Dr. Vincent Xu: Welcome to The ASCO Post Roundtable series on Updates in Renal Cell Carcinoma. I'm Dr. Vincent Xu, medical oncologist at the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and instructor of medicine at Harvard Medical School. Joining me today are two of my colleagues.
Dr. Bradley McGregor: Yes, I'm Brad McGregor. I'm also at Dana-Farber Cancer Institute, where I serve as the Director of Clinical Research for the Lank Center for Genitourinary Oncology and an instructor of medicine at Harvard Medical School.
Dr. David Braun: And hi, I'm David Braun. I'm an Assistant Professor of Medicine, Urology, and Pathology at the Yale School of Medicine and Yale Cancer Center, and the principal investigator for tumor immunology lab in the Center of Molecular and Cellular Oncology.
Dr. Xu: Today we'll be discussing recent updates in renal cell carcinoma, and we will be integrating those new developments into four patient case studies. Our second installment will focus on second-line therapies and beyond in clear cell renal cell carcinoma.
So let's move to our case. This is a 63-year-old man who has clear cell renal cell cancer, metastatic to bilateral lungs with multistation lymphadenopathy. He had an initial partial response to pazopanib therapy, but now has progression of disease in the multifocal lung nodules. His performance status is good, and he has a mild cough from the lung metastases, but is otherwise asymptomatic. What would you recommend next for this patient? Should he be treated with axitinib, or cabozantinib, or one of the combination VEGFR/TKI plus immunotherapy regimens, such as cabozantinib/nivolumab or lenvatinib/pembrolizumab? Should he receive tivozanib or combination immunotherapy with ipilimumab/nivolumab or nivolumab alone? So once again, lots of choices here Dr. McGregor, what do you think?
Dr. McGregor: Yeah, I mean this a struggle we deal with all the time because as great as these regimens are, you know, unfortunately a lot of these patients often progress, and we're left with what do we do next? I think the situation described here is something we don't see very often anymore, as combination therapy has certainly moved to the front line and most patients are getting an IO based regimen upfront. I mean, I think it's clear for someone that has the TKI alone in the frontline and is eligible for immunotherapy with no absolute kind indications, some sort immunotherapy regimen in the second line make sense.
I have used nivolumab and ipilimumab in that situation with understanding it's a double IO therapy and that chance to tail the curve that we see in the frontline setting. I think if you want to be a purist from the IO/TKI standpoint, the best data would be for lenvatinib and pembrolizumab. That was studied in the second line for patients who received prior immune checkpoint blockade or a TKI alone and showed impressive response rates done by immune RECIST criteria, which is fantastic. I think for patients who do get IO upfront then we're left with extrapolating from the TKI setting frontline where I think cabozantinib showing survival benefit in the METEOR trial, retrospective analysis as well as CANTATA trial showing that cabozantinib therapy is safe and no new toxicities post-IO. And then we also lenvatinib and everolimus, which showed improvement in survival in a randomized phase II vs everolimus. And then later on we can have tivozanib as well as other options. So a variety of options that are there without a doubt.
Dr. Braun: I would agree and echo all of that. I think the first thing I'll just note is it's kind of incredible what a deep therapeutic armamentarium there is now in the second-line setting for RCC that didn't exist 3, 4, 5 years ago. And so a lot of the time, and I talk to patients about this too, it’s not only the question of what do you do, but it’s the question of sequencing saying “The likelihood is a certain point. You're going to get immunotherapy, you're going to get Tivozanib. You're likely going to get lenvatinib and everolimus.” And it's a matter of thinking about the order of some of these agents. I 100% agree that someone who had a TKI monotherapy in the front line, which again, I think is becoming less and less common to see, but when it does happen, I really think that person should have an immunotherapy-based treatment in the second-line setting.
I think the classic data for this, the original data is from the CheckMate 025 trial from 2015, which was nivolumab monotherapy. And that's what had an overall survival benefit, a reasonably good response rate. But I think Dr. McGregor is absolutely right. I think there's conceptual reasons to believe nivolumab/ipilimumab might be helpful as well. And the data from Dr. Lee and colleagues at Memorial Sloan Kettering on pembrolizumab and lenvatinib in that second-line setting is also really compelling. And so I think any of those choices would be really reasonable in that second-line setting here.
Dr. Xu: Great. Yes. So I think this is really an area where in some ways the clinical trials, especially the randomized trials, haven't quite caught up yet to our modern practice because the first line has changed so much. So we haven't had time to do those really big second-line trials. What we know about randomized evidence in the second-line setting is largely in the post-TKI era when patients were receiving front-line TKIs. We know that the regimens that do have proven benefit in the second line after first-line TKIs include cabozantinib, nivolumab, and lenvatinib and everolimus, all of which have shown a survival benefit in this setting.
In the post-IO setting, as you both bought up, Dr. Braun and Dr. McGregor, lenvatinib and pembrolizumab in a nonrandomized trial had really impressive response rates in the 40% to 55% range in the second-line setting, and also axitinib and cabozantinib have both shown activity, post–immune checkpoint inhibitors. Finally, in patients who are third or fourth line, the only randomized trial we have in this specific third- or fourth-line setting has been TIVO-3 showing that tivozanib has activity after prior VEGF receptor TKIs, although without an overall survival benefit.
And so what about patients in the first-line setting who've received IO/TKI combos? Does it matter whether they receive single immune checkpoint inhibitor or double immune checkpoint inhibitor, how should we think about second-line therapy based on what they received in the first line?
Dr. McGregor: I think absolutely what you received frontline is what makes a difference, right? So if you get nivolumab/ipilimumab frontline, then cabozantinib or lenvatinib and everolimus are both very reasonable options. I think if you had a TKI-IO combination in the frontline based on what that TKI is, right. So if you had lenvatinib/pembrolizumab in the frontline, I would think about cabozantinib. If they had cabozantinib/nivolumab, I would think about lenvatinib/evorolimus. Or axitinib/pembro, you could do cabo or lenvatinib/everolimus.[ so certainly it does certainly make a difference. Then now we have another tool in armamentarium with tivozanib given the TIVO-3 data, which is an option in the third line and beyond. So it really does make a difference.
I think one of the key questions though is should you continue IO or should you switch? And I think we don't know that again, we alluded to the data from Dr. Lee looking at lenvatinib and pembrolizumab with a subset of patients who had received prior checkpoint inhibitors. Very good, very good responses. Is that driven by lenvatinib or is there really some synergy between IO and TKI? I think we don't know. I think there are ongoing trials in this very setting: CONTACT, looking at the role of cabozantinib with atezolizumab vs cabozantinib. Of note, in that trial, the dose of cabozantinib is actually 60 mg in both arms. So as opposed to Cavo nivo where the dose cab is lower with the IO (40 mg) and here, the dose is 60 mg and that's based on some phase I data. So that was well tolerated. And then we have the TiNivo-2 trial, which is just open, which looks at tivozanib and nivolumab vs tivozanib and in the switch to the Cabo contact in that trial, the dose of tivozanib with the nivolumab is actually lowered from the traditional starting dose of 0.89, with the hope to minimize some toxicity concerns.
So I think those trials be really important to answer. Should we continue IO or not? The other data we do have is someone had a TKI/IO, and did not get ipilimumab up front, we have data from FRACTION-RCC. That's presented by Dr. Choueiri showing about a 15% objective response rate with a combination of nivolumab/ipilimumab post IO. So that can be certainly considered in the future. So again, to earlier sort of embarrassment of riches, and to your point, Dr. Xu, I think that we're seeing some of these trials are catching up and we're going to be having some answers to some pretty critical questions as we get this next wave of trials.
Dr. Xu: Great. So Dr. McGregor great points there. I think lots of options, but I think my key takeaway is that we should really be prioritizing treatment modalities, TKIs that were not given in previous lines and try to expose patients to multiple mechanisms of action. And of course we still have available mTOR inhibition through everolimus or temsirolimus, although based on the response rates, response rates to mTOR inhibition in the general population for kidney cancer have certainly seemed lower than even the second and third line VEGFR TKIs.
Dr. Braun: Yeah, I think that's what think about rotating mechanisms of actions. The TKIs are not totally overlapping. And so that's a strong reason to start to rotate. We always think of them as anti-angiogenic agents targeting the VEGF receptor, but they have other targets. We know that cabozantinib hits MET and the Tam kinases; we know that things like lenvatinib hit EGFR and so that those nonoverlapping mechanisms of action is really critical to the success of one TKI rotating after another.
And I completely agree with Dr. McGregor as well. I think there is exciting sort of preliminary data to support the idea of IO post IO. Dr. McGregor mentioned a lot of those data from FRACTION-RCC and others. There's some great retrospective studies, including from Dana Farber from Dr. Ravi, another one from Dr. Goul, which looking back maybe as high as a 20% response rate for rechallenge with IO after progression on a prior IO therapy. But the trials that Dr. McGregor mentioned, CONTACT-03 and TIVO-02, are going to be the critical ones to robustly answer this in a prospective way. So that's the data we're going to need to really come to a firm answer on it.
Dr. McGregor: And to the point of new different types of actions. I think we're really looking forward to seeing data for belzutifan in the ongoing, accrued phase II trial, looking at patients who progress on multiple therapy, randomized to belzutifan vs everolimus in the treatment of advanced renal cell carcinoma. And so we've seen very exciting phase one/two data showing efficacy response rates over 20% in these heavily pretreated populations. And so, we look forward to phase III data, hoping to have a completely different target to utilize in our armamentarium. And maybe that will be another one that's used in combination. We've already seen data for cabozantinib/belzutifan. There are ongoing trials of lenvatinib and belzutifan vs cabozantinib. And so again, more to come, and we look forward to the developments and the treatment- refractory setting,
Dr. Xu: Lots to come, and the field is moving very, very fast. So key clinical takeaways from this case: patients with disease progression after prior checkpoint inhibition should receive a VEGF receptor TKI in the second-line setting. Conversely, patients who have disease progression after VEGF receptor TKI alone should certainly receive a regimen that includes immune checkpoint inhibition in the second-line setting. Patients who have had disease progression on both antiangiogenic and checkpoint inhibition should receive VEGF receptor TKI that has shown activity in the treatment-refractory setting that includes cabozantinib or combination of lenvatinib/everolimus. And there's also response rate in this setting to double checkpoint inhibition with ipilimumab/nivolumab as well. Metastasis-directed therapies as well we should not forget for patients who have limited areas of progression are still reasonable to have surgery or radiation, especially if the other areas of disease are well controlled on systemic therapy. And so this 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. Thank you.
