Exelixis, Inc. (EXEL) Earnings Call Transcript & Summary

Thanks for joining us, ladies and gentlemen. Please welcome, Susan Hubbard.

Hello, everyone, and welcome to the Exelixis Investor Briefing at the ESMO Virtual Congress 2020. I'm Susan Hubbard, Executive Vice President of Public Affairs and Investor Relations for Exelixis. We are very pleased to have you join us for a review of the CheckMate 9ER trial results, which were just presented a few hours ago in ESMO's presidential symposium session by the principal investigator for the study, Dr. Toni Choueiri of the Dana-Farber Cancer Institute. We have a very prestigious panel of physicians joining Dr. Choueiri today to discuss the results from CheckMate 9ER as well as data from 2 renal cell carcinoma cohorts of COSMIC-021 also being presented at the Congress. Following our panel discussion, we'll have a question-and-answer session where we'll field questions from the audience, which I've already received, so thank you, everybody, for sending your questions in. Before I turn the session over to Mike, I will remind you that during the course of this presentation, we will be making forward-looking statements regarding future events for the future performance of the company, including statements related to the clinical, therapeutic and commercial potential of cabozantinib; regulatory development and submission strategies; the development path for cabozantinib; and commercial planning for CABOMETYX. Actual events or results could, of course, differ materially. We refer you to Slide 2 of the presentation for applicable cautionary language. And now I'm very pleased to turn this over to Mike Morrissey, our President and CEO. On to you, Mike.

All right. Thank you, Susan, and welcome, everybody. It's great to have you all join us today. Really thrilled to finally be here with the ESMO presentation for CheckMate 9ER. We're looking forward to having a very robust and interesting discussion today. I hope you all had a chance to listen to the presidential presentation by Dr. Toni Choueiri and had a chance to look at the background on the data. So we're very excited about that and certainly looking forward to now taking some time today in the afternoon, over the next 75 minutes or so, to have a very robust discussion of the data from Dr. Choueiri first, a high-level summary, and then, I think, a very, very good panel. So it will be a great opportunity to ask some questions, get some more insights and just see kind of where this data is going in the future. So I'll stop there. Again, remind you that we have the sNDA filed. As we mentioned recently, we're commercially launch-ready. So it's just a great time to be part of Exelixis, and we're really looking forward to having this treatment option available to patients soon to help them live longer and recover stronger. So with that, I'll turn the call over to Gisela.

Thank you, Mike. I'm very pleased to introduce our distinguished panels today. And joining us for the discussion today is Dr. Toni Choueiri, the Director of the Lank Cancer Center of Genitourinary Oncology at the Dana-Farber Cancer Institute and the principal investigator of CheckMate 9ER. I'd also like to introduce Dr. Dan George, Professor of Medicine and Surgery at Duke Cancer Institute, Duke University School of Medicine; and Dr. Rana McKay, Associate Clinical Professor of Medicine at the University of California, San Diego. And finally, we are delighted to also have with us Dr. Sumanta Pal, Co-Director of City of Hope's Kidney Cancer Program and head of the kidney and bladder cancer disease team at the institution. I'll now turn the call over to Dr. Choueiri to review the clinical results from CheckMate 9ER that were presented earlier today in the presidential symposium session. Toni?

Thank you. Thank you, Gisela. Thank you, everyone. I hope you and your families are safe during this pandemic and just finished presenting the first result of 9ER, and we're going to go recap now. Next slide. Next slide. Great. So in terms of introduction, we know well nivolumab and cabozantinib. These are 2 drugs that have an overall survival benefit as a single-agent post TKI. And cabozantinib has a first-line designation from the CABOSUN study; and nivolumab, a first-line in combination with ipilimumab. We know nivolumab promote tumor -- antitumor responses by preventing cancer from evading immune detection. And cabozantinib really, beside the angiogenic, in fact, VEGFR, and besides targeting mechanism of resistance, it does have immunomodulatory properties that may actually counterpart tumor-induced immunosuppression. The combination was tested in a study at the NCI by Dr. Andrea Apolo and found to be safe, and we proceeded actually to a Phase III trial. There was also responses in the Phase I study. So next slide. So this is the schema of 9ER. It's 651 patients to be randomized to the combination of nivolumab and cabozantinib at 40-milligram once a day versus sunitinib at standard dose. These patients are untreated, clear cell histology and any IMDC risk group. So this study is not restricted to the intermediate and poor. The stratification factors are the IMDC risk score, the geographic region and the tumor PD-L1 expression. The primary end point, independently reviewed progression-free survival; and several secondary end point: overall survival, response rate, and safety and exploratory end point of quality of life. The median study follow-up, again, this is the first result, was 18 months. Next. So these are the results really in one study. The end point I talked about earlier were all met. Progression-free survival was doubled, 8.3 with sunitinib, times 2, 16.6 exactly with the combination, hazard ratio of 0.51. Overall survival also was significant with a hazard ratio of 0.6. 40% of patients -- the risk of death was reduced by 40% in the combination versus sunitinib. Similarly, objective response rate were actually doubled, up to 55% with the combination, with a CR rate a bit over 8%. The rate of PD as best response was low at 5.6%. Next. What about safety and health-related quality of life. Overall safety was not different between both arm much. But interesting here is the health-related quality of life. When you look at FKSI-19 and FKSI-DRS, which is a subset of FKSI-19, all the asterisks here indicate statistical significance. So the combination of cabo at 40-milligram once a day and nivolumab had statistically significant higher and better quality of life versus sunitinib. There was a consistent improvement over sunitinib, especially in the FKSI-DRS, on your right. On the left, there was a stability compared to baseline, where there was deterioration with the sunitinib arm. Next. So what do we conclude? We conclude here that CheckMate 9ER met all efficacy end points. So almost 50% risk of death decrease or progression. The risk of death itself decreased by 40%. The response rate, the absolute, the increase was 29%. And I did not show that here, but independent of risk groups, our PD-L1 status or bone metastasis, the benefit was consistent. The treatment was well tolerated with a low rate of treatment-related discontinuation. Actually, the treatment-related discontinuation of both drugs, cabo and nivo, due to treatment-related adverse event was less than 5%. And I presented here for you the quality-of-life data with the combination. We believe that these results support nivo/cabo as a potential first-line option for advanced renal cell cancer. Thank you.

Thank you, Toni. And now to start the panel discussion, let's bring back on screen our panel members. And to kick off the discussion and before stepping through the data in more detail, perhaps we could start with the key takeaway of each of you on an individual level for the 9ER study. Could we start with Dr. George?

Yes. Thanks, Gisela. We anticipated this study having seen results from other combinations of TKIs and immune checkpoint inhibitors. But with each drug in each combination, I think there are unique factors. One of the interesting things to me was the totality of the data here that we see, both the really robust radiographic progression-free survival results that separate early and stay separate through the curves; the overall survival benefit that again occurs early in this study and is seen throughout the population to this point in time with as much follow-up; and then finally, the response rates that we see as well. So the overall efficacy across the board for all 3 parameters was really robust. And then the other aspect to me is the safety tolerability that Toni spoke about. And I think one of the concerns we always have with combination therapy versus a monotherapy is how much more toxicity we're adding. I think one of the unique things here was that the company actually lowered the dose, starting dose of cabozantinib. We still saw the robust efficacy but helped with the tolerability and quality of life. So very impressive data from my perspective.

Thank you. Great. We go to Dr. McKay.

Certainly. I mean these data speak for themselves. This is a landmark study, and I think these data are practice-changing. Not only are patients living longer, they are living better. I think the efficacy data is impressive with regards to doubling of the PFS. The data is consistent across all subgroups by IMDC risk criteria, even though this study was done much later than the other 2 trials that have already reported out. And so I think this is definitely practice-changing. Additionally, I think the quality of life is critically important for our patients and how they feel on therapy. And the fact that they are living better, I think, is critically important, especially now as these therapies are working much better, that patients are staying on therapy for a longer time and how they spend their time on therapy is important. So I think these data are very exciting and impressive. And I agree with Dan regarding the totality of the data, not only from an efficacy standpoint, but also safety, tolerability. The data speak for themselves.

Great. Thank you. And Dr. Pal?

Thanks so much, Dr. Schwab. I would suggest that in the context of cabozantinib's original approval in kidney cancer through the METEOR trial that Dr. Choueiri presented several years ago, we talked about this trifecta benefit in terms of response rate, progression-free survival and overall survival. I'd suggest that we're seeing that once again here in the context of the 9ER trial with, I would say, perhaps a benchmark now that's been established in terms of progression-free survival. The investigator-assessed progression-free survival in excess of 19 months, to me, really sets the high watermark in terms of what we've achieved with TKI and IO combos to date. And I probably further really emphasize here that the activity of cabo with nivo really stands out in some very difficult-to-treat subgroups. Patients with bony metastatic disease, it represents one of those. You can see that in the forest plot that Toni presented today during his presentation. And of course, the benefit that we see across risk groups in kidney cancer also deserves mention, too. Many things that really make the 9ER data stand out in the pack.

Fantastic. Thank you. Dr. Choueiri, anything to add?

No. I think it's -- one of the things -- I really -- when I mentioned it, I personally, honestly, was a bit worried because this study just read and with the availability of not just immune checkpoint inhibitors after sunitinib, but also other treatments that are available, you always wonder with how overall survival is going to be. But I'm glad our patients are living longer, 40% decrease the risk of death, and they're living better. So no one could have said it better than Dr. McKay.

Fantastic. Thank you very much for that. And now we'd like to step through the data in a little bit more detail and perhaps starting with the baseline characteristics of the patients included in the 9ER study. And can we have the slide up? Yes. Dr. McKay, would you like to share your thoughts about the baseline characteristics relative to some of the more recent Phase III studies in advanced kidney cancer?

Certainly. I know all we want to do is compare these trials head-to-head, but I think it's critically important this is recognized that these are all different studies. They were all conducted at different times with slightly different patient populations. First, there is CheckMate 214 followed by KEYNOTE-426 and Checkmate 9ER. So just kind of thinking temporarily as drugs are getting approved and there's availability of treatments that patients can receive after their initial first line, this is a later study. I will point out that there are more poor-risk patients in this trial compared to the nivo/ipi trial and compared to the pembro/axi data. The CheckMate -- or KEYNOTE-426 data has the highest percentage of patients with favorable risk disease. Additionally, it's important to point out the difference in PD-L1 status across these different trials. While we don't use PD-L1 status to determine trial or treatment eligibility, it is a prognostic factor in RCC. And the biomarker to determine positivity was different in KEYNOTE-426 compared to the CheckMate studies, and rates of positivity range around 1/4 in CheckMate 9ER and CheckMate 214 compared to 60% in KEYNOTE-426. That's largely because of that differences in assays that are being used. Additionally, I think this trial is conducted in the post-CARMINA era. And we naturally would see a decreased rate of prior nephrectomy, so patients who have their primaries in place. In KEYNOTE-426 and CHECKMATE 214, 80% -- just over 80% of patients have had a prior nephrectomy and their primaries were removed, whereas that number for CheckMate 9ER is 68.7%. I think that's going to be critically important when we get to understanding the data around response because these patients have -- over 30% of patients have their primaries in place, which could be large renal tumors in the kidney. So I think these are the key points to mention regarding the baseline characteristics that are critical to meet.

Great. Thank you. Anything to add from anyone regarding the baseline characteristics?

I think the nephrectomy...

I would just add there, again, every study is a little different, but I would just say that the relatively low number of sarcomatoid patients in this also is a little bit biased against response. We know that immune checkpoint inhibitors are responding. Patients with sarcomatoid elements are responding better to immune checkpoint inhibitors. So seeing a relatively low percentage there is a little bit of a bias for this population kind of against response. But I think that's what happens with randomized studies. And as Rana said, it's really difficult with these cross-study comparisons, but it's just one of the things, when I look at this, that kind of jumps out as well.

Great. Thank you so much. Anything else? Okay. Perhaps we can move forward and then go to the primary end point of the study, progression-free survival, and it's up on the screen here. Could you share your impressions on this result and the curves, Dr. George?

Yes, sure, Gisela. This is a really important end point for our patients. And I know a lot of people focus on overall survival, and that's really critical. But disease control, preventing progression is really one of the most immediate and -- individual readouts that a patient can have regarding therapy. And as a physician treating these patients, this is really critical. I think Monty mentioned it. I mean there's a subset of these patients that are really sick. And in some of these subsets, they're symptomatic. They may have really high tumor burden. They may have really rapidly progressive disease and complications associated with that. Having disease control, preventing progression is really critical. And one of the things I look for in progression-free survival curves is the timing of that response. One of the things you'll notice in this study population with sunitinib is that there's about 30% of patients -- 25%, 30% of patients that progress on the first scan. That's at 3 months. The reality is that some of those are progressing a bit faster than that. That's just the first scan we looked at. By the second scan, we have 40% of patients progressing. We've shown in prior studies going back a decade or more, Susan Halabi and others, that those early progressors, those patients that progress on VEGF-targeted therapy within 6 months have a terrible prognosis. And it's not surprising that, that group of patients is probably what's driving the overall survival curves. But when you compare that to the experimental arm here, nivolumab/cabozantinib, what you see is a very little drop-off with that first scan, maybe 10% and maybe 20% by the time we get out to 6 months. We already see the hazard ratio of 0.5 forming there in those first 6 months. And that's really what's driving that overall survival difference as well. But I can tell you, just from a patient management perspective, that's huge. And being able to double your disease control rate within the first 6 months is really important. And you can see the numbers here are really strong. And then as we go out further, these curves -- these trends continue throughout. We don't see these curves coming together. If anything, we're starting to see a flattening of the nivolumab/cabozantinib arm that you're not seeing with the sunitinib arm. So if anything, you get out 12, 15 months, you see these curves kind of widening further. I think the numbers get small here. And I think we just need to see longer follow-up for this study, and I'm sure we will. But already, the hazard ratio is robust. The significance is robust, the p-value. And to me, this is -- I think Monty said it. I mean this is sort of a new watermark. This is sort of the -- every study we're doing now, we're seeing the improvements associated with this, a patient population historically that would live. I remember, when I started out, 10, 12 months was median survival. Now even in our worst-case scenarios, we're seeing that or better. So it's a really remarkable continuation of the progress we've made in the field. But in particular, speaking about this combination, it's a very robust effect.

Great. And we're seeing quite nice consistency between BICR-assessed PFS and investigator-assessed PFS. What are your thoughts on that?

Yes, I like that. I mean I think the reality is, Gisela, is that we like to see the blinded independent review because I think from a study perspective, that's probably the cleanest end point. You take the sort of the human element out of this in terms of -- is there any bias of the physician in terms of wanting to see a good result for our patients and whatnot. But the reality is, is that investigator assessments matter because that's the real-world data. When we get out into practice, that's really what's going to translate into the real world. And when you see those curves really bear each other, it tells me that, that signal is strong. That's a robust effect regardless of how you measure it. And so I find that very comforting when I see those curves widely separate and parallel each other between the 2 assessments.

Great. Thank you. Dr. Choueiri, what amongst the PFS subgroup stands out most to you and why? Next slide.

They all stand out. I mean one of the things is that I think in what -- I think, in what I presented, there isn't any subgroup that had a hazard ratio over 0.7. I'm not going to say over 1, but even over 0.7 for PFS. It's good to continue to see the good efficacy in bone metastasis. I don't want to say because this is brought up that if you have bone metastasis where we use cabozantinib because it's across all group. And it's partly because sunitinib doesn't perform well in patients with bone -- single-agent TKI, something that Dr. McKay actually is -- has worked on for a long time when she reported on this population. And now she has a randomized trial with cabozantinib with -- without radium with the Alliance. So I think if you look at all the subgroup that the lowest, I believe -- the highest hazard ratio was less than 0.7. So I like benefit across. I like what Dr. George said that it's the whole package. It's the whole robustness. We've seen trials where investigator-assessed PFS was the primary end point, like one of the in-motion trials. So you have to look at the whole package. And here, the hazard ratio even is better with independent-assessed progression-free survival 19.4 months. So you want to see everything. So in a way -- and I've got -- in a way, like lab experiment, under different conditions and whatever you do, you want to see things going the same way. And I think with that combination, I'm pleased to say everything points to the same positive results.

Great. Thank you so much. Turning now to overall survival, and the slide is coming up. Dr. McKay, what are your thoughts on the overall survival curves, the HR, the benefit observed?

Yes. I mean I think the overall survival is impressive. When we look at Kaplan-Meier curve, we want to see the curve separate early and continue to widen over time and not get near each other and hope to see a plateau, meaning long, durable benefit for some patients. And we're beginning to see that here. The curves separate quite early. They continue to widen over time. And I think as long as we get more long-term follow-up data, we're going to be hopefully able to assess where these curves plateau, but we're beginning to see some evidence of that. I think the hazard growth -- ratio of 0.6 with 40% reduction in the risk of death for these patients is clinically significant, meaningful and sort of where we would expect it to be when KEYNOTE-426 reported out at this time point. Now with longer follow-up with KEYNOTE-426, the hazard ratio has shifted away from, I think, initially, was reported at 0.59 for overall survival. So -- and now I believe it's closer to 0.68 or somewhere around there. And so this 0.6 is really impressive to see the curves separating early. And I think the hope would be that we will see a plateau of the curve over time.

Great. Thank you so much. Now let's turn to objective response rate, the CR rate, disease control, the third efficacy end point of the study. Dr. George, what are your thoughts on the response rate data?

Yes. Gisela, I think this was the sort of the third arm of that totality of efficacy that I referred to early on that I really like to see, and this was equally impressive when you look at this 55.7%, almost 56% objective response rate. Remember, when we measure objective response rates, there's a formality to this of criteria that these have to meet. And when we discuss an objective response rate, it has to be a 30% decline by a single dimension in the total tumor burden measure. And to see that in over half of the patients is really impressive. But I want to put that into a little bit of context because, again, I think we look at this data and you can almost get a little bit numb to it sometimes looking at it. But just recognize that these are individual patients. And on an individual patient perspective, they're not going to have a control arm to say, this is improving my survival. They're not going to have a comparator to say, I've got a longer progression-free survival than I would have had on a different treatment. All they're really going to have is the tumor measurements and are they decreasing. So to me, again, this is sort of our real-world marker. And the other markers are perhaps more definitive for a superiority. But to me, this is sort of what we look for every day with our patients, is the tumor shrinking. Sort of gets to that disease control point I mentioned earlier. And this is a cutoff. This is a 30% decline for regression. But there are patients -- and we'll see them in the waterfall plots to come. There are patients that don't quite make that measure that are still seeing some degree of regression. And to be able to see that in patients is really critical. The degree of decrease though matters. And one of the things we're finding is that the more regression that we see, the greater the duration of that benefit and really, the longer the survival for these patients because we're really reducing tumor burden. And again, for some of these patients, tumor reduction is critical because of the symptomatology associated with that disease burden. And Toni, Dr. Choueiri showed this with that quality of life, that's really extending out. It's bopping down initially because this is treatment, it's a shock to the system. Patients adjust. We adjust doses. We manage side effects. The quality of life improves, and then it gets better over time. And that longer-term quality of life is really related to tumor reduction, to reducing the burden of disease. And that's what we're seeing here. I think the last thing is the complete response rate. And you might look at this complete response rate and say, well, 8%, that's good, but we've seen better with some other studies. But remember a couple of things on the study. One -- and Rana pointed this out. It's really key. There was a much higher rate of patients with their primary tumors in place. For the cabo/nivo arm, it was 68%. So 32% of patients had the primary tumors in place. And that really tells me that those are large primary tumors that we're leaving in place, but this is high tumor burden that we're dealing with. These patients are not suited for a cytoreductive nephrectomy. And so that group of patients, it's very unlikely they're going to get a complete response. So right off the bat, you've got 32% that's unlikely to get a complete response. And then you have 16% that have bone metastasis. And bone metastasis are lytic. These are holes in the bone that don't sort of re-heal, so we never see that lytic lesion disappear. That's kind of a permanent effect. So now you're looking at another 16%. Almost half the population in this study was really not set up for a complete response. And so that 8% complete response rate might actually be much higher than that. If you look at actually the population, that's a realistic, and that's really how I think about it when I talk to my patients. I'm thinking about it in terms of whether or not that's a realistic goal, and if it is, I'm not sure I'm going to frame it at 8%. I might frame it higher based upon those subgroups of patients that could really achieve it.

Great. Thank you. Perhaps on the same slide here, Dr. Pal, we often hear that checkpoint inhibitor and TKI combination therapies are used in patients with first NRCC when a fast response is needed. What are your thoughts on the kinetics of achieving the response in terms of time to response and also duration of response observed on CheckMate 9ER?

That's such an important question, Dr. Schwab. I'll turn your attention to the third column -- in the third row rather, in the table on the right-hand side, which is median time to response. And as you can see there, significantly shorter with cabozantinib and nivolumab to 2.8 months versus the 4.2 months we see with sunitinib. The range for nivo and cabo starting at were just 1 month, so you can definitely get some very early responses there. I think that all the clinicians on this call will agree with me, Toni, Dan, Rana, that when we see patients in the clinic, there's certainly a subset of whom we know we've got to downsize tumor in very rapidly. These are the patients that walk into our clinic, for instance, with excruciating pain from their bone metastasis, from metastasis that are sitting in other critical areas. So it's just really useful to know that we're going to evoke a response very quickly. And then, of course, the follow-up to that is something that you brought up, which is how long is that response going to last. The median duration of response that we're seeing here of 20 months is incredibly impressive. And I think this is really what we're going for, right? When we combine a tyrosine kinase inhibitor in an immune-based agent, we want to see that there's sort of a tail on the curve. Not only do we evoke a response, but the immunotherapy element is actually helping sustain that response. And I think that's precisely what we're seeing with that median DOR of 20 months, almost double what we're seeing with sunitinib.

Great. Thank you. Going a little bit further on the response discussion and bringing up the waterfall plot. Dr. Choueiri, you discussed it already a little bit but without the visual support in the short summary, and here it comes. Would you like to give us your impression of the important findings on these waterfall plots and the depth of responses that we're seeing?

Yes. I mean the waterfall plot allow you to look at the data differently because like what Dr. George said, every patient, rather than having this overall response rate, every dot here, every plot, every time point is a patient, is a patient, could be a family member, that could be a friend that we want to look how they've been. And 95% of patients, when you have a second scan, had some sort of reduction. And that's actually when we have a patient in front of us, we're not always going and measuring in practice and say this is 18% versus 7% versus 80%. We look at shrinkage. Of course, if there's a huge shrinkage, that's great. But you look at any shrinkage. So 95% of patients had some sort of shrinking. That's a huge statement and definitely something quite beneficial to be able, with the next scan, when they happen, tell the patient, look, there is some sort of shrinkage. And we can see some of the shrinkage are deep. They're over 80%. They're deep shrinkage. And I think this brings the CR that folks were commented on, which is over 8%. And hopefully, several of these partial response is going to be CR. We know how well these patients do overall. So I think the data is quite compelling here with the combination when you look at the waterfall plots.

Great. Thank you so much. Let's now turn to safety and the tolerability profile of the combination as observed in the CheckMate 9ER study. So when looking at a high level of the exposure and discontinuation rate, what are your thoughts on what has been seen in CheckMate 9ER with respect to tolerability? And we'll address the question to all on the panel. Do you like to start, Dr. George?

Sure. I'm happy to. I think one of the things we think about when we look at these combinations, I mentioned this earlier, we're adding toxicity. We're adding a second drug. We've already got a VEGF-targeted TKI in both arms, and now we're adding a checkpoint inhibitor. And what is that doing to our tolerability? And there's a lot of different ways to look at it. And this shows some of them. The duration, how long are patients staying on study, that really speaks to both the response, the disease control as well as the tolerability. And the median duration here of 14.3 months is really impressive. I'm sure that, that number is going to continue to evolve as we get further follow-up as well. Patients with at least 1 dose reduction of cabo or sunitinib, 56.3% for cabo/nivo. Let's think about that for a second. They're starting out at 40 milligrams, right? This is not the maximum tolerated dose. And half of the patients are going down to 20 milligrams. I can tell you, when I do that in my practice, these patients tolerate cabo very well. My only concern with cabo at 20 milligrams is, is that enough? What's really impressive to me about this study and this data is that even with that dose reduction in half of the patients to 20 milligrams, we're still seeing our intention to treat population with these nearly 70%, 30% reduction in evaluable patients, 70% as PRs and durable, as Monty said, really durable PRs, and half of those patients are getting a dose reduction. So to me, I mean, that's what's really impressive about this combination in cabozantinib, in particular, is the efficacy across the range of doses. And this is the first study where we, from intention to treat, started cabo at 40 milligrams, big Phase III study in a way. And I think this is really evidence that the drug is very active at that dose level and even at the 20-milligram dose level in this combination. So I mean, those first 2 lines right off the bat are -- speak volumes to me about how we can use this and how it's going to translate into the real world. Because I can tell you, when we use these drugs in our real-world patients, that's what we do. We're in the 40-milligram to 20-milligram dose range for a lot of our patients, half or more. And to have that efficacy is really impressive. Now 40% of treatment discontinuation, we're going to expect that. Some of that is disease progression, right? And these patients are going to progress on both of these arms. But to see a 70% versus a 40% over the same time frame is really impressive difference, and I think that, again, speaks to the tolerability as well as disease control. And then treatment discontinuation due to disease progression, you can see that subset. And so consequently, the caveat -- the converse to that is that the treatment-related AEs leading to discontinuation, so 15.3%. For a combination study, it's really not bad at all. That's actually probably better than many of our combinations in not just kidney cancer, but in many of our other cancer types as well. So I look at this 15% discontinuation because of AEs as being really, again, speaking to the tolerability. With that dose reduction to 20 milligrams, most patients are able to stay on treatment. And you can see there having to stop cabo, only 6% had to stop cabo, 8% in the sunitinib arm, despite all the disease progression, patients progressing from disease before they can stop their drug. We're seeing less people stopping treatment because of cabozantinib than we are of sunitinib, even though they're on sunitinib a lot shorter. So I think, again, it really speaks to that whole picture here of the tolerability and efficacy combined.

Can I add one thing?

Yes, please, Toni.

I think in practice -- and it's hard, if I have to design back this study, et cetera, I will be more liberal in what we can do with cabozantinib, go up on the dose, go down, et cetera. But we know that's really very hard when you do an international study. But in practice, we're going to, like we do now, adjust the cabozantinib dose. Maybe we start at 40. There is a small subset that needed dose escalation. There's another subset where I can go to 20 and reescalate to 20 alternating with 40. In practice -- this is, again, in practice, this is not for the study, we do that. We do that with axitinib. I go up and down sometimes on 1 milligram. We have alternative regimen with sunitinib, et cetera, et cetera. The practice may be different and may take a lot from the TKI here, cabozantinib, and adjust the dose accordingly.

Right. Thank you. Dr. Pal, what are your thoughts on the choice of 40 milligrams as a starting dose for cabozantinib in this combination?

Well, I think Dan did such a phenomenal job of summarizing the data as it pertains to the treatment discontinuations and dose reductions and what have you. And I'm really glad that Toni articulated this concept of potentially titrating the dose. I'm still convinced that there's a subset of individuals out there who can really get away with cabozantinib at 60 milligrams about a significant degree of toxicity. And I hope that as we start to incorporate cabozantinib with nivolumab in the clinic, we'll have that flexibility potentially to up the dose in those individuals who are tolerating 40 milligrams exceptionally well. And Toni and I were first sort of introduced to one another through the Phase I experience for cabozantinib, gosh, I mean, I guess, over a decade ago now. And that was really our first primer on using the drug, and it was the first time in kidney cancer patients, believe it or not. And I think over the years, I've really become quite comfortable at titrating the dose of the cabozantinib, and much of the same way that folks talk about dose titration with axitinib and other agents. I'll point out one subtle element on this slide, and that's in this last row here related to which drug was discontinued. I know we oftentimes think about the immunotherapy component of a TKI/IO doublet as being the kinder and gentler component. But look what we've done here with cabozantinib at 40 milligrams. You can see the treatment discontinuation due to AEs for cabo is 6.6%, and that's more or less at parity with what we're seeing with nivolumab. So to me, that was particularly impressive, and perhaps it speaks to a very wide selection of 40 milligrams as the initiating dose.

Great. Thank you so much. And Dr. McKay, anything to add on the exposure and tolerability as it relates to this slide?

Certainly. I mean I think Monty and Dan and Toni did a really good job kind of going through the summary here. I think the key -- another key item to highlight is when we think of nivo/cabo, this is a regimen. This is a -- the 2 drugs are given together in a regimen. And the rate of patients needing to discontinue this regimen because of a treatment-related AE was 3%. So patients are on this regimen for a long time, and only 3% actually had to stop the regimen, whether it be both drugs together, have to stop it and go on to something else because of a tox. That's really low. And so I think that, that is something that's going to be clinically meaningful in practice as it's being used. I think there may have been some like fear around the combination and toxicity. And I think these toxicity data, these -- sort of the disposition, treatment exposure and discontinuation, I think, actually are quite surprising, and this really highlights just how tolerable this regimen is. And so that 3.1% really stands out to me as being quite impressive. And I think we can go on to the next slide here showing the tornado plot of the adverse events, and really, first, I'll draw your attention to the Grade 3 and higher adverse events. That -- those are the bars that are highlighted in dark blue and in dark orange. And they're actually comparable between cabozantinib -- nivolumab/cabozantinib and also sunitinib. So there's not significantly more severe toxicity with this doublet compared to single-agent sunitinib. When we look at the lighter-shaded bars, we do see slightly more diarrhea and more AST, ALT elevation, but this is lower grade toxicity that is managed with either dose reductions or supportive therapies as opposed to higher grade toxicity. So with this doublet of 2 drugs together, we're seeing comparable Grade 3 and higher AEs when we compare to sunitinib. And the other piece to bear in mind is these patients are staying on therapy for twice as long as patients on SUTENT. So they have twice as long of an opportunity to get an AE. The better a patient does and the longer they stay on a regimen, the more time they have, the more opportunity they have to get an adverse events because they're on the therapy. So these patients are on this regimen for twice as long as the sunitinib patients, and their Grade 3 or higher AE is comparable. And it's 2 drugs. So I think this is incredibly meaningful, I think, for patients and clinicians. This is an incredibly safe combination to give that's quite tolerable for patients. So I'm really impressed with this data.