Tailored Therapy Approaches for Upfront mRCC Treatment

Daniel J. George, MD: I’ve got to ask Rana to comment because she’s already talked about some of these new tailored therapy approaches, and the one we haven’t touched on is the Phase 3 PDIGREE study, and for my colleague, Dr Tian Zhang, I’d be remiss if I didn’t give a shout-out. This is another innovation in the field, it’s an adaptive, maybe not tailored, but an adaptive design.

Rana, any thoughts on that study and other studies that give us an idea of how we can begin to navigate not just making 1 treatment decision up front, but how we can begin to merge some of these strategies together?

Rana R. McKay, MD: Absolutely. The PDIGREE trial answers a credible question, and, even now, that’s more important with the Checkmate-9ER data being positive. It’s a critical question in the field of how we can escalate therapy for people who need therapy escalation, and can we do so for people who aren’t in the CR category and aren’t in the PD-L1 category? For the bulk of our patients who are in the middle, how can we get those responses to be deeper? How can we convert somebody with stable disease into a responder? That’s the messaging behind the PDIGREE trial. Patients start out with nivolumab/ipilimumab as the backbone, and then, depending on their response, if they fall into that middle category of non-CR, non-PD-L1, then they’re randomized 1-to-1 to continuing the nivolumab or adding cabozantinib to the nivolumab. It’s a critical trial answering a critical question in the field.

There are other trials that have been reported out. The TITAN-RCC trial reported at ESMO last year. The HCRN study led by Dr. Michael Atkins and our OMNIVORE trial at the University of California San Diego Medical Center also looked at answering the question of whether everybody needs nivolumab/ipilimumab up front. A third of the patients have toxicity; does everybody need it up front, or can we take those patients who don’t have a CR and don’t have a PR, and then layer in the ipilimumab? Whether we do 2 or 4 doses at a time, can we layer it in later to see if we can convert patients into responders or not?

Now, these studies were small. They were phase 2, but they weren’t randomized trials to compare it with the standard of care, which is nivolumab/ipilimumab up front if you were going to do the IO/IO combination, but they were illustrative of the fact that the upfront ipilimumab is important. For all of these 3 studies in aggregate, the CR rate was quite low: less than 10%, ranging from 2% to 0% in some of the trials. For the conversion rate, the rate of converting somebody who’s got stable disease into a responder was about 10%. It speaks more to the idea that, if we had a biomarker to identify them, then, yes, but we don’t. It recommended against that approach without more data, but these trials are very illustrative because a clinician may be faced with the idea, “Let me try the nivolumab, and then if they don’t do well, I’ll add in the ipilimumab. I want to spare the patient the toxicity.” It’s about shying away from that. These trials have shown us that. If there is somebody who you are worried about with the ipilimumab, and you’re worried about toxicity, there is this 10% conversion rate. The early phase 1 studies showed that you can salvage patients with ipilimumab/nivolumab, but it can’t be a received practice.

Daniel J. George, MD: Yeah. It’s a great study even though you might consider that a negative result. It’s an informative result because there’s such a temptation to do just what you said, and that is to say “Well, let me start with 1 and add another.” We do it all the time in oncology, and we think, “Well, that won’t matter,” yet here’s a study showing that, in fact, it could matter a lot. You’re absolutely right. It’s an important, informative study in terms of whether you’re considering that combination. To get the best results, you need to consider that up front.

Transcript Edited for Clarity