Cisplatin and Gemcitabine With or Without Berzosertib in Patients with Advanced Urothelial Carcinoma - Tian Zhang

June 9, 2021

In this conversation with Alicia Morgans, MD, MPH, Tian Zhang, MD, highlights a phase II trial lead by Sumanta Kumar (Monty) Pal evaluating the efficacy and safety of cisplatin and gemcitabine hydrochloride with or without berzosertib works in treating patients with urothelial cancer that has metastasized, presented at ASCO 2021. Berzosertib is an ATR inhibitor with preclinical data suggestive of increased anti-tumor activity when added to cisplatin and gemcitabine. The primary objective of the study was to assess whether berzosertib improves the progression-free survival of patients treated with cisplatin and gemcitabine. Tian Zhang shares the findings of this study which include a lack of improvement in median progression-free survival, a trend towards inferior survival, with more hematologic toxicities.

Clinical Trial Information: NCT02567409 - A Randomized Phase 2 Trial of Cisplatin/Gemcitabine With or Without M6620 (VX-970) in Metastatic Urothelial Carcinoma

Biographies:

Tian Zhang, MD, Assistant Professor of Medicine, Division of Medical Oncology and the Department of Medicine, Duke University School of Medicine, and the Duke Cancer Institute.   

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.


Read the Full Video Transcript

Alicia Morgans: Hi. My name is Alicia Morgans, and I am a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to have here with me today a good friend and colleague, Dr. Tian Zhang, who is an Associate Professor of Medicine at Duke in North Carolina. Thank you so much for being here with me today.

Tian Zhang: Absolutely. Thanks so much for having me, Alicia.

Alicia Morgans: Wonderful. I wanted to talk with you about a recent ASCO presentation from ASCO 2021. It is a randomized phase II study of patients who have urothelial carcinoma receiving cisplatin and gemcitabine with or without berzosertib, and really giving us an understanding of how this phase II trial went, and some of the insights we can learn from the study that you and the team have done. Can you tell us a little bit about it?

Tian Zhang: Sure. First, thanks so much for highlighting this as part of the UroToday program. It was a randomized controlled study run by Dr. Monty Pal, Dr. Lucky Lara, and the group through the UN1 mechanism of early Experimental Therapeutics Clinical Trials Network. And so, it's a great way to bring forth investigator-initiated trials to test hypotheses.

This particular trial was based on improving cisplatin and gemcitabine for the treatment of metastatic urothelial cancer, and our audience knows that cis and gem are our go-to staples for first-line treatment of metastatic urothelial cancer. Berzosertib is an ATR inhibitor, and the thought was, and also in preclinical trials studies, they showed that berzosertib can actually improve platinum sensitivity in these [inaudible 00:01:48] mice that had tumors. And so there was a lot of interesting preclinical work that went into it, and a phase I study actually treated 40 patients with advanced cancers, and there was a colorectal cancer patient who actually had a complete response to berzosertib.

So, a lot of good things leading up to this particular randomized phase II study, and this trial specifically enrolled patients with metastatic urothelial cancer and randomized them to either our standard chemotherapy, cisplatin, and gemcitabine, or the triplet of cisplatin and gemcitabine with berzosertib.

Alicia Morgans: Great. So thank you for really walking us through that. What did you find? I think your primary endpoint was progression-free survival?

Tian Zhang: That's right. So the primary endpoint was to improve progression-free survival with secondary endpoints of response rates and overall survival as well as the toxicity of the triplet. And we were very hopeful, but the median progression-free survival for this randomized study was actually not improved. It was about eight months for both cohorts and the hazard ratio was right around one.

And then the median overall survival was actually the reverse of what we were hoping for. It was 19.8 months for the control cohort of cisplatin and gemcitabine-treated patients versus 14.4 months for patients treated with the triplet. And so, certainly not what we had intended or hoped for.

I think what we learned also was that the triplet with berzosertib was a bit more toxic for these patients. There were more grade 4 thrombocytopenia and neutropenia events, and then also more grade 3 anemia events. And so these patients, a lot of them had to dose-reduce either cisplatin, gemcitabine, or berzosertib. About 20% had to decrease their dose of berzosertib.

So, through it all, I think we learned that this combination was more toxic and not actually more beneficial for this population.

Alicia Morgans: I'm sorry that's what your findings were, but one thing that I think this study does emphasize is really the activity of gemcitabine and cisplatin, which has been sort of the cornerstone of our approach to the treatment of urothelial carcinoma for a number of years now. So, I think this does suggest that we are on the right track.

And I think one of the reasons, we touched before recording, that the patients who were getting the berzosertib may have gotten a lower overall cumulative dose of cisplatin, which perhaps is one of the reasons that it was maybe not as effective as a combination. What are your thoughts?

Tian Zhang: That's right. That is one of the reasons that I think this group of investigators and we were thinking of the patients that were initially randomized to the triplet, we knew there could be more toxicity in terms of hematologic toxicity. And so, the initial doses of cisplatin and gemcitabine were lowered from the standard doses of cis and gem of 70 and 1,000 mg/m2. They were lowered to 60 and I think 875 mg/m2 for cisplatin and gemcitabine respectfully. And so because of that, the cumulative doses were lower for cisplatin. It was about 370 for patients treated with the standard chemotherapy of the doublet and then about 250 mg/m2 for patients treated with the triplet.

And so, could that have affected the decreased efficacy? Possibly. And then we also, very hypothesis sort of driving and thinking about future work, could there be other DNA damage-sensing mechanisms in the cell? Is ATR inhibition enough? Are we looking at an unselected population where DNA damage is not the driving force of cytotoxicity? All of these things are kind of in the back of our heads as we are thinking about planning future studies and what we might need to do to improve the efficacy of berzosertib and other combinations of it.

Alicia Morgans: Absolutely. And maybe even in a radiation sensitization approach, cisplatin and berzosertib, maybe that's the next big thing for bladder sparing. Who knows? But I do think it's important to do the work and to make the discoveries so that we can continue to move on the path to finding the best treatments we can for our patients.

So, I really do commend you and the team for excellent work and thank you so much for taking the time to share all of this with us today. Whether a study is positive or negative, we can absolutely learn something from it and advance the field, and you and the team have proven exactly that.  So congratulations on a study well done, and thank you for taking the time today.

Tian Zhang: Definitely. Thanks so much for having me.
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