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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston, in the U.S. I'm so excited to have here with me today, Dr. Giuseppe Procopio, who is a Medical Oncologist at the National Cancer Institute in Milan, Italy, really joining us today, to review his exceptional presentation at ESMO this year, looking into new treatments for patients with metastatic collecting duct renal cell carcinoma, an underserved population that truly needs therapies.

So thank you so much for being here with me today, Giuseppe.

Giuseppe Procopio: Thank you very much for this kind invitation, and the opportunity to talk about this clinical trial that we planned some years ago.

Alicia Morgans: Wonderful. So tell me a little bit about the BONSAI trial. Who were the patients, and how did you set up your analysis?

Giuseppe Procopio: So, the BONSAI trial was a prospective clinical trial designed in a very rare and awful disease, patients having collecting duct carcinoma. This is a very aggressive disease without a clearly defined standard of care treatment. So some years ago, we decided to plan a prospective clinical trial, in order to assess the safety and efficacy of new treatment options, specifically wanting to analyze multikinase inhibitors, a new generation of multikinase inhibitors, like cabozantinib, because it is very, very active in several kinds of tumors, specifically in renal cell carcinoma.

So, we planned to involve 23 patients in a model scientific experience, at my comprehensive cancer center. And all patients received a standard pathological review. So this was mandatory before being involved in this clinical trial. And these patients received cabozantinib, up to the full dose, as front-line therapy. So all patients did not have previous medical treatment for other events of the disease.

And the hypothesis was the strength, was the efficacy, in terms of objective response rate, and the overall disease control in this study population.

Alicia Morgans: Wonderful. So I think it's so interesting that this was a first-line approach to the treatment of these patients because as you've said, there isn't an accepted standard approach for these patients. I have seen some give chemotherapy, for example, but because this disease is so rapidly progressive, and especially in many of the patients, presents highly metastatic, it can be very difficult to actually get chemotherapy safely to these patients.

So I think it's wonderful that you offered an option that may be somewhat less toxic. And I think that one of the purposes of this trial, of course, was to understand the feasibility of using cabozantinib and the toxicity in this patient population. So what did you find?

Giuseppe Procopio: Yeah, of course, as you said, this is a very aggressive disease, and unfortunately, the prognosis is very, very bad. And often, the life expectancy is very, very short, less than six months for many patients with the meds after the diagnoses, and the activity of chemotherapy, a platinum-based regimen, is very, very limited. And so, we have to try to investigate new therapeutic options, of course.

About our experience, cabozantinib was safe. Of course, the key message is, cabozantinib is safe in Phase I. So no unexpected adverse events are reported in this experience. And the treatment could be feasible, also irrespective of the other factors, like co-morbidities, or like the site of [inaudible 00:04:04] meds to the environment. So cabozantinib is, of course, a treatment option for these, at least in terms of safety. About efficacy, because the primary goal remains efficacy. The study was designed according to Simon's two-stage optimal design.

And this study was positive because it meets the primary goal. Because the objective response rate was reported in [inaudible 00:04:29] 35% of the patients. And 4% of them are complete response, one case. But, we have to consider that the global results, and unfortunately, half of the patients, 48%, are in nearly progressive disease, and had a very, very short life expectancy. This study suggested that in my opinion, some patients may have a benefit, more or less than 35%, 40%. This is a good quarter in favor of our [inaudible 00:05:04] target and the terms. But at the same time, we were able to characterize their biology, and their molecular profile, off of their remaining [inaudible 00:05:17] alpha for the patient, in order to understand what are the reasons for the early resistance to cabozantinib.

And according to this trial, we wanted to [inaudible 00:05:30] learn from a subsequent trial, having a characterization, a molecular characterization, of the disease, that in order to tailor treatment, according to molecular profile. So for example, a tumor signal for a patient having an androgen perandrogenic signal, a patient having any more related signal, or patients that potentially would have more benefit from chemotherapy.

And we have a plan for this second clinical trial, in the front-line to characterize the profile, and then, to define the treatment according to the tumor signal. It is a very ambiguous problem, but hopefully, to understand better the disease, and then, to try to offer to our patients a better treatment.

Alicia Morgans: I completely understand that this was not a magic bullet or a perfect treatment, but I do also find hope that you did have some responses. And one patient with a complete response is very, very exciting. Because when I've seen these patients in my clinic, I have not been able to change the disease course with the treatments I've tried, very much at all. So something is happening for some of these patients.

I really look forward to an understanding with you, who can benefit from this, and who might need something else. But I also commend your group for taking on the treatment for this particular patient population, because, in GU oncology, this is one of the most under-investigated populations I think we have.

Giuseppe Procopio: Yes.

Alicia Morgans: So if you had to make a conclusion, or a summary, of your findings for the audience, what would that be?

Giuseppe Procopio: Collecting duct remains a very, very aggressive disease. And we have a preference to analyze this disease in a multidisciplinary team, of course, in terms of pathological review, for example, urologists and medical oncologists. So we have to treat this in a multidisciplinary team, but in preference, these patients should be assigned to a comprehensive cancer center, and be able to offer a better therapeutic option as a preference in our clinical trials.

As you said, often these patients are excluded from a clinical trial, if we will look at the non-clear cells, and general papillary type O2, the majority of the patients. So collecting ducts often are excluded from this. So we have to try to define a prospective trial but only for this limited disease. Because also small, a limited number of patients may [inaudible 00:08:37] have positive for understanding, because of the 23 patients that we had, for us, additional information, and hopefully, before the next few to have more and more information, for example, combinations.

Alicia Morgans: I think that is a great way to go, and a great message for the audience to think about how to best care for these patients. We don't see them often, but when they do, they definitely stick with us, because they do need a better approach to therapy. So I commend you and your team for focusing on this patient population and hopefully, finding an option for at least some of them. Fantastic work. And thank you for taking the time to talk with me today.

Giuseppe Procopio: Thank you very much.