Elizabeth Nally: Thank you so much. Yeah. We know when we looked at the quality of life data that's available out there in the adjuvant setting kidney cancer and we saw the same recurring pattern. There are obviously differing toxicity rates between the treatment and placebo arms, but there was that same quality of life analysis that followed, that showed no difference between the two arms. And I think from our experiences in clinic, we know that these drugs have toxicity that can be lifelong. And so, it didn't quite resonate with us. I know there are lots of people doing work on quality of life tools and there's been suggestions that we need better tools in the immunotherapy area to capture that toxicity and also capture the patient experience. And what we felt would be the next best step is actually asking our patients what they think of the treatment.
And so, I sat down with a group of patients at our institution and asked them about their experiences in immunotherapy to come up with a new toxicity framework. And this is how these four categories were developed, life-changing, significant long-term term, significant short-term, and non-significant.
Elizabeth Plimack: Fantastic.
Elizabeth Nally: And so, patients felt that these categories were much more reflective of their experiences. And we were really fortunate to get access to the toxicity and quality of life data from the IMmotion010 trial. This was a big global randomized phase-three led by Monty Powell. And we explored the frequency of those categories within the toxicity data, and we recategorized the CTCAE graded events according to this new framework. And we really highlighted that there was a discrepancy. Over 30% of grade one to two events were recategorized as significant or life changing, really highlighting that the way we as physicians define toxicity is not in line with how patients perceive it. And the next step was looking to explore whether these toxicity categories, whether they have any detriment on quality of life, because they feel much more reflective of that the actual patients experience. And when we looked at quality of life in the trial measured using the FKSI-19, a common kidney cancer tool, we were fortunate there was lots of long-term data in the IMmotion010 trial. They followed these patients up for up to five years.
Elizabeth Plimack: Well, one of the things we learned from the very rich long-term follow-up, is that some patients stop filling out the surveys. And you showed us that especially when you characterize this life altering, the ones in that category, remember that graph-
Elizabeth Nally: Exactly.
Elizabeth Plimack: ... tend to be the ones that aren't filling them out. And so, this really spoke to me in the audience because when I see quality of life data, like for IPI and NIVO that quality of life is not impacted, we know it is, but we can't see it because we're not measuring that in that patient at that point in time. So the long-term follow-up that you had from this study I think is a huge benefit to what we can learn about quality of life. And I also want to say the categories that you remade instead of CTCAE, to make these categories is brilliant. Because we complained for a long time in the immunotherapy era that if you have joint aches that are grade two for the rest of your life, that's going to be in the red box for your assessment.
Elizabeth Nally: Totally.
Elizabeth Plimack: That's life altering. And that's what we need to be measuring so that we can really, one, understand ourselves what we're causing, what the price of success is, and the other is to have these conversations with our patients at the get-go a little differently.
Elizabeth Nally: Totally. And what you said about the musculoskeletal rheumatological issues, they were the life-changing events along with the endocrine events that really... And sometimes it was a grade two event, but if that grade two event was still lingering at two years on and the patient was then needing methotrexate having been cured of their cancer, that is probably what's driving that long-term quality of life deterioration that we're seeing in this life-changing population. And I think it's so important that we collect this data in our long-term follow-up so that we can better inform our future patients. One of the other things we did on the study, is we looked at patients' expectations before they started the treatment. If a patient had a low expectation of what their potential toxicities were going to be, the regret score was higher. And it really, really highlighted to us that that initial counseling meeting, that I think has become a really complicated discussion with patients, we know that immune checkpoint inhibitor has a survival benefit, but we need to make sure that our patients are fully aware of the potential toxicities.
And sometimes, I think, as clinicians we focus on the severe acute things. The patients that we remember are those that are admitted to ITU that we're going up to see every day. But from a patient perspective, they seem to be more focused down the line on the long-term toxicities.
Elizabeth Plimack: Right. Absolutely.
Elizabeth Nally: And in our initial counseling session, we need to talk about the long-term side effects too.
Elizabeth Plimack: Right, right. I agree. I think this is one of the most difficult conversations I have-
Elizabeth Nally: Totally.
Elizabeth Plimack: ... around treatment decision-making in general, is in the adjuvant space.
Elizabeth Nally: Totally.
Elizabeth Plimack: Because we know we're over treating people. We know for some patients it's futile. It's hard to know who will benefit. And while some people have no side effects, some people are in your category of they're fine, your lowest quartile, but then the life altering is exactly that, life altering and it can be permanent. So the way you have reframed the way we grade toxicities and the way, hopefully going forward, we start to manage quality of life and ask questions, I think is practice changing from a trial's perspective.
Elizabeth Nally: And that's exactly what we hope to drive for the future, is that our perioperative trials capture this long-term data. Because at the moment we don't really have it, and we need it in order to inform our future patients. And we recognize that carrying a trial on is expensive and it's difficult, but maybe even if we just follow up that life-changing proportion, if we know that life-changing toxicity is associated with the deterioration in quality of life, then maybe just following those patients will give us that long-term data that we need.
Elizabeth Plimack: I absolutely agree. And I think we need the long-term data for both efficacy reasons and for quality of life reasons. So I'm behind you. It is expensive. Sometimes we ask and we don't get it, but it would be great to see. I just want to ask you a little bit about regret because I've started to think about this more in the context of bladder sparing trials that we're doing, in terms of the sandwich approach, and then of course in the adjuvant space in kidney and bladder. How do we think about regret? Obviously we want to prevent it. You actually measured it. You actually asked patients, "Did you regret your decision?" Is this something we should weave into our trials going forward so that we can understand that as well?
Elizabeth Nally: I think regret is a really complicated thing. And I talked about some of the limitations with asking patients about their regret level. We know that we ask patients over a year down the line and that is susceptible to survivorship bias, but I think it's a really powerful information to have to inform our future patients. If a patient's not in front of us and we're able to say, "However many percent of patients that have gone before you, at two years down the line, this is how many regretted that decision," I think that's a really powerful statement that patients can get on board with. And it would just help shape that adjuvant counseling conversation, which we know is time-consuming and really complicated.
Elizabeth Plimack: But we have to get it right.
Elizabeth Nally: Totally.
Elizabeth Plimack: We have to get it right.
Elizabeth Nally: Yeah.
Elizabeth Plimack: And that's how we're going to help our patients though.
Elizabeth Nally: Absolutely.
Elizabeth Plimack: Well, thank you so much. I really see this as groundbreaking work. Thank you so much-
Elizabeth Nally: Thank you.
Elizabeth Plimack: ... for presenting it and talking about it today.
Elizabeth Nally: Thank you so much.