Alicia Morgans: Hi. I'm delighted to have here with me today Dr. Darren Feldman, who's the Section Head of Germ Cell Cancer and an Associate Attending at Memorial Sloan Kettering Cancer Center. Thank you so much for being here.

Darren Feldman: Thank you so much for having me.

Alicia Morgans: Of course. So, you have done a lot of groundbreaking work, actually worked with a team that's really trying to move the needle for patients with testicular cancer, which many of us believe is such a curable disease, and it is, but when we get into refractory cases of people who are suffering from testicular cancer, it can be very, very challenging to know what the right treatment is even if we are hopeful and know that, at the end of the day, we may still cure patients.

And I know that a lot of the work that you've been doing has been in clinical trials for men with testicular cancer and I'd love to hear about some of them perhaps starting with the international TIGER trial.

Darren Feldman: Absolutely. So, the TIGER trial is a randomized Phase III study that is going on all over the world. It's being conducted in three continents and, I think, at last check 13 different countries around the world including North America, Europe, and Australia/New Zealand. It's a study for patients who have germ cell tumor, whether it started in the testicle or extragonadally and have progressed after first-line chemotherapy, typically with bleomycin etoposide cisplatin, BEP, or etoposide cisplatin EP or VIP.

And for patients who have progression, they are eligible for the study. They're randomized in a one-to-one fashion to either get standard conventional-dose chemotherapy with a regimen called TIP (taxol, ifosfamide, and cisplatin), or high dose chemotherapy with STEM cell transplant with a regimen known as TICE.

The trial is going to enroll 420 patients, 210 will be assigned to each arm and the primary endpoint is overall survival. The reason this trial is important is that, at present, we really don't have level one evidence as to what the best approach, conventional-dose chemotherapy or high dose chemotherapy with stem cell transplant, is most effective in the second-line setting. And we need to establish that and that's where the TIGER trial comes in.

Alicia Morgans: I think the TIGER trial is such a critically important trial. I treat a number of patients with testicular cancer and we end up facing this question when patients have progression after their primary therapy, which is this population, regardless of what that primary therapy was, as long as it was basically standard of care. Do you need to go to high-dose chemotherapy and autologous stem cell transplant, which is really the big guns, or can you get away with salvage chemotherapy essentially, which is what TIP is?

And that question, it's very stress-filled, as you know, you treat a lot of men with testicular cancer. It's stress-filled from the physician perspective, the patient perspective, oftentimes the mom's perspective because these are young men in many cases. So, this trial will help us to understand which is the best option. And are you able then also to look at subgroups to say, it's the best option for this group but not for that group? Is that why you're such a large trial, but it looks like you'll have the power to do some of that subgroup work too?

Darren Feldman: Absolutely. That's a great, great point. So, we have used an international prognostic factor study group criteria for stratifying patients into risk groups and that criteria puts patients into very low, low, intermediate, high and very high-risk groups based on an international collaboration done by the International Prognostic Factor Study Group to define what are the prognostic factors for outcome in the second-line setting.

And so, we will have the ability in the trial to look at both the overall benefit of one regimen versus the other as well as the benefit, potentially, of high-dose chemotherapy for specific subsets.

It's very important to understand whether high-dose chemotherapy and stem cell transplants are providing a survival advantage because it is a more toxic therapy. So, I view the trial as a winner no matter what it shows, which is really how you should view trials overall, that the data determines what is best for patients.

So, let's say the study shows that high-dose chemotherapy is superior and leads to more patients surviving, well then, we have improved survival in this disease, in this young population of patients who really need to know that. Let's say it doesn't. Then we know that standard-dose salvage chemotherapy like TIP should be the standard of care and we can spare patients from toxicity unless they progress after TIP. And then, thirdly, maybe we'll find that it's superior for some patient populations and not for others. And that would be a benefit, in terms of risk, tailoring treatment.

Alicia Morgans: Absolutely. And the risk stratification that you've built in through that international consortium that has developed that risk stratification, or categorization, based on many, many patients and the data that they've provided will help us as clinicians say, "Okay, I can categorize this patient as low-risk, high-risk, wherever in the middle and I'll be able to hopefully predict, yes, I need this high-dose, autologous stem cell transplant or, no, I can save them that toxicity and salvage chemo is the way to go."

Darren Feldman: Absolutely. And this prognostic model is built-in as strata in the study. So, patients are stratified in the study at the time of randomization based on their IPFSG risk group as well as the continents of enrollment. Those are the two strata.

Alicia Morgans: Wonderful. And do you have biomarkers built-in as well to help understand, if we can, at a more basic biologic level, what could be driving some of the outcomes we see?

Darren Feldman: Absolutely. So, we have a built-in collection of blood and tumor samples for banking. The tumor samples will undergo whole-exome sequencing so that we can identify genomic predictors, mutations, or copy number alterations that might predict for the outcome to overall and to one treatment approach versus the other.

We also have a blood for germline sequencing that's being collected on patients on the study so that we can look to see if there are certain snips in the germline associated with the outcome of the study, as well as toxicity.

Alicia Morgans: Wonderful. So, Dr. Feldman, You have a program also that helps to support patients in this setting, right?

Darren Feldman: Yes. So, one unique thing that we have ongoing at Memorial Sloan Kettering is we have a genomic sequencing initiative for patients with rare tumors such as germ cell tumors. So, if a patient has a germ cell tumor that's refractory to initial therapy, or relapsed after initial chemotherapy, so second-line or later, we have a program that can perform genomic sequencing on their tumor to try and identify a mutation or copy number alteration in their tumor that could be potentially targeted with a novel drug as part of a clinical trial or outside of a clinical trial if it's an already approved drug for that potential target.

And so, because these patients don't have that many options left, especially options with a high degree of efficacy once they progress after high-dose chemotherapy, we really are pushing this initiative. Now, the great thing about this initiative, which we call Make-an-IMPACT, is that patients do not have to come to our center to have their tumor profiled.

We can do everything remotely. They can consent to this over the phone. They can have their blood drawn for a sample that we need, as well as their tumor, sent to us remotely. And then, we will analyze and get them the results in approximately six to eight weeks.

And so, this will open up options to patients actually all over the world. We've already profiled patients as far as Australia, Chile, Germany, the US, Canada, really all over the world. And so, I want to make this available to any patient that finds themselves in a situation where they have relapsed or progressive germ cell tumor after initial therapy so that they can access this resource that we have. There's no cost to it. It's paid for through our research funds.

Alicia Morgans: Wonderful. So, it sounds like there's a whole lot of hope for these patients with multiple initiatives looking for treatments and potentially even understanding how we use the treatments that we already have better, and how we find new treatments for patients with refractory disease, as well as really trying to better characterize the genetics and genomics of the tumor for those patients with refractory disease.

Do you have any just overarching messages for patients, their families, for clinicians, that treat men with testicular cancer from all that you do?

Darren Feldman: Yes. Thank you for asking me that. So, I feel very strongly that we should not forget that this is a very curable cancer and that for the majority of patients, if you're a patient right now who's just been diagnosed with testicular cancer, you should understand that you most likely have a very favorable prognosis and a very high chance of cure, and should be encouraged by that.

However, if you're in a situation where you have a high-risk form of the cancer or have progressed after initial chemotherapy, or certainly after high-dose chemotherapy, it really behooves you to reach out to a center of excellence to have more expertise on your care, which can improve your access to treatment options like clinical trials, as well as surgical management, which can be very specialized in this disease and not available at certain centers.

So, I really believe in patients being referred when they have relapsed, or even high-risk initial disease, being referred to a center of excellence, which I think can improve their outcomes.

Alicia Morgans: Absolutely. Well, thank you so much for sharing your time and for the work that you do. I really appreciate it.

Darren Feldman: Thank you so much for having me.