Investigator Initiated Phase I Dose-escalation Trial and 7 Subsequent Expansion Cohorts - Andrea Apolo

April 25, 2021

Petros Grivas, MD, PhD and Andrea Apolo, MD highlight results from a pooled analysis of a landmark phase I dose-escalation study and 7 subsequent expansion cohorts. In this study combinations of cabozantinib and nivolumab (CaboNivo) and cabozantinib, nivolumab, and ipilimumab (CaboNivoIpi) demonstrated promising efficacy and safety in a dose-escalation phase I study among patients with metastatic genitourinary (mGU) tumors. This study sought primarily to assess clinical activity, safety, and tolerability of both combinations. Secondary objectives included the detection of Epithelial cell adhesion molecule (EpCAM) + circulating tumor cells (CTCs) and biomarker correlatives.  


Andrea B. Apolo, MD, Investigator Genitourinary Malignancies Branch NIH Lasker Clinical Research Scholar Head, Bladder Cancer Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD

Petros Grivas, MD, PhD, Associate Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center.

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Petros Grivas: Hello, I'm Petros Grivas. I'm a medical oncologist at Seattle Cancer Care Alliance, an associate professor at the University of Washington, and an associate member of the Fred Hutchinson Cancer Research Center. I am really excited today to be able to discuss with a great colleague and friend, Dr. Andrea Apolo, from the NCI, who has made major contributions in the field of genitourinary cancers. Andrea, thanks for joining. Can you introduce yourself and discuss your phase 1 trial that was very nicely reported and presented at ASCO GU Symposium?

Andrea Apolo: Hi, my name is Andrea Apolo. I'm a medical oncologist at the National Cancer Institute in Bethesda, Maryland. Thank you so much for having me here to discuss the final results of the phase 1 trial plus expansion cohorts of cabozantinib and nivolumab and cabozantinib, nivolumab, and ipilimumab in patients with genitourinary tumors, which was presented as a rapid oral presentation at GU ASCO 2021. So, I have a lot of interest in the combination of cabozantinib and nivolumab, and I can start off a little bit kind of just saying what the background for that is. So, preclinical work done at the NCI with cabozantinib in urothelial cancer cell lines and tumor xenografts and HGF/SCID mice demonstrated that the MET/HGF pathway, which is targeted by cabozantinib, may be active in urothelial carcinoma. And that was initially something that I wanted to pursue clinically.

So, I initiated a few years ago a phase 2 trial of monotherapy cabozantinib in patients with urothelial carcinoma that were refractory to platinum-based chemotherapy. And I noticed that cabozantinib did have monotherapy activity and that was published in Lancet Oncology. And the overall response rate was 19%. We did correlatives within the patients treated with cabozantinib and we noted that cabozantinib has immunomodulatory properties, and that was a rationale for combining it with nivolumab and nivolumab and ipilimumab. So, I initiated a phase 1 clinical trial with a combination of Cabo/Nivo and Cabo/Nivo/Ipi at multiple dose levels. We had eight different dose levels and we've published that in the first 54 patients. So, what I presented at GU ASCO 2021 is the pooled analysis of the phase 1 study plus the seven expansion cohorts. We expanded in bladder cancer. We expanded in kidney cancer and in rare GU tumors, including adenocarcinoma of the bladder, penile cancer, squamous cell carcinoma of the bladder, among others.

And this is a very heterogeneous group of GU tumors. The overall response rate that we found was 38% and the complete response was 11%. These responses were deep and durable, with a median duration of 23 months and the time to respond was two months. And when looking at it by tumor type, the overall response rate for the kidney cancer cohort was 63% and this included patients with sarcomatoid. The overall response rate for bladder cancer was 42%, with 21% of patients having a complete response. We also saw responses in rare tumors, including adenocarcinoma, urachal of the bladder, squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, penile cancer, adrenomedullary, and chromophobe renal cell carcinoma.

And based on the safety and preliminary activity that we saw in renal cell carcinoma and rare GU tumors, this informed the development of several phases 3 trials that have been initiated, including the CheckMate-9ER study, the COSMIC-313 study, the Alliance PDIGREE study. These were all in frontline renal cell carcinoma. And the Alliance ICONIC phase 2 trial is in rare GU tumors with the combination of cabozantinib, nivolumab, and ipilimumab.

Petros Grivas: Thank you so much, Andrea. This is really exciting data, and I was really thrilled to see this data at ASCO GU Symposium. And thank you for an excellent summary. I think it's important for the audience to keep that data in mind. Let me ask you this. I think this question is useful for junior faculty and colleagues. You really, really pursued this investigator-initiated study. That took a lot of time and effort. Any comments about how to get these trials off the ground, utilizing relevant preclinical data as you did in your case?

Andrea Apolo: Yeah. Thank you for asking that question. I think it's important for young investigators to do investigator-initiated studies based on preclinical work that they have or interests that they have, where they see a potential activity in molecules within potentially certain tumor types. They're not easy but they are definitely a high reward. And they are high risk, but it is important to do these studies. And generally, they are small. This was a phase 1 trial, but they may have a big impact. And this is a good example of how a small phase 1 trial, that eventually I had some expansion cohorts, really had a large impact when the activity was seen, and then they were taken into a phase 3.

Petros Grivas: Absolutely. I think it's a great message because this trial that you just described that you started based on this relevant preclinical data actually set the foundation and the stage for large practice-changing phase 2 trial. So it's a very important message, as you pointed out. Andrea, let me ask you, you have done a lot of work in research particularly urothelial cancer with major contributions in the field. Tell me a little bit more about how you think about the angiogenesis mechanism and how it can partner with immunotherapy. We have seen studies combining chemotherapy with angiogenesis not really panning out. Dr. Jonathan Rosenberg led a great effort with Alliance, with GemCis [inaudible] with no significant overall survival benefit. Do you believe that the IO plus antiangiogenesis pathway has a small, let's say, impact on tumor microenvironment, T-cell presentation, and do you see this panning out potentially in urothelial cancer as well as a registrational pathway?

Andrea Apolo: This is a great question. And I think it's a difficult question to answer because my initial interest was in anti-angiogenic agents. That is kind of what led me to study cabozantinib because one of its targets is VEGFR, and I had several trials looking at anti-angiogenic agents as monotherapies in patients with bladder cancer that did not have activity. TRC105, lenalidomide, I tried this alone or in combinations, and some of them did have some immunomodulatory effects but they did not have any monotherapy activity or even when I use them in combination. So I can't speak for other anti-angiogenic agents, but specifically, cabozantinib had a specific... It looked like modulation of the microenvironment that it made good sense to combine it with another active therapy. So cabozantinib had monotherapy activity.

So combining it with something else that has activity or combining two active agents, at least you're going to get an additive effect. The hope is that you will get a synergistic effect, and there is a good biological rationale for them. So I can't say that all anti-angiogenic agents will behave this way. This may be something particular to tyrosine kinase inhibitors that are multi-targeted. Which one is the important target? We are actually studying that in the lab, what targets are the most important. And we don't know yet, but we know that this agent, in particular, does have a very, very, I don't know if I can say synergistic activity, but really excellent response and activity in these gene tumors.

Petros Grivas: Absolutely. And I would agree with you. And again, for the audience right now, we use single-agent checkpoint inhibitors in advance urothelial cancer, but there are some very exciting combination studies. And what you just said, Andrea, I think illustrates this rationale. There is a phase 3 trial combining pembrolizumab with lenvatinib, for example, versus pembrolizumab placebo in cisplatin unfit patients or [inaudible] high in platinum unfit patients in the frontline setting.

And there are some other agents like sitravatinib with nivolumab that Dr. Msaouel presented. And I think these trials in the context of the data you presented at ASCO GU, I think it raises enthusiasm for those ongoing studies. Let me ask you a little bit of a different question, Andrea, about your experience. You did a fantastic job at ASCO GU, summarizing the advances in metastatic urothelial cancer in a very nice flow and elegant way. Let me ask you about the CTLA-4 inhibition, which was part of your trial. Do you see that this may have at all, you know... down the road, are you interested to see what happens with the CheckMate 901 trial with Ipi/Nivo? I'm interested in your insight into that question.

Andrea Apolo: Oh, that's a great question. And I think we don't know the answer yet as to what the effects are if we were to combine all these different things together. We do have early evidence, but how it's going to turn out in terms of survival and outcomes, we don't know yet. Really, the question that I had with ipilimumab, the CTLA-4 inhibitor in my phase 1 trial, was safety because cabozantinib can be difficult to tolerate for some patients. And ipilimumab can double the immune-related side effects. So one of the questions that I had in doing the triplet combination of cabozantinib, nivolumab, and ipilimumab was safety. Can this be given safely? What about the overlapping toxicities like hepatotoxicity and diarrhea? How do you manage these?

So, these were all kinds of questions that we worked on and addressed during the phase 1 trial. Within my phase 1 trial with the cabozantinib/nivolumab and the cabozantinib, nivolumab, and ipilimumab, the doublet and the triplet, we didn't really compare their efficacy. And that is something that, a question that comes up a lot, why in your phase 1 trial was the doublet more active than the triplet? And the truth is that the trial was not designed to really check efficacy or the triple versus the double because of the way that we enrolled. We enrolled the patients in the doublet first. Then we started doing bladder and kidney expansion cohorts. So all my rare tumors were going into the triplet, really difficult to treat rare tumors like the medullary, small cell of the bladder, these tumors that don't respond that well.

So, it's not a fair comparison in terms of the tumor types that were in the triplet versus the doublet. Now, there are large trials I am asking the question of what is the role of CTLA-4 inhibitor in bladder cancer. And we saw from earlier studies of the CheckMate 032 data with Nivo/Ipi that Nivo/Ipi is very active in bladder cancer without cabozantinib, and different dosages may be more active. And that is what the CheckMate 901 study is also going to ask in the frontline setting. And we await the data. We don't have the data yet, but I think that it is active. Is it going to be active enough to justify the toxicity? I think we await that data.

Petros Grivas: Absolutely. I think you covered all the major points there. Let me ask you before we close up, Andrea, do you see the potential exploration of the combination of Cabo/Nivo in maybe LN disease spaces? Is that at all like neoadjuvant trials to try to improve upon pathological complete response rates and EFS? And the second question, because you were involved in leading these efforts, what will be the right endpoint in such a neoadjuvant trial, based on the collaborations with FDA and the works that you have led?

Andrea Apolo: That's a terrific question. And I think there are a lot of uncertainties in the neoadjuvant and in the adjuvant space right now for bladder cancer and what the right endpoints are in terms of neoadjuvant setting. Can we use pathologic CR as your endpoint for the adjuvant studies? Can we use DFS and really make a label change based on a positive DFS study? So there are a lot of questions as to how or what are the good endpoints when you are designing a trial in those spaces right now. In terms of the activity of Cabo/Nivo and taking it to earlier states of disease, it is something I think that could potentially be done because the response rate was really high in patients with bladder cancer. One concern or one issue that does come up is that cabozantinib, as a VEGF inhibitor, may have some wound healing issues, and you definitely don't want to worsen any potential surgical complications in patients undergoing radical cystectomy.

So, that has been studied a little bit in kidney cancer and cabozantinib did not seem to have... patients that received it did not seem to have any worst surgical outcomes. So it is potentially an indication or potentially a question that we could ask in the neoadjuvant setting. So I think there is a lot of interest right now in moving this combination forward, and it is being moved forward right now within other trials right now. So those are being designed right now. And I am happy to say that there is a lot of interests not only in kidney cancer but also in bladder cancer to move this forward.

Petros Grivas: Absolutely. And we see a lot of advances in urothelial cancer. Very, very exciting. I totally agree with you. Maybe a last quick question. Any priority, let's say, in the biomarker work that you would like to see across IO and the angiogenesis studies, of course, on your phase 1 trial?

Andrea Apolo: Yeah, no, we did a lot of biomarker work because I think it is really important to not only see what biomarkers are prognostic but also which ones are predictive of response to therapy, so we can better select the patients in our trials. We looked at the tumor and peripheral blood biomarkers and so far, we really haven't found a good predictive biomarker. I am very excited about the data that was presented on the adjuvant IMvigor010 trial with ctDNA, potentially really identifying minimal residual disease and selecting a patient population that would benefit the most from therapy. So I think applying that in the metastatic setting would also be interesting in terms of the response that you get to therapy and correlating that with ctDNAs. I've done that with CTCs and we see a nice response, and I'm actually excited about that data too. But I think they are different. And I think combining the ctDNA and the CTC together would be great biomarkers in assessing the burden of disease and response to therapy.

Petros Grivas: Very exciting data. I have to congratulate you once again for the successful completion of this important phase 1 trial, setting the foundation for practice-changing studies. It is really amazing. And for all your contributions to the field and looking forward to working more with you. It's exciting to work together in changing the field. Thank you for your time today.

Andrea B. Apolo: Thanks so much, Petros, and thanks for having me and inviting me to be here today.