Dr. Vincent Xu: Welcome to The ASCO Post Roundtable Series on Updates in Renal Cell Carcinoma. I'm Dr. Vincent Xu at Dana-Farber Cancer Institute and the Lank Center for Genitourinary Urinary Oncology and a medical oncologist and instructor of medicine at Harvard Medical School. Joining me today are two of my colleagues.
Dr. David Braun: Hi. I'm David Braun. I'm an Assistant Professor of Medicine, Pathology, and Urology at the Yale Cancer Center in Yale School of Medicine, and principal investigator of a tumor immunology laboratory in the Center of Molecular and Cellular Oncology here at Yale.
Dr. Bradley McGregor: Yeah. I'm Bradley McGregor. I'm also at Dana-Farber Cancer Institute, where I serve as a Director of Clinical Research for the Lank Center for GU Oncology and an instructor of medicine at Harvard Medical School.
Dr. Xu: Thanks Dr. McGregor and thanks Dr. Braun. Today, we will be discussing recent updates in renal cell carcinoma and integrating these new developments into four patient case studies. Our third installment will focus on adjuvant therapy in renal cell carcinoma.
In this case, we have a 45-year-old man who is evaluated for painless hematuria. A CT urogram is done, which shows a right-sided kidney mass. Radical nephrectomy reveals a 7.2-cm, pT3aN0 clear cell kidney cancer, grade 2, extending into the renal vein. One month after surgery, the patient is well recovered and has had no further episodes of hematuria and is back to his baseline level of health.
What would you recommend next for this patient? Should he receive adjuvant sunitinib for 1 year, which is FDA approved? Adjuvant pembrolizumab for 1 year, which is also been FDA approved? Or would you opt for imaging surveillance alone? We'll start with Dr. Braun.
Dr. Braun: Yeah. This is a great question. And I think it's going to be an individualized discussion with the patient. As you mentioned, we'll start off with adjuvant sunitinib while that is technically an FDA approved option, and so I think it's worthwhile to have a conversation. And at least one trial, the S-TRAC trial did show about a year of relapse free survival benefit. That's with a year of toxicity of sunitinib.
And I guess while there's no formal updated mature OS data, every bit of overall survival data that's been presented showed no difference, really overlapping curves between sunitinib and no therapy. And so it's something where I'll mention to patients, but I haven't had a single patient in a long time opt for adjuvant sunitinib.
Adjuvant pembrolizumab is, obviously, newer but a really appealing therapy. And so this is based on the KEYNOTE-564 trial presented by Dr. Choueiri, and ultimately, published then led its FDA approval, which showed a significant disease-free survival benefit for patients who received an adjuvant pembrolizumab for 1 year compared to placebo.
I think a couple things that's worth noting. I think while the data is only available or mature for disease-free survival, and that really shows a clear benefit—though, again, I think we have to be reasonable. It's a modest benefit, it's there, but it's modest. The overall survival data is not yet mature.
I think in contrast to S-TRAC, while it's not yet mature, the shape that's taking form looks to be one that is likely to continue to spread out with every... Unlike S-TRAC, which was completely overlapping, here with every update of KEYNOTE-564, we see those overall survival curves separate more and more, as more events accumulate.
And so, ultimately it becomes a conversation with the patients. We say, "Look, there's an FDA-approved agent in pembrolizumab. It has a proven disease-free survival benefit, the benefit is modest. And it's not that the toxicities are necessarily zero that's... Overall, fairly modest, but there are non-trivial rates of lifelong effects like type 1 diabetes or adrenal insufficiency.
And that we truthfully don't know what the overall survival benefit is quite yet. But there's sort of encouraging preliminary results. And I have that full conversation with the patient. And I would say many of them opt for adjuvant pembrolizumab, but not everyone. And I think both are reasonable choices.
Dr. McGregor: I would agree with everything that Dr. Braun just said. I mean, I think the field for adjuvant therapy in renal cell carcinoma is certainly evolving. As Dr. Braun alluded to, we have the S-TRAC trial showing progression-free survival benefit, but no overall survival benefit with extended follow-up. And that’s in the setting of other trials with TKIs, with axitinib, sorafenib, pazopanib showing no benefit in either PFS or OS. So I think while it is approved, I think the toxicity profile, the high distress rate makes that not a very appealing option.
Just other direct target therapy, we just had data presented for everolimus. And this was a large cooperative trial of over a 1,000 patients and really impressive that this was carried out, and the investigators should be commended for doing this trial. And it is actually quite interesting that the study did not meet its primary endpoint.
This include a very wide spectrum of patients. They went down to T1b high-grade all the way up. So very different group populations. That means from endpoint, if you look at some of the higher risk patients like T3 or higher, they look like there's maybe a signal there. Although again, there was a high discontinuation rate for toxicities. And so I think that treatment is probably not ready for the patient.
And as Dr. Braun said, I think immunotherapy is certainly where it's at right now. And I think, as you point out, it does come down to an individualized patient discussion. We have pretty compelling disease-free survival data for pembrolizumab. Early data for OS is compelling. And even with an additional 6 months follow-up, there are more events in the placebo than the pembrolizumab arm. And so we're hopeful that's going to translate into overall trial benefit.
And to sort of help that discussion, I often use different clinical nomograms. I'll use, I really like the ASSURE nomogram. You can put the information, the size, the age, and all those things. And you say, "Okay. Well, this is your risk of relapse at 2 years." And then I'm able to plug in that hazard ratio and say, "Okay. This is what I expect your benefit at 2 years in this therapy." And it can really sometimes help make that decision because when we talk about a 10% risk of needing steroids, 2% risk of diabetes, having some numbers to compare, at least at 2 years—it’s not perfect. I'm not doing Kaplan-Meier Curves and saying, this is what happens over the course of that, but it helps frame that discussion a little bit.
Of course, this is all in this setting of other ongoing trials, which did not meet their primary endpoint. So Prosper RC looking at perioperative nivolumab did not meet its endpoint. A year of adjuvant atezolizumab in a very similar group to the KEYNOTE-564 did not mean its primary endpoint.
And then nivolumab/ipilimumab for 6 months also did not mean its endpoint vs placebo. So I think further analysis of all this data and extended follow-up is really going to be important as we look to have discussion. But I think, at this point in time, it does come down to that individualized discussion.
And if I am looking to use pembrolizumab in that setting, I really am limited to those patients in the trial. So the trial did not include all patients with RCC. This had T2, grade 4 sarcomatoid features or higher. So any T3, T4, M1-AD within a year. So if someone had a nephrectomy 3 years ago and has lung met would not have been eligible and that's how I to think about that.
So if I am going to think about pembrolizumab, I really am limited to that patient population with a caveat. I may look at a T1. If I get T1b, that's grade 4, that's almost a T2. You can think about this and all. But it is important to realize what those entry criteria were in the trial and use those as we start thinking about how to apply this to our patients.
Dr. Braun: And I really like the individualized risk assessment that Dr. McGregor mentioned. And I think that's such a helpful thing. And my hope is we're going to see that continue to evolve because I think we know it's a fact there are patients who are cured by surgery alone. And that group of patients, which is not small, gets no benefit from getting adjuvant therapy. We just have no ability to know who those patients are.
And so, as new tools develop, new biological tools, cell-free DNA, cell-free methyl DNA. Dr Xu, you yourself have done really nice biomarker work on things like M1 NED. As we get better biological tools to risk assess and say, these are patients that are unlikely to relapse, maybe cure their disease by surgery alone. Hopefully, it'll make this adjuvant discussion a lot easier in the years to come.
Dr. Xu: Great. The key is really, I agree it's a risk-benefit discussion, in the absence of a statistically significant overall survival benefit. Even though there is some evidence that adjuvant pembrolizumab might be headed in that direction, it really is weighing the disease-free survival benefit vs the risks of immunotherapy. And when we look at the adjuvant pembrolizumab trial, the benefit was not the same in all subgroups.
And so looking at patients with high-risk vs intermediate-to-high risk vs M1 NED, the hazard ratio was 0.28. So a much more favorable hazard ratio for disease-free survival, specifically in the M1 NED cohort. And so even though those patients were small in number on the trial, certainly that's a population where I would strongly consider adjuvant pembrolizumab if the patient would meet eligibility.
Dr. McGregor: I would echo that. And I think one of the important things is when I am concerned in adjuvant pembrolizumab or any adjuvant therapy, is you really... as we just talked, we don't want to over treat. We also don't want to under treat. Right?
And so I think it's really important that if you're thinking this, and you may see a patient 2 months after surgery. I'll get a fresh set of scans and I'll make sure that they truly are without any evidence of disease. And if there's any possible, like hey there are these lung things, it's unclear. I actually in that situation, I err on this side up. I'm just going to watch you because I would hate to give pembrolizumab alone in that situation with a thought that maybe a doublet therapy may offer a benefit.
So, if there's any concern for metastatic disease following surgery, I actually—as much as I worry about overtreatment, I really do worry about undertreatment. And I will say, "Hey, I just don't know what to make of this. I worry that pembrolizumab alone may not be enough. Let's just do a close follow-up scan in 6 weeks or 8 weeks for make any calls."
Dr. Xu: It's a great point. We've all certainly seen those patients who come to surgery have 4-mm lung nodules. And we're not really sure if they're metastatic and sometimes it's worth taking the time to find out. So as patients start getting adjuvant pembrolizumab, we've all seen more and more patients will progress on adjuvant pembrolizumab. And despite adjuvant therapy may become metastatic. Dr. McGregor, Dr. Braun, maybe starting with Dr. McGregor, what do you offer to these patients? Somebody has new metastasis after adjuvant pembrolizumab, should they receive VEGFR TKIs? Should they receive combinations? What should we do?
Dr. McGregor: Yes. I mean, anyone who says there's the right answer here, there is no right answer. But this is a data-free zone. And we're making up a little bit as we go. I think it's very clear that patients who get IO pembrolizumab alone, they are patients who progress. And what do we do in that situation? We don't know. There's a hope that maybe studies like TiNivo-2 or CONTACT-3 may give us a hint of an idea, like, okay, maybe continuing IO, is that beneficial? But that's in the third-line setting and not going to be in this situation.
And so I think this does... again, comes down to that discussion with a patient. Arbitrarily, a lot of people said, well, if it's been over 6 months since you received immunotherapy, I'd re-challenged the immunotherapy either with nivolumab or the TKI and IO. If you progress on IO within that 6 months, it does come down in that discussion. I think it's compelling to think about often IO/TKI. At the same time, if you say, "Well, we progress on IO, let's go right to cabozantinib.” Or that and everolimus. It does come down to that discussion with the patient, and more trials and data help guide decision.
Dr. Braun: Yeah. I totally agree. I don't think there's a right answer. I don't think anyone knows at this point. I think... my hope is as we gain more experience, there’ll be published series, there’s going to be databases and registries like the IMDC, which can keep track, which will give us, hopefully, some early looks about how people do after adjuvant pembrolizumab. And, ultimately, needing actually prospective trial data.
I think people bore from sort of the platinum paradigm of it's within a certain amount of time, don't re-challenge with IO vs afterwards. And I think there's some reasonable biological rationale there. If you think of something like pembrolizumab, long ago, when the drug was first making appearances, they looked at receptor occupancy on the T cells. How long it's actually hanging onto the T cells? It's a long time. It's many, many, many months. And so if you're actually getting progression on pembrolizumab or a few months after pembrolizumab, chances are the pembrolizumab is still there and the patient is progressing through it.
I think, at that point, where I'd lean today is probably switching to another therapy. Whereas, if it's a year or 2 years later, the pembrolizumab’s clearly out of the system. It's not on any of those T cells anymore. There's at least a reasonable chance. We don't know. But there's a chance that disease might still be sensitive to anti–PD-1 therapy. And so giving this the benefit of the doubt and giving an immune-based therapy again, I think is very reasonable. But I’ll fully acknowledge that’s a kind of hand wavy, theoretical idea, but we’re going to need the data ultimately to make firm decisions.
Dr. Xu: There’s lots of questions unanswered here. And I think while we don’t have a lot of prospective trials answering these questions, we’ve all seen in clinic patients who initially had a response to immunotherapy, went off treatment, for example, for toxicity. And then after relapse had a subsequent response again, to re-challenge with immunotherapy. And so, especially for those patients who are 2 years or 1.5 years out from adjuvant immunotherapy, that approach certainly may still have some merit.
Dr. McGregor: Right.
Dr. Braun: Absolutely.
Dr. Xu: So key clinical takeaways, adjuvant pembrolizumab has demonstrated disease-free survival benefit, possibly has a trend towards improving overall survival, and has shown good tolerability in clear cell renal cell carcinoma. Given the less favorable toxicity profile and inconsistent evidence for clinical benefit, adjuvant sunitinib should not be routinely recommended. Surveillance still remains a important standard of care option, especially for patients with lower recurrence risk and or high concern for potential immunotherapy toxicity.
That brings us to the end of this case. Please see the other segments for further discussion about the latest data in renal cell carcinoma or visit ASCOPost.com.
