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Monty Pal: Welcome to UroToday. My name is Dr. Monty Pal and I'm a Medical Oncologist at the City of Hope Comprehensive Cancer Center. I'm delighted today to be here with Dr. Rana McKay who is an Assistant Professor at the University of California San Diego School of Medicine. Surprises me that her title isn't full Professor. She has a zillion publications and trials under her belt. Rana, thanks so much for joining us today.

Rana McKay: Thank you so much, Monty, for having me. It's a pleasure.

Monty Pal: Absolutely. So big news coming out of your group with the trial of beva/atezo for non-clear cell kidney cancer. I've been waiting for this data for a long time and I'm so excited to see on the podium and a couple of days. Can you give us a sneak peek?

Rana McKay: Oh, of course. So we are so excited about this study. As you know, patients with non-clear cell RCC really represent an unmet need in the field. They are ... have historically been excluded from large randomized Phase 3 studies that have guided the practice of patients with RCC. What we do for these patients is extrapolated from other studies.

And really we don't have a lot of robust data to guide the treatment paradigm for these patients. And they comprise a very heterogeneous group of patients with papillary chromophobe translocation and with each iteration of the next who that comes out, there's another laundry list of other histologies that have been added. So we specifically designed the study to investigate the combination of atezolizumab and bevacizumab in patients with non-clear cell RCC or patients with clear cell RCC that have greater than 20% sarcomatoid differentiation, which has been associated with worse outcomes in patients with RCC.

The trial was a multi-center Phase 2 single arm, open label study. We initially had the trial designed around 40 patients, but actually in the middle of the trial, increased the sample size up to 60. The primary endpoint of the study was actually objective response rate. And so this is the first splash of the data, teasing out sort of the ORR for this patient population. As a whole taking in this very heterogeneous population, their response rate was 34% actually, which is actually quite remarkable for this very heterogeneous and poor risk population.

When you tease it out of looking at the patients who had sarcomatoid differentiation, whether it was clear cell or non-clear cell, the response rates were up to 54%. And in the pure non-clear cells that didn't have sarcomatoid differentiation, the response rate was on the order of 26%, which is actually robust, I think, for this patient population and comparable, if not better than what they would be receiving with TKIs, which at the present time, the standard for these patients is Sutent, given that that's the best data that we have from the ASPEN and ESPN studies.

We also did some very robust biomarker work looking at PDL-1 expression and though PDL-1 expression does not seem to drive ... be a pure predictor of response in people with a clear cell RCC, we actually see a pretty dramatic effect for the non-clear cell population. So, taking out the clear cells, which are sarcomatoid, just looking at your non-clear cell, the response rates were over 60% for the PDL-1 positive patients versus 10% for the PDL-1 negative patients.

So it's still not a pure biomarker, but the PDL-1 status did seem to differentiate out those responders versus non-responders. Now, that exploratory analysis was done in 34 patients. So we're looking to actually update and expand to the full 60, but just goes to highlight that potentially in a biomarker specific population, the combination is certainly efficacious.

Then, of course, we look at AEs and the regimen is just so well tolerated. Only five patients discontinued treatment for toxicity. Only four patients required a steroid dose higher than pred of 40 for immune-related AEs. And for the most part, the combination was fairly well tolerated by patients.

So we're really excited about this combination and whether we're there right now to actually change practice based on our trial or whether we need a trial with a comparator arm to demonstrate that this should potentially be a new standard for patients with non-clear cell RCC is yet to be determined. But we are certainly excited about the first splash of the data.

Monty Pal: Fascinating. Fascinating. And you know, I have to tell you, I've had a similar experience with beva/atezo. It's perhaps one of the best-tolerated doublets I've ever had my hands on.

Rana McKay: Yeah.

Monty Pal: So completely mirroring the experience that you've had, the efficacy I agree with you is striking. I mean, 26% for those non-clear cell subsets excluding sarcomatoid. Phenomenal. Can you tell us a little bit, I know this might be challenging about the responses within individual subsets, maybe within papillary, maybe within chromophobe and so forth. Can you parse it out that much?

Rana McKay: We can. We have, but for some of the subsets, the sample size is just a little too low. So with regards to the papillary, the response rates on the order of about 24 to 25%. Chromophobe patients, the response rate I think was just under 20%. Surprisingly, the unclassified, which I would have thought would have had a worse response rate just given the aggressive phenotype had response rates on the order of 29%. So we had one medullary that had a complete ... that had a response.

So, once you get into those less common histologies that ... it's like less than five patients per sample size. But I think we can speak to the papillary, we can speak to the chromophobe. We can speak to the unclassified response rates between the 20 to 30%.

Monty Pal: Now, I'm going to wrap this up with a very difficult question for you. Okay. So brace yourself.

Rana McKay: Okay.

Monty Pal: But you're a community-based oncologist. Just you're sitting there in front of a papillary patient with advanced disease, for instance. Obviously, atezo might be hard to get your hands on for renal cell carcinoma, but would you be tempted to maybe try to get bev and nivo and pair those together? Is it too soon with the data that you're presenting? What do you think?

Rana McKay: Well, I think it's probably a little premature, especially because our data didn't combine nivo specifically with bevacizumab though you may be inclined to reach for that doublet given that nivo is FDA approved for non-clear cell. But I think what I would definitely stress is that really clinical trial enrollment for these patients or referral to a tertiary care center or academic center where they have access to clinical trials so they can ... patients can get access to maybe more novel combination therapies.

But I think until more data is available, I wouldn't necessarily rush to off label use. I think if you're able to get atezo and able to get the bev, the atezo is going to be challenging. I think there's a lot of data, but, I wouldn't necessarily pair it with another combo like nivo/bev, cause we didn't really specifically look at that. Though we'd like to think that the nivo and atezo or not necessarily 100% comparable.

Monty Pal: Well said. No, I tend to agree with you there. Yeah. Maybe just a little bit too exploratory at this point.

Rana McKay: Yeah. Yeah.

Monty Pal: Well, gosh friend, I learned a ton from this discussion today. I'm so looking forward to your presentation. Thanks for joining us.

Rana McKay: Of course. Thank you, Monty. Thank you for having us.

Monty Pal: Absolutely. And for UroToday, it's Monty Pal signing off. Thanks so much for joining us.