevacizumab arm.
No difference in the placebo arm. Another important thing is that tumors that were enriched for hepatocytes by a special analysis called X cell deconvolution analysis that tells you cells of origin in your mix in the tumor. So tumors enriched with hepatocytes had also tended to have a higher [00:06:00] benefit from Bevacizumab with Improved hazard ratio in favor of Bevacizumab for PFS and a trend for improved OS.
We also did the genetic analysis looking at mutations at the DNA level and noted that there were mutations in the something called the PI3K pathway in about 10 percent of patients. Activation of the PI3K pathway was associated with less benefit from Bevacizumab. So, these are intriguing findings. They may allow us to maybe pursue these biomarkers further, refine them a bit more, validate them, and maybe be able to select the best population for the study.
OncologyTube: Fantastic. Okay. So you went over the rationale. So thank you for doing that. Um, uh, just to put a fine point, I believe you already covered this, but just so we can break it up, um, uh, for our viewers here, the IMBRAVE151 study showed a modest progression free survival [00:07:00] benefit with atizolizumab and beficizumab and chemotherapy.
What factors do you believe contributed to this outcome and how does it compare to existing treatment options for advanced biliary, uh, tricancer? Yeah.
Anthony B. El-Khoueiry, MD: So as far as, The modest benefit, uh, it depends how you measure it, right? When we measure it by hazard ratio, which was 0. 67, that’s actually a 33 percent reduction in the risk of progression or death.
So it’s meaningful. When we look at medians, it looks more modest. So the median PFS with Bevacizumab was 8. 3 months, the, and the median PFS with placebo was 7. 9 or something like that. Nonetheless, so the study met its primary end point of improvement and progression free survival. What contributed to this We don’t know, right?
We had a hypothesis why Bevacizumab may be beneficial. Hopefully, this is why we had the improvement in PFS. When we looked at specific subgroups like site of origin or age or performance status, you know, several [00:08:00] other factors for subgroup analyses, they seem to favor Bevacizumab for all these subgroups.
So there was not a unique subgroup that jumped out at us. However, The benefits seem to be more clear or more accentuated in patients with intrahepatic cholangiocarcinoma or gallbladder cancer. Now, you asked me, sorry, how it compares to existing options. Sure. That’s a great question. You know, it’s hard to compare across studies.
And this is a smaller study than the studies that have been completed like the Topaz and the Keynote 966. So, nonetheless, side by side, the The arm that contains gem sarbenes cisplatin atezolizumab with placebo compares very favorably, looks comparable to what we’ve known historically when we treat with gem sarbenes cisplatin and anti PD 1 or PD L1.
The addition of BAF again seems to improve progression free survival, but [00:09:00] you know, again, this is a signal seeking trial, and we’re not going to change the standard of care based on this at this point. All
OncologyTube: right. Um, the study identified potential predictive biomarkers like high VEGF, uh, A, gene expression and, uh, hepa, uh, hepatocytes, uh, hygiene signature.
How might these biomarkers help guide treatment decisions in patients with advanced biliary tract cancer and what further? research is needed to validate their utility in clinical
Anthony B. El-Khoueiry, MD: practice? Yeah, again, great question. So the idea, if we can validate these, uh, markers, is that we would be able to select patients up front and enrich our population for the combination with Bevacizumab and, and really get the maximum benefit in that population.
Now, the challenge is that this VEGFA gene expression is done on it, what we call a transcriptomic assay and, uh, what we defined as high or low was based [00:10:00] on being higher than the median or lower than the median. So it’s hard to do that in an individual patient before enrolling them into a clinical trial, et cetera.
So we are looking. at other assays. Potentially, there may be surrogates for the gene expressions for VEGF A. So we’re looking at blood levels. We may look at certain immunohistochemistry measures that are associated with VEGF A expression, which may be easier to perform on an individual patient and select them for the, for the future study based on that or not.
So it is intriguing that we found a potential population that may have more benefit. Now the job is to refine these biomarkers and make them easier standardized assays that we can test and select patients according to. All
OncologyTube: right, well this has been an interview here with Dr. Anthony B. El-Khoueiry, MD medical doctor, associate professor of [00:11:00] medicine at USC Norris Comprehensive Cancer Center and at USC in Los Angeles.
Thank you so much for sitting down with us. Thank you very
Anthony B. El-Khoueiry, MD: much.