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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, Hielke-Martijn de Vries, who is a Ph.D. researcher at the Netherlands Cancer Institute. Thank you so much for being here with me today.

Hielke-Martijn de Vries: It's great to be here.

Alicia Morgans: Wonderful. I wanted to talk with you a little bit about a presentation that you gave at GU ASCO 2022. Can you share with us a little bit about this interesting research?

Hielke-Martijn de Vries: I'll be glad to do that. Definitely. First, I'd like to credit, Michiel MS van der Heijden, who is the PI of the study, who set up the whole study, and who gave me this opportunity to present it at the ASCO GU 2022. And the study we conducted is researching immunotherapy with or without radiation therapy for advanced penile cancer patients. And these patients right now, there are not that many treatment options.

The standard of care is neoadjuvant chemotherapy, which we have previously conducted a trial at the Netherlands Cancer Institute. And what we saw there is actually a good response rate, with high toxicity and very early progressors again. So that's why we were looking for something else. And we were also doing some translational research, and it showed that there was a [inaudible] of immunotherapy actually, with a high rate of high-risk human papillomavirus, high PDL1 positive status, and a lot of antitumor T-cells.

Alicia Morgans: Absolutely. And I just want to comment that I commend you and your team because this is a tumor that's relatively rare, and it is hard to do good clinical trials because it's hard to pull together a population to actually study them. And to echo your comments too, that standard of care can be very challenging for patients with penile cancer, particularly if they've had any intervention biopsy, for example, lymphadenopathy that might have been resected because there is a high rate of infection and healing difficulties making neoadjuvant chemotherapy approaches actually pretty challenging. So I love that you are doing this work and would love to just pause and give you the opportunity to tell me about your study.

Hielke-Martijn de Vries: Yes. So what we did is we set up a trial and we included 32 patients with advanced penile cancer that could either have distant metastasis or local regional metastasis, which is still stage four in penile cancer. And these patients had a performance status of zero to one. And they actually could not have any previous treatment with PD1 or PDL1 blockers, but any other treatment would have been okay. And we have two arms in the trial, but it is not randomized.

So all the patients received atezolizumab every three weeks. And part of the patients received also radiation therapy, according to the same schedule which is used for chemoradiation in our center. We made a decision for Arm A or Arm B based on the clinic. If it was possible to give these patients radiation therapy and if we would expect a benefit from it, they would go in that arm.

We followed them up with CT thorax/abdominals [inaudible] every 12 weeks. And the primary endpoint of the trial was progression-free survival of 35% or more, which is quite ambitious for penile cancer, actually. And the safety of the trial actually of the patients was acceptable with atezolizumab grade three to four treatment-related toxicity of 10%. The radiotherapy-related grade three to four toxicity was higher at 65%. But if we zoom in on that, we see that there was 50% of patients who had a clinically insignificant lymphocyte count decrease.

The other radiation therapy-related toxicity was a lot lower. The response rate in the trial, especially in Arm A was the best overall response at 44%, but it's difficult there to make a distinction between immunotherapy or radiation therapy, which is possible actually in the other arm with only atezolizumab. And there were 12 patients and two patients had responses making a best overall response rate of 17%. Although we saw these responses and durable responses as well, we did not reach our primary endpoint of one-year progression-free survival.

And when we looked further and compared Arm A and Arm B, we did not see any difference between the two arms in progression-free survival, which is interesting, because one arm is also receiving radiotherapy. And then we looked at two different biomarkers, PDL1 status, which we scored positive if there were more than 50% tumor cells positive. And we saw that the patients who were PDL1 positive had a slightly better progression-free survival and overall survival, but the data is still too immature to make any hard conclusions out of that. And the same counts actually for human papillomavirus present, high-risk human papillomavirus, we also saw a slightly better progression-free and overall survival. But the data is still immature and the two patients that were actually in Arm B and responded to atezolizumab only were both PDL1 and high-risk human papillomavirus positive.

Alicia Morgans: So it's so interesting to hear about how these different subgroups may do better or worse. And it makes sense that the HPV positive, PDL1 positive group may have this synergistic type of response. So really interested and look forward to hearing where some of your additional studies may take us. So as you think about your study and all that you've found so far, I'd love to hear where we go from here, both in terms of your long term follow up, but also in terms of next steps and next approaches for using this type of treatment for patients with penile cancer.

Hielke-Martijn de Vries: Well, at this moment, we are still looking at the pretreatment and on-treatment biopsies, which we are analyzing. And we are looking if there are other biomarkers for response. And since we saw also a partial response to atezolizumab or early progressors, we are looking if there might be a resistance mechanism, which we could unravel. And if we could see what type of combination therapies might be best to try next. I think we are not... the next step is not a randomized trial, but to try out two different combinations to see if there would be a better response at that as well. But actually, we are... as we saw good responders and efficacy of immunotherapy, we are very enthusiastic to test this in the future, yes.

Alicia Morgans: I am very enthusiastic to see where it goes.  Again, neoadjuvant chemotherapy approaches can be very challenging in this population, as you explained, and penile cancer patients certainly have unmet needs in terms of having better outcomes. So I sincerely congratulate you and your team and appreciate the work that you are doing. I look forward to seeing future results from this study, and I appreciate your time and your expertise today.

Hielke-Martijn de Vries: Yes, thank you for having me here.