An Expert Discusses PARP Inhibition, Vaccines and Emerging Therapies in Kidney Cancer

Jessica Skarzynski

The field of kidney cancer treatment could soon be expanding thanks to the inclusion of PARP inhibitors, vaccination-based strategies and emerging therapies such as Fotivda (tivozanib), according to research presented at the 2019 Kidney Cancer Research Summit.

In an interview with OncLive®, CURE®’s sister publication, Dr. Sumanta K. Pal, a medical oncologist at City of Hope, discussed the developing findings in these areas and what they mean for patients with renal cell carcinoma (RCC).

CURE®: PARP inhibitors are used in treating ovarian, breast and prostate cancers, but what role do they play in RCC?
Pal: One of the things that was demonstrated (during the summit) was that it looks as though PARP-1 tends to be expressed at higher levels in RCC, which is a concept that was somewhat foreign to me, but it does jive with some of the recent work that’s being done by the Memorial Sloan Kettering group led by Ari Hakimi, suggesting the role of DNA damage-repair mutations in RCC. So when you put those two elements together, it really does set the stage for the potential utility of PARP inhibitors. And one question that came from the audience, asking is this something that’s been done before in RCC, and everybody just really drew a blank. It’s certainly an area of therapeutic need.

And beyond PARP, I can see us using other novel classes of drugs: ATR inhibitors, ATM inhibitors, and other things that really help in DNA repair, and those sorts of agents that are directed at those pathways may really play a role in this disease.

Are we still looking into the potential of vaccines in kidney cancer?
There’s definitely a role for vaccination-based strategies. I think in terms of novel immunotherapy techniques, we’re going to hear a lot at this meeting that’s centered around CAR technologies in RCC. I myself have been working with CRISPR in the development of CD-70 allogeneic CAR-T cell. We discussed that last year at the Kidney Cancer Association meeting for the first time, and we’re approaching a timepoint where we might ultimately see studies based on that technology evolve, which is very exciting.

It’s always been challenging in RCC to pinpoint one particular antigen to go after with CAR-based technologies. In the case of the CRISPR-based technology, we have a unique target that we are going after. And I think that it really stands to benefit a broad swath of patients with RCC based on expression of this unique target.

Can you discuss the recent data involving other therapies such as Fotivda?
Tivozanib has a really interesting history. If you look back a couple of years, you’ll probably recall the discussions we were having around the TIVO-1 clinical trial, where there was a real discordance because we saw a benefit in terms of progression-free survival, but a lack of benefit, maybe even a trend in the opposite direction, for overall survival, and that caused a lot of pause.

In the TIVO-3 study, which was recently announced via press release, we really had a chance, again, to demonstrate the activity of tivozanib, this time in the third- and fourth-line setting. We had already reported out the data at ASCO GU this year, suggesting what I think is a pretty impressive improvement in progression-free survival in these heavily pre-treated patients.

What we had a chance to do more recently, in the context of the press release, is outline the fact that there seemed to be no significant difference in OS (overall survival), not that trend towards worse survival with tivozanib as we’d seen previously. So I think that allays a lot of our fears that there might be some downstream impact.

And, of course, the thing to keep in mind is that we have very little control as clinical trialists over what patients are going to get in studies beyond their prescribed therapies in the trial. With that in mind, accounting for all of those characteristics, OS was a bit of a wash in the study.
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