Moshe C. Ornstein, MD, MA

 I’m going to turn to you, Scott. Do you believe DFS [disease-free survival] as the primary end point is appropriate? Obviously, the FDA thinks so, and that’s why all these adjuvant trials have used DFS as the primary end point. If a trial meets the DFS end point but doesn’t meet the OS [overall survival] end point, are you OK with that? That’s one question I’d like you to address.

Second, you’ve done a lot of translational research, and you think of biomarkers. As Moshe alluded to, I’m sure there’s an effort from KEYNOTE-564 to look at biomarkers in those patients to see if there’s a subgroup of patients who benefit from adjuvant pembrolizumab and will be cured with 1 year of adjuvant pembrolizumab rather than have relapse and unfortunately die by not receiving adjuvant therapy within 12 weeks from nephrectomy. It’s like the data from the adjuvant therapy with an anti–PD-1 in bladder cancer. Is DFS a good end point, even if OS isn’t met? And talk about biomarkers.

 The issue of OS and adjuvant therapy is challenging. Obviously, we’d love to have an OS end point, but it adds time to the analysis and elements beyond the control of the study that you’ve designed. Up until when the patient progresses, they’re governed by the study and the study therapies. After they progress, they can receive any treatment you choose. You’re trying to measure OS when patients are getting heterogeneous therapies for their recurrent disease. That’s very challenging.

I went to an FDA talk at ASCO [American Society of Clinical Oncology Annual Meeting], and it was confusing. They said they recognized the practical features of allowing a surrogate for OS, such as DFS, and they accept that end point, but they want OS. It wasn’t clear what the message was supposed to be.

I’d be disappointed if we knew we had data like these in hand with a very compelling hazard ratio, but we weren’t allowed to use pembrolizumab, and we were going to wait another 2, 3, or 4 years to see how the OS data matured. I recognize that limitation, and I tell my patients that we can’t say for sure if this is going to extend their life, but what we know and what we’ve measured so far look promising. I’m comfortable with the DFS data, but with the expectation that the study will follow the cohort and ultimately show you OS. If they shut everything down and never measured the OS, that would be an error, and that would be an error on our regulatory agencies to not force the company to monitor and report the OS. But how that breaks may be challenging to interpret.

We love to have biomarkers. Everybody wants biomarkers. When you look across the frontline metastatic setting, it’s very vexing. There are a lot of gene expression analyses in the phase 3 trials that don’t travel very well. They seem to be context specific, JAVELIN vs CheckMate. I don’t think we’re going to have anything soon that’s going to be a slam dunk to assess our patients. Circulating tumor DNA looks very provocative in certain situations. My understanding of the lure of kidney is that it doesn’t shed a lot of DNA, and that isn’t an easy tool to apply specifically for kidney. I’m not sure that’s going to be the answer, but we shouldn’t stop looking. We’d obviously love to understand better. How can we steer the therapy toward the patients who need it the most and are likely to benefit?

 We’re out of time. I’m sorry. We have to wrap it up. Thank you for your thoughtful answers, your insightful comments, and the tremendous effort and information you provided to the practitioners and listeners. I’d like to wrap it up by thanking you both for joining me on this program, and by thanking the listeners who will hopefully find this program very informative and helpful for their practices. I’d like to thank the 

™team for their support and for staying late this evening. Thank you all. We hope to see you soon on the next program with 

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Scott Tykodi, MD, PhD, discusses using DFS as a primary end point in trials, as well as the usage of biomarkers.

DFS vs OS Primary Endpoints in KEYNOTE 564

 We’re going to finish our program with a discussion about the data from KEYNOTE-564, what it brings, and how we think about adjuvant therapy. Does 1 year of pembrolizumab for patients who qualified for that trial—pembrolizumab for 1 year over placebo—cure patients who wouldn’t have otherwise been cured if they didn’t receive adjuvant pembrolizumab for 1 year and wouldn’t have been salvaged with doublet or triplet later, when they recurred? Or are we merely delaying recurrence? This is a question I’m still grappling with. I have that discussion with patients. Obviously, they’re important data. There’s a trend toward OS [overall survival] with pembrolizumab over placebo from the Kaplan-Meier curves, but I’d like to get your thoughts on this, starting with Moshe. What do you think? How are you interpreting the data? What are you telling your patients?

 It’s a great question. When it comes to adjuvant therapy in general, it’s a tricky business because you have patients who are cured with surgery alone—even if they didn’t get any therapy—and we’re overtreating them by giving them therapy. On the other side of the spectrum, you have patients who are still going to have a recurrence possibly around the same time and still have the same end point in terms of survival, even if they get adjuvant therapy. We’re looking for whether we can isolate those patients for whom there’s a tangible benefit not just in DFS [disease-free survival] but also in OS.

My approach since this has been approved is that for patients who are high risk and M1 NED [no evidence of disease], acknowledging the relatively small numbers, those patients should get or at least be strongly considered for adjuvant pembrolizumab. I’m giving it as a standard for those patients. Certainly, we’re hopeful that the OS benefit moves from being just a trend and translates into a significant benefit, although it’s going to take time for that to mature. This is an I/O [immuno-oncology] therapy, and systemic therapies have improved over time, which means that it’s more challenging to find end points for survival in an adjuvant setting in which many patients are already cured.

For patients who have intermediate-high risk—which didn’t make up most of the patients—I talk to them about the fact that those 2 ends of the spectrum exist. It’s important to take the patient’s perspective into consideration. A lot of patients think, “If I have a recurrence in 2 years and I die from the disease without taking an approved immunotherapy in the adjuvant setting, how am I going to feel about myself as a patient and about the oncology team?” That’s a real consideration, because we don’t know, and there’s a chance that the OS benefit pans out.

This is different from the S-TRAC study, where the curves were completely overlapping. The long-term benefits of immunotherapy can take time to mature. Even in the intermediate high-risk group, most patients have been electing to receive adjuvant pembrolizumab regardless of their risk. I’ve been giving it to most patients. I generally will give it unless a patient is concerned about the toxicities after we discuss them. I believe the label is very broad in terms of what they allow in the adjuvant setting. I don’t think it’s as specific as the inclusion criteria in KEYNOTE-564. I worry that there might be patients with [much] lower risk who might be given adjuvant therapy because of the temptation by a physician to do something and the temptation of a patient to receive something to feel like they’re doing something. But in general, for patients who would have met the inclusion criteria for this trial, I’m offering it as an option, and most patients elect to receive it.

 To follow up on that question, I have 2 questions for you, Moshe. What therapy will you give that patient who accepts your recommendation to receive adjuvant therapy? If you give them pembrolizumab for 1 year and then they relapse, are you concerned that you’re compromising their response to subsequent immune checkpoint therapy?

 The short answer is that we don’t know the answer. Over time, we’ll have follow-up data from KEYNOTE-564 about subsequent therapies. In terms of my practice, I haven’t seen a patient with explosive disease while on pembrolizumab in the adjuvant setting, but the decision in terms of what to do for subsequent treatment will depend on 2 main factors. One is the timing of recurrence: whether it’s immediate while they’re on therapy, soon after discontinuing therapy after a year, or 3 or 4 years down the road. Those patients would be treated differently. Also, some of this has to do with the nature of the recurrence. Are they recurring by way of a couple of small pulmonary nodules that have suddenly met criteria for PD [progressive disease]? Or are they recurring because they suddenly have lots of bone metastases or new liver metastases? I’d treat both of those differently. Frankly, I haven’t been faced with that a lot because it’s still relatively new, but the timing and the nature of progression will determine the subsequent therapies in my clinic.

Moshe Ornstein, MD, MA, discusses his approach to adjuvant therapy while treating patients with advanced clear cell RCC.

Adjuvant Therapy Treatment Approaches for Patients with Advanced Clear Cell RCC

 Here’s the design of KEYNOTE-564. The key eligibility criteria included confirmed clear cell RCC [renal cell carcinoma], nephrectomy within 12 weeks prior to randomization—that’s important—good performance status, and stratification factor M0 vs M1 NED [no evidence of disease]. This trial recruited patients who had metastatic disease, oligometastases that were resected to no evidence of disease status. That’s the M1 NED. That’s one stratum. The other one within the M0 group was further stratified by ECOG 0 vs ECOG 1 and US vs non-US sites. The experimental arm in KEYNOTE-564 was pembrolizumab at 200 mg IV [intravenously] every 3 weeks for 1 year vs placebo for 1 year. The primary end point was disease-free survival [DFS] by investigator. The key secondary end point was OS [overall survival]. The other secondary end point was safety. In the next few slides, we’ll see the efficacy results from KEYNOTE-564.

Here are the patients who were eligible. There were 3 cohorts of patients. The vast majority of those patients were in the intermediate-high [risk cohort], and fewer patients—5% to 8%—were M1 NED and had high risk as defined by pT4, or any tumor—any pT—any grade, but node positive. Those plus the M1 NED constituted about 13% of the recruitment, and the vast majority of patients were intermediate-high [risk], pT2, grade 4, or sarcomatoid, N0, M0, and then any grade but pT3, N0, M0.

At the bottom are data for disease-free survival at 5 years by UISS [UCLA Integrated Staging System] and for the M1 NED, the ECOG 2810 study. The probability of relapse is highest for M1 NED, and next is the node-positive patients. Next is patients who have T4 disease, and then pT3 disease, which this patient presented with. That patient will have a relapse rate of 20% to 45%. The pT3 [category] comes in different flavors: pT3a, pT3b, or pT3c. The higher the grade, the higher the probability of relapse. That speaks to why I’m not sending those patients to Scott [Tykodi] or Moshe [Ornstein] at their institutions. Those patients have only 20% probability of relapse at 5 years if they have pT2 disease, grade 4.

The list of the criteria is on the slide. As I mentioned, 86% or 87% of those patients had M0, intermediate-high risk. Those were the T2, grade 4, or sarcomatoid and T3 disease. Eighty-five percent of the M0 high-risk [patients] were M1 NED.

[Let’s look at] the couple of markers for the primary end point, disease-free survival. This is intent to treat by investigator assessment. The green curve represents patients treated with the pembrolizumab, and the red [curve] is patients treated with placebo. At the 2-year mark, there’s about an 11% delta for disease-free survival probability between the 2 arms. That had a hazard ratio of 0.68 at the time of the initial analysis at ASCO [American Society of Clinical Oncology Annual Meeting] 2021. That was a statistically significant difference for DFS between the 2 arms. At subsequent follow-up with a minimum follow-up of 2½ years, that 11% difference is maintained, with a hazard ratio a little lower, at 0.63. [This is] a significant difference for the delta for disease-free survival probability at 2 years.

Looking by risk category—intermediate-high risk, high risk, and M1 NED—for all 3 cohorts, there’s a separation of the curves for disease-free survival between the treatment arm, pembrolizumab vs placebo, with hazard ratios of 0.68, 0.60, and 0.28. But a cautioning note here: for the high risk and the M1 NED, because the number of patients is small, I’d interpret that with caution. If you look at the confidence interval for high risk, the upper bound is 1.10. It crosses the 1. The hazard ratio is 0.6. The difference is numerically higher, but it’s a small number of patients, so one has to be careful in interpreting this.

When you have an adjuvant therapy and you haven’t shown significant improvement in OS because the OS data are still immature, safety becomes important. One will look at the subgroups for trends or hints. You can look at the forest plot and argue about whether forest plots are useful. When you look at the randomized phase 3 trials, you can see patients treated with pembrolizumab across all those categories of subgroups, including age, sex, ECOG [performance status], region, and tumor grade. PD-L1 status favored pembrolizumab over placebo, although one has to be careful about putting too much emphasis on subgroup analysis with forest plots from these trials.

This is the interim OS in the intent-to-treat population. The primary analysis had a median follow-up of 24.1 months on the left, and [the updated analysis] had a 30.1-month median follow-up. The top curve, the green curve, represents patients treated with pembrolizumab; the red curve represents patients treated with placebo. The hazard ratio is 0.54, but only a third of the deaths have been observed. These are still immature data for OS. We need longer follow-up to say whether this will cross the prespecified statistical significance. However, it’s important to know that there have been more deaths on the placebo arm. You can see patients with events at the latest follow-up: 43 vs 23. There’s a difference there, but the median hasn’t been reached for either arm.

[Looking at] the adverse events [AEs], if we focus on the [updated analysis], there are higher [rates of] all-cause AE in the pembrolizumab arm vs the placebo arm—especially when you look at grade 3 and higher adverse events, which were almost double with pembrolizumab over placebo. That’s no surprise. But there were only 2 deaths in the pembrolizumab arm and 1 death in the placebo arm. Those 2 deaths aren’t necessarily from the study. They weren’t necessarily treatment related. The serious AEs were almost double with pembrolizumab vs placebo, and serious AEs leading to treatment discontinuation were 10% vs 1%, which wasn’t a surprise. Even in the healthy, fit population, such as patients postnephrectomy, there are patients who develop toxicity from an anti–PD-1, which leads to discontinuation. Grade 3 and 4 treatment-related adverse events were 18.6% vs 1.2%. Immune-related adverse events were lower: about 9% vs 0.6%. Around 8% of the patients required high-dose corticosteroids for management of immune-related adverse events.

[This slide] talks a little more about the adverse events. We’re all familiar with adverse events from pembrolizumab monotherapy. Side by side in that tornado plot are patients treated with pembrolizumab and patients treated with placebo. Top to bottom are adverse events we expect from an anti–PD-1: fatigue, rash, pruritus, thyroid disorder, diarrhea, arthralgia, nausea, myalgia, and asthenia. The median time to first onset of these adverse events in the pembrolizumab arm is about 6 months.

Nizar Tannir, MD, describes the data, criteria, and end points of the KEYNOTE-564 trial.

Design, Criteria, and Endpoints of KEYNOTE 564

 This is a summary of the results of the TKIs [tyrosine kinase inhibitors]. You touched on it, Scott. All the trials with a targeted agent were negative except the one that you pointed out: S-TRAC, which led to the approval of sunitinib. ASSURE is the cooperative group study. PROTECT was with pazopanib. ASSURE was sorafenib vs sunitinib vs placebo. ATLAS was axitinib vs placebo. The SORCE trial was 2 doses of sorafenib vs placebo. Then we’ll talk a little about EVEREST, the latest study that was presented at ASCO [American Society of Clinical Oncology annual meeting] 2022. I put it in red because it’s a negative study in my opinion, although it was teetering on—you can see the upper bound of it, 95% confidence interval being 1. But the hazard ratio is only 0.85. I’d like to get your thoughts on this. Let’s go through the data from KEYNOTE-564.

Here is [the phase 3 EVEREST study] presented by Chris Ryan, [MD,] at ASCO [in June]. It was 1 year of everolimus vs placebo. Fifty-five percent of the recruited patients had very high risk, defined here as pT3a, grade 3 or 4, or pT3b-c or T4, any T, any grade but node positive vs the intermediate-high risk. They used relapse-free survival and not disease-free survival [DFS], like most of these adjuvant trials. There was a 63% improvement in 6-year relapse-free survival. The overall hazard ratio was 0.85, which didn’t meet the prespecified 

 value. We’ll see what the FDA will say, but I don’t think this is going to be a factor in the adjuvant setting. Especially now that we have other trials with combinations of immune checkpoint inhibitors coming out. I’ll go through those slides to show all the adjuvant trials in the IO [immunotherapy] space.

These are the studies of adjuvant IO in RCC [renal cell carcinoma]. We’ll talk about KEYNOTE-564 in detail. We’re awaiting the results of IMmotion010, CheckMate-914, and RAMPART. There was a statement that PROSPER RCC was negative. The primary end point for most of these was DFS. For PROSPER RCC, it was event-free survival. PROSPER RCC was a little different from the others because it isn’t strictly an adjuvant IO therapy because patients had a biopsy with the primary tumor still in situ, started on nivolumab when the primary was still in place, then had the nephrectomy, and then received further adjuvant nivolumab. The RAMPART trial, which would be the latest to read out in a couple of years, is a triplet similar to CheckMate-914, which is a triplet of dual checkpoint blockade vs monotherapy with anti–PD-1 vs placebo. RAMPART has observation rather than placebo, which was the control arm in CheckMate-914.

Dr Nizar Tannir describes data presented at ASCO 2022 from EVEREST investigating everolimus vs placebo for patients with high-risk disease.

Clear Cell RCC and the KEYNOTE 564 Trial

 In the interest of time and the topic of adjuvant therapy based on the recently approved pembrolizumab from KEYNOTE-564, I’d like to go to the next segment and talk a little about adjuvant therapy and get your thoughts about that. Let’s talk about this case quickly and then review some of the data for adjuvant therapy for clear cell RCC [renal cell carcinoma].

This is a 65-year-old man who developed abdominal pain and was found to have a right renal mass that measured 4.6 cm in the right kidney. He didn’t have metastatic disease, weight loss, hematuria, fever, or pain. He had a CT scan of the chest, which was normal. Laboratory results were normal. He underwent a right radical nephrectomy, and the pathology was consistent with clear cell RCC. It was grade 3, measuring 5.2 cm in size. There were no sarcomatoid or rhabdoid features. The tumor invaded branches of the renal vein. He was staged as stage III (pT3a) because of the renal vein involvement. There were no lymph nodes sampled, and he didn’t have metastatic disease. He clearly had stage III disease.

What do we have now in terms of data that can guide us in recommending adjuvant therapy? Here’s a question to both of you, starting with Scott. Since the approval of pembrolizumab in the adjuvant setting based on KEYNOTE-564, which I will review in the next few slides, have you used pembrolizumab as adjuvant therapy in a patient like this?

Yes. We were a participating site in KEYNOTE-564 and had a couple of patients in the study. Since the FDA approval, I’ve used it for a handful of other patients. The complete menu of options is sunitinib, which was approved in 2017, and pembrolizumab. I don’t think I’ve ever had a patient who came to me from the community and got adjuvant sunitinib. I’ve done it myself in a handful of patients. But as we teach our fellows, show them the breadth of negative studies of targeted monotherapy of the adjuvant studies that have been done. It’s quite disappointing. You wonder whether the S-TRAC trial is just a funny outlier and there isn’t true efficacy there.

I’m not gung ho on the TKI [tyrosine kinase inhibitor], and I’ve embraced pembrolizumab as having a more convincing data set and hopefully less overall toxicity. You obviously can create some problems in a subset of patients. But I’d be surprised to see patients offered sunitinib unless they have some strong contraindications to IO [immunotherapy]. Pembrolizumab is clearly the drug of choice in the adjuvant space.

 Have you seen more referrals to your practice from urologists, the community, or other medical oncologists who wanted to refer to your center for your recommendation regarding giving them adjuvant pembrolizumab? At our center, we have seen huge numbers of patients being referred, both internally from our urology colleagues as well as from outside. I’d like to know if you’re seeing the same thing in Seattle and Cleveland.

Most of our referrals have come from our own surgical team. Not that many have come from the community. One interesting feature of KEYNOTE-564 is the breadth of risk enrolled in that study, all the way down to T2 high-grade tumors. I have never had a patient referred to me with a T2 for adjuvant therapy. Urologists [don’t know] that’s even a connection there. It’s got to be an ugly stage III before they start thinking about systemic therapy being appropriate. Does your surgical team hand off their T2 tumors to you, or is that something you don’t get very often?

 Our urologists have been sending us stage III, T4s, and T3 if they are node positive. You’re right. We’ll show these data. KEYNOTE-564 included patients with T2 disease if they had sarcomatoid or grade 4. As we’ll show in the slides, that was the bulk of the patients. The bulk of the patients—86%—enrolled on the drug were T2 high grade. Moshe, what’s your view at the Cleveland Clinic?

 It’s interesting. After sunitinib was approved 4 or 5 years ago for adjuvant therapy, there was initially a wave of patients being referred. But as the data—in terms of DFS [disease-free survival] and the absence of OS [overall survival] advantage—became more apparent to the urologists, those referrals slowed. Now it’s a rush. We’re seeing a lot of patients. Ours come primarily internally, but we have extremely high surgical volumes, so we’re seeing a lot of patients and many referrals.

We also aren’t seeing the T2 patients. But even this patient presented here is a T3a and falls into a risk that was included in the trial, albeit on the lower end of the risk. This patient didn’t have sarcomatoid features. Although this patient isn’t a T2—they were T3a—it isn’t necessarily the highest of risks. But this patient certainly would have been approved. Now it’s almost automatic when there’s a T3, stage III or above. We’ve even started getting more referrals for metastasectomies based on the data that I’m sure you’ll show.

Experts discuss the use of pembrolizumab as an adjuvant therapy in advanced clear cell RCC.

Adjuvant Therapy in Clear Cell RCC

 Scott, are there any instances in which you would consider switching from an IO [immunotherapy]-TKI [tyrosine kinase inhibitor] or an IO combination to another regimen? Is there a particular situation in which the patient doesn’t tolerate pembrolizumab-lenvatinib and you go, “Instead of reducing the lenvatinib dose, I’m going to switch to cabozantinib-nivolumab,” or you stick with the same regimen and dose adjust to tolerance?

 [There are] a couple of scenarios. If you have given ipilimumab-nivolumab, gone through the combination dosing phase, and you’re on nivolumab monotherapy and progressing, it isn’t evidence-based, but it’s tempting to add cabozantinib to nivolumab and do nivolumab-cabozantinib as your second-line regimen. I’ve certainly done that for many patients. In a sense, it’s a transition from IO-IO to IO-TKI.

We referred to the desire to have a study that will guide us as to whether there’s true synergy in that setting. There’s also a cooperative group study looking at risk-adapted use of cabozantinib in that fashion. It would be lovely to have those data. But it’s such a natural transition to make, particularly in a patient who has had success, an early response, and then lost it a year after starting therapy. It feels right to try to extend the use of the IO compound.

Conversely, I did pembrolizumab-axitinib when it was the only IO-TKI, and now we’ve gone to some of the competitors. Often, with the patient who had early success, a partial response, and didn’t have a lot of toxicity but is beginning to progress through it, I have certainly used ipilimumab-nivolumab in the salvage setting many times. There’s a decent response rate for ipilimumab as a salvage drug, in the 15% to 20% range for most data sets. You don’t see depth of response. You don’t see CRs [complete responses] emerge in that context, but the response rate and the disease control rate rival giving a targeted drug in that setting. You’d like to feel that the personal track record of the patient who had good IO tolerance and some success maybe enriches for the likelihood of success. I certainly have done that as well. I’ve gone both ways with changing a doublet, one vs the other, depending on where we started.

 Moshe, [what are] your thoughts on that?

 Interestingly, although I give more IO-TKI in the frontline setting than IO-IO, an argument to give IO-IO up front is the benefit of giving ipilimumab in the frontline setting, which appears to be far superior than giving ipilimumab in the salvage setting. In some ways, when you give an IO-TKI up front, you lose out on the true benefit of ipilimumab, which is probably that it contributes to that tail of the curve in the combination of ipilimumab and nivolumab in the treatment-naïve setting.

I generally shy away from giving salvage ipilimumab. I might give it to a patient who had a nice initial response to an IO agent, but I’d give it in a subsequent setting and not immediately following the frontline setting. I’d reserve it for a later line of treatment. I have also done the addition of cabozantinib to nivolumab. With a patient who got ipilimumab-nivolumab per the CheckMate 214 study, has been on nivolumab monotherapy for 12 to 18 months, and has a slow PD [progression of disease], there’s the potential for synergy there. By adding the TKI to the IO, there might be more of a benefit than giving the TKI as a monotherapy, although we don’t know. We have ongoing trials to determine that.

We have clinical trial data, although they aren’t randomized, for giving lenvatinib and pembrolizumab in patients who have received prior IO-based combination therapy. The response rates look very impressive, but it isn’t randomized. I have given IO-TKI combinations in refractory settings. As a general rule, I don’t give a doublet followed by a doublet. I generally give an IO-based combination followed by a monotherapy. Recently, as many patients are fortunately doing well in the long run, I almost feel like it’s a reset in their tumor biology. If they can tolerate it, I’ll give them a combination therapy in the third, fourth, or even fifth line. But as a standard, I don’t switch. I start with a combination and then switch to a monotherapy.

Dr Scott Tykodi explains the scenarios in which he would switch a patient to another regimen without dose reduction first.

Moshe C. Ornstein, MD, MA | Authors

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Design, Criteria, and Endpoints of KEYNOTE 564

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Switching Therapies in Advanced Clear Cell RCC without Dose Reduction