Novel Triplet Combination Regimens in Frontline RCC


Ongoing studies assessing triplet regimens in frontline advanced RCC and their influence on treatment decisions are discussed, including efficacy outcomes.

Dr. Robert Motzer: Well, let's move on to maybe the final topic. And that is the these triplets now that are being studied for RCC and the recent data that came out with COSMIC-313. And I didn't know, Brian, what's been your take on that trial and where it's going and whether it's a new standard of care?

Dr. Brian Rini: I think it was a great idea. Let's combine all the active mechanisms, that's how we've cured germ cell and other tumors. I think toxicity was very limiting, almost 60% high dose steroid use. I think the average Cabo dose was like 23 milligrams. So the take home for me is that toxicity compromised drug delivery, and that compromised drug delivery perhaps prevented a strong efficacy signal. I know there was a PFS advantage, but we didn't really see a big response rate advantage or high numbers. We didn't see a high CRA, we didn't see a survival advantage. So I think for triplets to become adopted, it's either going to have to be an overall survival signal or some really, really robust non-OS signal, like a CRA of 25% a PFS of three years, something that just really knocks your socks off because you're talking about a lot of drugs with a lot of toxicity for a lot of time. And I think the appetite for that, especially in patients who have more favorable or more or low volume disease is not going to be there. So COSMIC didn't achieve OS, at least yet. We'll see what further analyses show. Merck had a big triplet study that's completed accrual, there's other plans in the works for triplet. So I think COSMIC's the beginning of the story, not the end, but it was mostly a toxic story for me.

Dr. Elizabeth Plimack: I would agree. I just want to highlight one point you just said, which is for a lot of time. So these drugs work for a long time, so people are on them for a long time. And so if you're layering toxicities for a long time, that's a cumulative tox load that we don't really talk about. The CTCA don't really capture it, maybe quality of life does while people are on study and filling out those forms. But I agree. I think there's good things about sequencing therapy. You can manage toxicity a little bit at a time, you have something to go to at these progression events. There maybe even something biologic to switching, going back to the old days of switch maintenance therapy studies, those kinds of things. So it's not intuitive to me that everything upfront would work. I agree it was a good idea, we've tested it. I'm not surprised the toxicity was high, I'm not surprised at compromised drug delivery, but OS is where we should all focus our lens on this and other studies.

Dr. Brian Rini: And I would just add your comment about duration of toxicity. We really should be reporting that. I had a chance to go back and pull an old Sunitinib 2/1 paper that we wrote years ago. I was giving a talk on the role of TKI monotherapy, which is a difficult talk to give. And so I pulled that data and we put like almost swimmers plots to say, well, the number of toxicity might be the same, but the duration spent in grade two is most of that toxicity in a couple days of grade three or whatever. And I don't think quality of life captured that, that's a different discussion. But it shouldn't be too hard to report duration of tox in some sort of swimmer's plot or something. I tell patients, I'd rather have a day of grade three toxicity than two years of grade two.

Dr. Elizabeth Plimack: Absolutely.

Dr. Brian Rini: As a dramatic example, but I think the field needs to do a better job of reporting toxicity in a meaningful way to patients.

Dr. Elizabeth Plimack: And I think this is a great problem to have that people do so well for so long on treatment. And so I think our ways of measuring how well they do in all facets need to evolve.

Dr. Robert Motzer: I think that's a great point in terms of not capturing the duration of toxicity, because we're faulted just by the high grade. One day of a grade three diarrhea is not as much of an impact to the patient as two months of grade two diarrhea. And so it's really the duration or the chronic toxicity that seems to have the most impact. And so I agree with that, that's something we should definitely be start capturing on our trials.

Dr. Brian Rini: I think before we're all done, that I think patients will have apps on their phones and they'll say, Oh, I had three bowel movements today and itchy skin and I was this tired," and it'll just capture on a daily basis and then it'll read out in some form. That's my dream anyway because data capture-

Dr. Elizabeth Plimack: People do that.

Dr. Brian Rini: We all run clinical trial units and the amount of time we spend capturing meaningless data in immense, again, totally different topic. But I think technology is already there with wearables and such, we're just not taking advantage of it.

Dr. Elizabeth Plimack: Totally agree.

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