Enfortumab Vedotin and Stereotactic Radiation Tested Before Surgery in Muscle-Invasive Bladder Cancer in STAR-EV Trial - Tian Zhang
October 2, 2024
Leslie Ballas and Tian Zhang discuss the STAR-EV trial, a new study combining enfortumab vedotin (EV) and radiation for muscle-invasive bladder cancer patients ineligible for cisplatin. Dr. Zhang outlines the trial's design, which uses three EV cycles followed by targeted radiation and cystectomy. The study aims to improve complete response rates from 36% with EV alone to 60% with the combination. They explore eligibility criteria, potential synergy between EV and radiation, and the importance of timely post-treatment surgery. While small with just 19 patients, STAR-EV is viewed as an important step in exploring EV-radiation combinations and advancing bladder preservation strategies. Dr. Zhang concludes by discussing the trial's role in generating hypotheses for future larger studies and potentially expanding treatment options for bladder cancer patients.
Biographies:
Tian Zhang, MD, MHS, Associate Professor, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
Leslie Ballas, MD, Director, Hematologic/Bone Marrow Transplant/Cellular Therapies Disease Research Group, Cedars-Sinai Medical Center, Los Angeles, CA
Biographies:
Tian Zhang, MD, MHS, Associate Professor, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
Leslie Ballas, MD, Director, Hematologic/Bone Marrow Transplant/Cellular Therapies Disease Research Group, Cedars-Sinai Medical Center, Los Angeles, CA
Read the Full Video Transcript
Leslie Ballas: Hi, thank you so much for joining us. I'm Leslie Ballas. I'm a radiation oncologist at Cedars-Sinai Medical Center in Los Angeles. I am honored to be joined today by Dr. Tian Zhang, an associate professor in the Department of Internal Medicine at UT Southwestern Medical Center, who is a specialist in GU oncology. Thank you so much for joining me today, Dr. Zhang.
Tian Zhang: Thanks for having me, Dr. Ballas. Thanks again for the opportunity to talk about our newly launched investigator-initiated trial STAR-EV. This trial is really based on the premise that bladder cancer is the ninth most common cancer worldwide, and that muscle-invasive bladder cancer certainly needs more treatment options. And up to about 50% of that patient population cannot receive cisplatin-based chemotherapy. And concurrently, we know a good number of patients have benefit from neoadjuvant chemotherapy with surgery or trimodality therapy with maximal TURBTs followed by chemoradiation. And in the past five years or so, we've gained experience with this new antibody-drug conjugate called enfortumab vedotin. We've seen some really nice intraluminal responses even for patients with metastatic disease, seeing their bladders clear. And so EV is our standard of care in metastatic disease for bladder cancer. And there was a cohort of EV-103 where patients with localized cisplatin-ineligible bladder cancer received EV alone with 36% pathologic complete responses.
And so based on that, and also with some safety information that Dr. Ballas, you and I, and our centers participated in, 60 patients were treated with EV and radiation, with very similar side effect profiles, with rashes and neuropathy as the most common adverse events. And so as we looked at that data and also the promising aspects of EV intraluminally, we designed an investigator trial with EV and radiation followed by cystectomy to really try to improve those pathologic complete response rates. This is the schema of STAR-EV. We're enrolling patients with urothelial carcinoma, good ECOG performance status, clinical T2 to T4A disease, no nodal disease. Everybody would be ineligible for cisplatin with planned cystectomy. These have to be surgical candidates. Everyone is treated with essentially three cycles of enfortumab vedotin, day one and day eight every three weeks. And then followed by radiation in dose level one with sequential radiation, and then dose levels one and two, that radiation is propelled forward for concurrent radiation therapy.
And this is a higher dose, more stereotactic radiation directed to the tumor itself, not whole bladder radiation. And then everyone would be followed by cystectomy. Surgical endpoint to define that pathologic CR rate. We are basing it on that historic 36% pathologic CR rate that I mentioned from EV alone. And our alternative hypothesis that we're basing the sample size on is that we would improve that to about 60% pathologic CR rates. We do have a two-stage design where the first stage we enroll eight patients. If we have three or more pathologic CRs, then we're going on to stage two to enrolling 11 more patients, small trial, 19 patients total. But hopefully we'll be able to see many of these patients having pathologic complete responses. Here's the entire list of eligibility criteria, key eligibility criteria. Of note, we are not allowing patients with small cell or plasmacytoid components, but mixed histologies otherwise are allowed, so can have some squamous components as well.
And we're really defining that cisplatin ineligibility via the Galsky criteria: poor renal function, grade two or higher hearing loss, New York Heart Association class III or more heart failure, or patient refusal to receive cisplatin. And you see the rest of our inclusion-exclusion criteria here. Many of them are very standard for bladder cancer as well as for patients treated with enfortumab vedotin. And with that, I'm happy to say we are open and enrolling here at UT Southwestern. It's a single-center study and we're certainly happy to see patients as they come through our clinics.
Leslie Ballas: Thank you. That certainly is really exciting. And the combination of radiation and enfortumab vedotin is something that I think we're all anxious to see take place in trials and see safety profiles in a prospective fashion. And so I guess just to discuss, you've made it clear that the radiation enfortumab vedotin combination is to help improve on that path CR rate. As a radiation oncologist, I'm so used to seeing patients come to me who've already had maximal TURBT. Is a TURBT a part of this study? And if so, is there a requirement for it to be complete? Is a biopsy alone enough?
Tian Zhang: We've talked about TURBT with our surgeons, and it's not written directly into the eligibility criteria as a completion TURBT, but we would expect many of those patients will have had some form of a good resection, a good scraping, if you will, intraluminally before they start on this regimen. It's not a formal exclusion criterion, but we would expect many of these patients will have had a good TURBT prior to going on trial.
Leslie Ballas: Okay. And are you expecting that there will be synergy of radiation and enfortumab vedotin beyond just the two combined?
Tian Zhang: I would hope so. We haven't tested this specifically for the combination of enfortumab vedotin and radiation, but we would certainly hope that the addition of radiation to EV would increase the potential for more pathologic complete responses and good tumor responses. The hope is that we get to a future state where we can consider a true bladder preservation trial. And I'm sure in your clinics, in my clinics, many patients are asking about how they might be able to preserve their bladder and keep their bladder for longer. This trial is very small, but it would hopefully be hypothesis-generating in order to think about new trials moving forward.
Leslie Ballas: Do you have a timeframe in between the EVRT and the cystectomy that you are aiming for? Sometimes surgeons get nervous about operating in a radiated field.
Tian Zhang: Yeah, it's a great question. We had a lot of discussions with our multidisciplinary team and our urologists in designing the trial and our DLT period, so you saw the spacing of radiation, but the dose-limiting toxicity period is that perioperative timeframe from end of our neoadjuvant treatments until surgery. And a delay of over eight weeks was written in as one of the definitions for DLT because we thought if our enfortumab vedotin or the radiation itself caused a toxicity that was delaying people's time to surgery, that might impact their overall outcomes. And so that was a definition that was built in because we were considering potential patients who might be delayed going to surgery. I hope not. We're hopeful, but it's one of the things that are built into really thinking about that perioperative time period very closely and not wanting to delay surgery for our patients.
Leslie Ballas: Yeah, absolutely. Well, I think this is a really exciting trial, and even though you said it's only 19 patients, it's the start, I think, of pioneering work in combining radiation and enfortumab vedotin and one of many things that's going on in the bladder preservation general space. We're very excited to see what this trial shows. And thank you so much.
Tian Zhang: Thanks so much for your support, and I appreciate your role today for highlighting it as part of the ESMO proceedings.
Leslie Ballas: Hi, thank you so much for joining us. I'm Leslie Ballas. I'm a radiation oncologist at Cedars-Sinai Medical Center in Los Angeles. I am honored to be joined today by Dr. Tian Zhang, an associate professor in the Department of Internal Medicine at UT Southwestern Medical Center, who is a specialist in GU oncology. Thank you so much for joining me today, Dr. Zhang.
Tian Zhang: Thanks for having me, Dr. Ballas. Thanks again for the opportunity to talk about our newly launched investigator-initiated trial STAR-EV. This trial is really based on the premise that bladder cancer is the ninth most common cancer worldwide, and that muscle-invasive bladder cancer certainly needs more treatment options. And up to about 50% of that patient population cannot receive cisplatin-based chemotherapy. And concurrently, we know a good number of patients have benefit from neoadjuvant chemotherapy with surgery or trimodality therapy with maximal TURBTs followed by chemoradiation. And in the past five years or so, we've gained experience with this new antibody-drug conjugate called enfortumab vedotin. We've seen some really nice intraluminal responses even for patients with metastatic disease, seeing their bladders clear. And so EV is our standard of care in metastatic disease for bladder cancer. And there was a cohort of EV-103 where patients with localized cisplatin-ineligible bladder cancer received EV alone with 36% pathologic complete responses.
And so based on that, and also with some safety information that Dr. Ballas, you and I, and our centers participated in, 60 patients were treated with EV and radiation, with very similar side effect profiles, with rashes and neuropathy as the most common adverse events. And so as we looked at that data and also the promising aspects of EV intraluminally, we designed an investigator trial with EV and radiation followed by cystectomy to really try to improve those pathologic complete response rates. This is the schema of STAR-EV. We're enrolling patients with urothelial carcinoma, good ECOG performance status, clinical T2 to T4A disease, no nodal disease. Everybody would be ineligible for cisplatin with planned cystectomy. These have to be surgical candidates. Everyone is treated with essentially three cycles of enfortumab vedotin, day one and day eight every three weeks. And then followed by radiation in dose level one with sequential radiation, and then dose levels one and two, that radiation is propelled forward for concurrent radiation therapy.
And this is a higher dose, more stereotactic radiation directed to the tumor itself, not whole bladder radiation. And then everyone would be followed by cystectomy. Surgical endpoint to define that pathologic CR rate. We are basing it on that historic 36% pathologic CR rate that I mentioned from EV alone. And our alternative hypothesis that we're basing the sample size on is that we would improve that to about 60% pathologic CR rates. We do have a two-stage design where the first stage we enroll eight patients. If we have three or more pathologic CRs, then we're going on to stage two to enrolling 11 more patients, small trial, 19 patients total. But hopefully we'll be able to see many of these patients having pathologic complete responses. Here's the entire list of eligibility criteria, key eligibility criteria. Of note, we are not allowing patients with small cell or plasmacytoid components, but mixed histologies otherwise are allowed, so can have some squamous components as well.
And we're really defining that cisplatin ineligibility via the Galsky criteria: poor renal function, grade two or higher hearing loss, New York Heart Association class III or more heart failure, or patient refusal to receive cisplatin. And you see the rest of our inclusion-exclusion criteria here. Many of them are very standard for bladder cancer as well as for patients treated with enfortumab vedotin. And with that, I'm happy to say we are open and enrolling here at UT Southwestern. It's a single-center study and we're certainly happy to see patients as they come through our clinics.
Leslie Ballas: Thank you. That certainly is really exciting. And the combination of radiation and enfortumab vedotin is something that I think we're all anxious to see take place in trials and see safety profiles in a prospective fashion. And so I guess just to discuss, you've made it clear that the radiation enfortumab vedotin combination is to help improve on that path CR rate. As a radiation oncologist, I'm so used to seeing patients come to me who've already had maximal TURBT. Is a TURBT a part of this study? And if so, is there a requirement for it to be complete? Is a biopsy alone enough?
Tian Zhang: We've talked about TURBT with our surgeons, and it's not written directly into the eligibility criteria as a completion TURBT, but we would expect many of those patients will have had some form of a good resection, a good scraping, if you will, intraluminally before they start on this regimen. It's not a formal exclusion criterion, but we would expect many of these patients will have had a good TURBT prior to going on trial.
Leslie Ballas: Okay. And are you expecting that there will be synergy of radiation and enfortumab vedotin beyond just the two combined?
Tian Zhang: I would hope so. We haven't tested this specifically for the combination of enfortumab vedotin and radiation, but we would certainly hope that the addition of radiation to EV would increase the potential for more pathologic complete responses and good tumor responses. The hope is that we get to a future state where we can consider a true bladder preservation trial. And I'm sure in your clinics, in my clinics, many patients are asking about how they might be able to preserve their bladder and keep their bladder for longer. This trial is very small, but it would hopefully be hypothesis-generating in order to think about new trials moving forward.
Leslie Ballas: Do you have a timeframe in between the EVRT and the cystectomy that you are aiming for? Sometimes surgeons get nervous about operating in a radiated field.
Tian Zhang: Yeah, it's a great question. We had a lot of discussions with our multidisciplinary team and our urologists in designing the trial and our DLT period, so you saw the spacing of radiation, but the dose-limiting toxicity period is that perioperative timeframe from end of our neoadjuvant treatments until surgery. And a delay of over eight weeks was written in as one of the definitions for DLT because we thought if our enfortumab vedotin or the radiation itself caused a toxicity that was delaying people's time to surgery, that might impact their overall outcomes. And so that was a definition that was built in because we were considering potential patients who might be delayed going to surgery. I hope not. We're hopeful, but it's one of the things that are built into really thinking about that perioperative time period very closely and not wanting to delay surgery for our patients.
Leslie Ballas: Yeah, absolutely. Well, I think this is a really exciting trial, and even though you said it's only 19 patients, it's the start, I think, of pioneering work in combining radiation and enfortumab vedotin and one of many things that's going on in the bladder preservation general space. We're very excited to see what this trial shows. And thank you so much.
Tian Zhang: Thanks so much for your support, and I appreciate your role today for highlighting it as part of the ESMO proceedings.