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Alicia Morgans: Hi, my name is Alicia Morgans, and I'm a GU Medical Oncologist at Dana-Farber Cancer Institute. I'm so excited to have here with me today, Dr. Giulia Baciarello, who is a GU Medical Oncologist in Milan, Italy, at the National Cancer Institute, there. I'm so excited to speak with her today about a presentation that she did at ESMO 2021, looking at cabazitaxel in patients with refractory germ cell tumors. Thank you so much for being here with me today, Dr. Baciarello.

Giulia Baciarello: Thank you very much, Alicia. I'm very happy to be here and to present this study.

Alicia Morgans: Well, great. Thank you. So why don't we start by explaining why this study was necessary, and what the study involved?

Giulia Baciarello: Yes, of course. So first of all, this was an academic trial, so we made a very huge effort to design it. We know that germ cell tumors are a very rare disease, and even in the metastatic setting, we can actually cure the vast majority of patients. When a patient relapses after the first line, cisplatin-based chemotherapy, we still can cure them in almost [inaudible 00:01:06] 20 to 50% of cases, according to [inaudible 00:01:10] large criteria. However, when our patients experience disease progression after two or three lines, the prognosis is really very poor, and currently, we do not have any standard treatment in this setting.

So that's why we, since we know that taxanes are active in germ cell tumors, we high prioritized that cabazitaxel, which is a second-generation taxane, may have some activity in this setting, with limited toxicity, especially for our concerns with peripheral neuropathy. Plus, since it may cross the blood-brain barrier, we also hypothesize a potential activity on brain metastasis.

We included patients who relapsed, whose tumors relapsed after two or three lines of chemotherapy, including standard taxane-based chemotherapy, and high doses, and patients with brain metastases. They received up to six cycles of cabazitaxel every three weeks. And the primary endpoint was favorable disease rate, which we defined as complete response or partial response with normalized tumor markers. And we also made an exploratory analysis to evaluate the overall disease control rate.

So, we actually included 37 patients. More than one-third of them had already received taxane-based chemotherapy, and more than one-third of them had already received high-dose chemotherapy. So this was a highly pretreated population. And cabazitaxel induced a favorable response rate in almost 6% of patients, while the overall disease controlled rate was achieved by 26% of patients.

Only four patients had brain metastasis, so we could not perform efficacy analysis on this subgroup.  And at six months, almost 20% of patients still had stable disease, while almost 60% of them were still alive. Cabazitaxel was also safe, in fact, only seven patients experienced a grade three or more adverse event. So actually, what we've seen is that cabazitaxel is safe, but it has probably limited efficacy in dissecting, especially in highly pretreated populations.

Alicia Morgans: I think that's so important to know, and interesting, of course, that this population did include some men who had already had taxane chemotherapy. So of course, that may come into play as well. So given the tolerability, and noting that some patients, in this extremely heavily pretreated population, did have responses, or at least stable disease, for six months, which actually is not always what we see in these patients, are you and the team moving this approach forward to see if it might have some efficacy in a larger trial?

Giulia Baciarello: Well, actually what we've seen is that, even if we achieved stable disease for a good number of our patients, it seems that this therapy, at least in monotherapy, in an unselected population, had quite a limited efficacy, we may use it, why not, in some patients, since even in the absence of a direct comparison with other monotherapy, with a taxane, or other polychemotherapy, it seems to have quite a similar activity and possibly limited toxicity.

I do not think that we will support another trial, especially a larger Phase II trial. We know that Phase III randomized trials are quite impossible in this setting, but no, we would want to do that, at least in an unselected population.

Alicia Morgans: I think that makes sense. Especially, since there is some interest in using some novel approaches, some targeted therapies, perhaps. But, I really commend you and the team for doing this work, because germ cell tumors, when it becomes this advanced, is highly aggressive and is devastating for these patients, and having options for this, very clearly, unmet need, is critical. So, I appreciate that you and the team, and of course, the patients, have done this.

So if you could summarize the findings, what would your summary and conclusion be?

Giulia Baciarello: I think that men with refractory disease still have a poor prognosis, and we still do not have any standard treatment. I think that we should stop doing Phase II trials, or trials in an unselected population. We need to better define, which are the potential drivers of tumor progression, or some potential targeted alteration. We know that we have done some other trials, especially as you said, with targeted agents, but we did not show any clinical activity like with TKI, or immune checkpoint inhibitors, even if a good percentage of patients, especially seminoma patients, actually expressed PDL1. So we probably should design a sort of umbrella trial, in order to better define the right therapy for each patient.

Alicia Morgans: Well, I think that's a fantastic idea, and I sincerely look forward to you and the team working on that and trying to help us define the biology, so that we can match that biology and understand what's driving cancer, with the appropriate treatment. I think that makes the most practical sense.

So thank you so much for doing the work, and of course, for taking the time to go through your presentation with us today, we appreciate it.

Giulia Baciarello: Thank you very much.