ATLANTIS Trial Explores Precision Medicine in Urothelial Carcinoma - Robert Jones
June 27, 2022
Alicia Morgans speaks with Robert Jones about the ATLANTIS Trial, focusing on an embedded randomization that studied the efficacy of Cabozantinib in urothelial carcinoma patients post-chemotherapy. Dr. Jones explains that the ATLANTIS platform aims to explore precision medicine in urothelial cancer and includes an "all-comers" arm to ensure broader patient participation. Unfortunately, the study found that Cabozantinib did not significantly improve radiographic progression-free survival or overall survival. Despite the negative results, Dr. Jones emphasizes the value of the collected translational samples and the potential for future trials, particularly in a biomarker-precision medicine setting. The conversation concludes with questions about the future of vascular endothelial growth factor targeting in urothelial cancer, suggesting that more research is needed.
Biographies:
Robert Jones, PhD, Professor of Clinical Cancer Research, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Biographies:
Robert Jones, PhD, Professor of Clinical Cancer Research, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Related Content:
ASCO 2022: A Randomised, Double Blind, Phase II Clinical Trial of Maintenance Cabozantinib Following Chemotherapy for Metastatic Urothelial Carcinoma: Final Analysis of the ATLANTIS Cabozantinib Comparison
ASCO 2022: Discussant: Is There a Role for VEGF-TKIs in Bladder Cancer?
ASCO 2022: Is There a Role for VEGF-TKIs in Bladder Cancer?
ASCO 2022: A Randomised, Double Blind, Phase II Clinical Trial of Maintenance Cabozantinib Following Chemotherapy for Metastatic Urothelial Carcinoma: Final Analysis of the ATLANTIS Cabozantinib Comparison
ASCO 2022: Discussant: Is There a Role for VEGF-TKIs in Bladder Cancer?
ASCO 2022: Is There a Role for VEGF-TKIs in Bladder Cancer?
Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be at ASCO 2022, where I have the opportunity to speak with Dr. Rob Jones about the ATLANTIS Trial and one of the embedded randomizations within it, looking at Cabozantinib in urothelial carcinoma after chemotherapy. Thank you so much for talking with me today.
Robert Jones: It's a great pleasure.
Alicia Morgans: Wonderful. Well, I wanted to talk with you about the presentation that you gave at ASCO this year. Can you tell me a little bit about the ATLANTIS model overall and then we'll get into the arm?
Robert Jones: Yeah, sure. So, the data I've presented are just one part. One embedded randomization within a platform. So, the ATLANTIS platform was actually developed as a means of trying to explore precision medicine that is biomarker-driven hypotheses in urothelial cancer. And indeed, we presented some data for Rucaparib earlier in the year at the GU meeting 2022. Part of during the process of developing the platform, however, our patient partners were very clear that although patients were really enthused by the concept of precision medicine and wanting to take part in precision medicine trials, they were really keen that we should include an option for all patients.
So, in other words, even if your biomarker negative, you still get to take part in the trial. And so, actually, this particular embedded randomization is all the patients who were not eligible for any of the biomarker-directed randomizations within ATLANTIS. So, it's a sort of hotchpotch of different patients essentially enriched for patients who do not have particularly markers of DNA repair deficiency or biomarkers of antigen receptor sensitivity.
Alicia Morgans: Well, and that's so important, I think, from a patient perspective. So many patients are left out of trials when we even think about the eligibility criteria in terms of fitness and everything else. So, I think it's wonderful that you studied an all-comers population, of course, without those patients who met those other specific criteria. So, who were the patients in this embedded randomization?
Robert Jones: So, we are exploiting the window of opportunity, which is the maintenance arena. So, in other words, patients who've completed their first-line chemotherapy for advanced urothelial cancer. We did the biomarker testing during the chemotherapy because that takes time. And then, at the end of chemotherapy, if they still had ongoing clinical benefit, that is, partial response, stable disease, complete response, then patients were offered randomization within the platform.
Alicia Morgans: Okay.
Robert Jones: So, this is within 10 weeks of completion of chemotherapy.
Alicia Morgans: So, similar to the JAVELIN 100 type approach?
Robert Jones: Exactly. Yeah.
Alicia Morgans: Very good. So, what did you find when you looked at Cabozantinib in the setting?
Robert Jones: So, to cut a long story short, it doesn't work. Okay? Now, remember this is a randomized phase two screening trial. So the statistics are not the same as those of a randomized phase three trial. The primary endpoint was radiographic progression-free survival. And what we saw was a hazard ratio of 0.89 in favor of Cabozantinib, but the P-value, the one-sided P value, was 0.35. So, there's really no difference in terms of progression-free survival. Similarly, with the secondary endpoint of overall survival, there was no difference between the two arms within this randomization.
Alicia Morgans: Well, sometimes when we have negative trials we're still able to learn. We always learn with the negative trial, of course, but we're still sometimes able to learn about subgroups or about some of the basic biologic correlatives that we do. Are these things that you and the team are looking into?
Robert Jones: So, we've had extensive translational sample collection. We did because of the nature of the trial, of course. We do know something about the genetics of these patients because nearly all of the patients underwent Foundation One profiling. In fact, there were within the whole platform, we identified three patients with putative biomarkers for Cabozantinib activity. Unfortunately, none of them were because it was done retrospectively, none of them were included in this part of the randomization. So at the moment, we don't have any particular clues there.
Alicia Morgans: Okay. But what are you planning to do either with this data or with the ATLANTIS platform overall? What are next steps?
Robert Jones: So, the ATLANTIS platform itself, of course, as it currently is designed, is no longer really viable because all the randomizations are against placebo. And, of course, placebo is no longer the standard of care. In fact, we closed recruitment to this randomization early because Avelumab became available. And it was, therefore, we felt it was unethical to continue randomizing patients against placebo. But clearly, there is now the opportunity of essentially starting again and comparing with immunotherapy. So, I think, ideally, we'd be looking at a randomization of Avelumab plus or minus a novel drug, again, hopefully, in a biomarker-precision medicine setting.
Alicia Morgans: Fantastic. And, of course, there's always those patients who don't achieve stable disease or better in the metastatic setting from chemotherapy who still need active approaches too, but maybe not on the ATLANTIS trial. Yes.
Robert Jones: Yeah. So Andrea Apollo completed a trial of Cabozantinib in that platinum refractory population. And there is some clinical activity for Cabozantinib in that population.
Alicia Morgans: Well, some hope yet perhaps then. And anything else you'd like to add or to summarize related to the study?
Robert Jones: I think so, obviously, Cabozantinib, although it's a multi-targeted tyrosine kinase inhibitor, its primary activity is probably through vascular endothelial growth factor receptor targeting. And, of course, we've seen a number of early-phase and some late-phase trials of other drugs targeting the vascular endothelial growth factor axis and that all of them have given us some hints of activity but never shown enough activity to really make a difference. And, I guess, there's a question that we probably now need to begin asking as to whether actually there is any future in vascular endo field growth factor targeting in urothelial cancer. Our conclusion would be not in an unselected population, but, of course, the selection biomarkers for vascular endothelial growth factor we have really drawn blanks all the way with that.
Alicia Morgans: Well, it sounds like we have a lot of work to do then as we do in urothelial cancer in general, but each step that we make in each trial that we do certainly teaches us something. So I so appreciate that you and your team took the time and, of course, congratulate you, your team, and the patients who participated in helping us understand this disease a little bit more clearly. Thank you so much for your expertise today.
Robert Jones: Thank you.
Alicia Morgans: Hi, I'm so excited to be at ASCO 2022, where I have the opportunity to speak with Dr. Rob Jones about the ATLANTIS Trial and one of the embedded randomizations within it, looking at Cabozantinib in urothelial carcinoma after chemotherapy. Thank you so much for talking with me today.
Robert Jones: It's a great pleasure.
Alicia Morgans: Wonderful. Well, I wanted to talk with you about the presentation that you gave at ASCO this year. Can you tell me a little bit about the ATLANTIS model overall and then we'll get into the arm?
Robert Jones: Yeah, sure. So, the data I've presented are just one part. One embedded randomization within a platform. So, the ATLANTIS platform was actually developed as a means of trying to explore precision medicine that is biomarker-driven hypotheses in urothelial cancer. And indeed, we presented some data for Rucaparib earlier in the year at the GU meeting 2022. Part of during the process of developing the platform, however, our patient partners were very clear that although patients were really enthused by the concept of precision medicine and wanting to take part in precision medicine trials, they were really keen that we should include an option for all patients.
So, in other words, even if your biomarker negative, you still get to take part in the trial. And so, actually, this particular embedded randomization is all the patients who were not eligible for any of the biomarker-directed randomizations within ATLANTIS. So, it's a sort of hotchpotch of different patients essentially enriched for patients who do not have particularly markers of DNA repair deficiency or biomarkers of antigen receptor sensitivity.
Alicia Morgans: Well, and that's so important, I think, from a patient perspective. So many patients are left out of trials when we even think about the eligibility criteria in terms of fitness and everything else. So, I think it's wonderful that you studied an all-comers population, of course, without those patients who met those other specific criteria. So, who were the patients in this embedded randomization?
Robert Jones: So, we are exploiting the window of opportunity, which is the maintenance arena. So, in other words, patients who've completed their first-line chemotherapy for advanced urothelial cancer. We did the biomarker testing during the chemotherapy because that takes time. And then, at the end of chemotherapy, if they still had ongoing clinical benefit, that is, partial response, stable disease, complete response, then patients were offered randomization within the platform.
Alicia Morgans: Okay.
Robert Jones: So, this is within 10 weeks of completion of chemotherapy.
Alicia Morgans: So, similar to the JAVELIN 100 type approach?
Robert Jones: Exactly. Yeah.
Alicia Morgans: Very good. So, what did you find when you looked at Cabozantinib in the setting?
Robert Jones: So, to cut a long story short, it doesn't work. Okay? Now, remember this is a randomized phase two screening trial. So the statistics are not the same as those of a randomized phase three trial. The primary endpoint was radiographic progression-free survival. And what we saw was a hazard ratio of 0.89 in favor of Cabozantinib, but the P-value, the one-sided P value, was 0.35. So, there's really no difference in terms of progression-free survival. Similarly, with the secondary endpoint of overall survival, there was no difference between the two arms within this randomization.
Alicia Morgans: Well, sometimes when we have negative trials we're still able to learn. We always learn with the negative trial, of course, but we're still sometimes able to learn about subgroups or about some of the basic biologic correlatives that we do. Are these things that you and the team are looking into?
Robert Jones: So, we've had extensive translational sample collection. We did because of the nature of the trial, of course. We do know something about the genetics of these patients because nearly all of the patients underwent Foundation One profiling. In fact, there were within the whole platform, we identified three patients with putative biomarkers for Cabozantinib activity. Unfortunately, none of them were because it was done retrospectively, none of them were included in this part of the randomization. So at the moment, we don't have any particular clues there.
Alicia Morgans: Okay. But what are you planning to do either with this data or with the ATLANTIS platform overall? What are next steps?
Robert Jones: So, the ATLANTIS platform itself, of course, as it currently is designed, is no longer really viable because all the randomizations are against placebo. And, of course, placebo is no longer the standard of care. In fact, we closed recruitment to this randomization early because Avelumab became available. And it was, therefore, we felt it was unethical to continue randomizing patients against placebo. But clearly, there is now the opportunity of essentially starting again and comparing with immunotherapy. So, I think, ideally, we'd be looking at a randomization of Avelumab plus or minus a novel drug, again, hopefully, in a biomarker-precision medicine setting.
Alicia Morgans: Fantastic. And, of course, there's always those patients who don't achieve stable disease or better in the metastatic setting from chemotherapy who still need active approaches too, but maybe not on the ATLANTIS trial. Yes.
Robert Jones: Yeah. So Andrea Apollo completed a trial of Cabozantinib in that platinum refractory population. And there is some clinical activity for Cabozantinib in that population.
Alicia Morgans: Well, some hope yet perhaps then. And anything else you'd like to add or to summarize related to the study?
Robert Jones: I think so, obviously, Cabozantinib, although it's a multi-targeted tyrosine kinase inhibitor, its primary activity is probably through vascular endothelial growth factor receptor targeting. And, of course, we've seen a number of early-phase and some late-phase trials of other drugs targeting the vascular endothelial growth factor axis and that all of them have given us some hints of activity but never shown enough activity to really make a difference. And, I guess, there's a question that we probably now need to begin asking as to whether actually there is any future in vascular endo field growth factor targeting in urothelial cancer. Our conclusion would be not in an unselected population, but, of course, the selection biomarkers for vascular endothelial growth factor we have really drawn blanks all the way with that.
Alicia Morgans: Well, it sounds like we have a lot of work to do then as we do in urothelial cancer in general, but each step that we make in each trial that we do certainly teaches us something. So I so appreciate that you and your team took the time and, of course, congratulate you, your team, and the patients who participated in helping us understand this disease a little bit more clearly. Thank you so much for your expertise today.
Robert Jones: Thank you.