Dr. Vincent Xu: Hello. Welcome to The ASCO Post Roundtable Series on Updates in Renal Cell Carcinoma. I'm Dr. Vincent Xu. I'm a medical oncologist in the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, and Instructor of Medicine at Harvard Medical School in Boston. Joining me today are two of my colleagues.
Dr. David Braun: 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 of a laboratory, The Center of Molecular and Cellular Oncology.
Dr. Bradley McGregor: And I'm Brad McGregor. I'm also at Dana-Farber Cancer Institute, where I serve as Director of Clinical Research for The Lank Center for GU Oncology, and an Instructor of Medicine at Harvard Medical School.
Dr. Xu: Today, we will be discussing recent updates in renal cell carcinoma and integrating these new developments into four patient case studies. Our first installment will focus on front-line therapy in metastatic clear cell kidney cancer. So, let's start with the first case. This is a 62-year-old woman with hypertension, who was evaluated for mild left flank discomfort and headache. She had CT scans, which demonstrated a 10-cm left renal mass, a 1-cm bone lesion in the left pelvis, and 10 bilateral lung nodules, up to 2.5 cm.
A biopsy of a lung nodule is done, which shows metastatic clear cell renal cell carcinoma. An MRI of the brain shows a 0.9-cm right frontal lobe metastasis. The patient remains active and takes brisk walks daily with her dog. She has baseline labs, which are notable for a hemoglobin of 10, otherwise normal blood counts, and a calcium of 9.5, with a normal albumin level. She undergoes SBRT radiation to the brain metastasis, and she tolerates this well. What would you recommend next for this patient?
There are a lot of options in the front-line setting, including ipilimumab and nivolumab, axitinib and pembrolizumab, axitinib and avelumab, cabozantinib and nivolumab, lenvatinib and pembrolizumab, cabozantinib alone, debulking nephrectomy, or even active surveillance. So, lots of choices here. Dr. Braun, what is your opinion about her first line treatment options?
Dr. Braun: This is an interesting question. I think there are a lot of good options for upfront treatment for this patient. I guess, for a new patient with a diagnosis of metastatic renal cell carcinoma, and particularly clear cell renal cell carcinoma, there's always a few thoughts that go through my mind. First of all, is there an opportunity for local therapies, either surgery or targeted ablative radiotherapy, and there are particular circumstances where I think of that. Is there oligometastatic disease, where we might get a patient to NED, or no evidence of disease, through local therapies? Is there something where there's a particular lesion that's symptomatic or likely to cause problems? In this case, that is maybe the brain lesion, even potentially the bone lesion, if there's this cortical breakthrough. And then finally, when thinking about local therapies, is really the bulk of disease in one area.
So, there are cases where a patient might have metastatic disease, but 95% of the disease is really within the kidney, and there's minimal disease and indolent behaving disease elsewhere. And those are times I'll consider upfront local therapies.
For a patient like this with active brain and bone metastases, those are pretty risky factors. And so, this is not a patient I would think of for a debulking nephrectomy, a cytoreductive nephrectomy. This is someone who I would think about potentially targeted therapy, for instance, for that brain lesion, but then really moving right to systemic therapy. And that brings us to what are the options? For a patient like this who has clearly IMDC intermediate-risk disease within anemia? Though again, I would say with the brain and bone metastases, I worry that while technically prognostically intermediate risk disease, this is acting in a biologically more aggressive fashion, really combination of front therapy, either IO, IO with nivolumab and ipilimumab, or an IO/TKI combination of which there's many.
And I think as we know, there's, there's no perfect answer here. There's lots of good options. There's no head to head comparison of all of them. I think as ESMO comes upon us, we'll be sort of soon entering the era of potential triplet therapy as well. For me personally, I think of a couple factors when choosing. One is, are there reasons a patient can't get one therapy or another, are there are immune conditions that might make me nervous about IO therapy? Are there bleeding considerations or cardiovascular considerations that make me nervous about TKIs? The other thing is how urgently do I need a response? I think again, while we don't have head-to-head comparisons, and I think there's a general thought that the IO/TKIs have better upfront response rates and certainly lower primary progressive disease rates. And so if this is a patient with really quickly advancing disease, impending, visceral crisis, we can't afford not to get a response.
This patient might never see a second line. I would probably think an IO/TKI has one of the highest response rate. Otherwise the one we have the longest follow-up, and at least personally I believe might have the longest and strongest durability of response, is a combination of two immunotherapy agents, ipilimumab and nivolumab. And so whether I think many right answers here for this patient, I really would think about treating local lesions first, at least the brain, potentially the bone, depending on how that looked radiographically, and then probably thinking of an upfront therapy with nivolumab and a lab.
Dr. Xu: Thanks Dr. Braun. So lots of things to consider lots of answers, which are not entirely wrong but not perfect. And with pros and cons between the choices. Dr. McGregor, what do you think?
Dr. McGregor: Yeah, I 100% agree with everything that Dr. Braun just said. When we have a patient who presents with de novo metastatic disease, I think the first thing is local therapy. And I think we talked about other things and the question is, should we take out that kidney or not? I think 5, 6, 7 years ago, based on data from the interferon era, every single patient who was having metastatic disease was undergoing an upfront cytoreductive nephrectomy, given the improvement in survival in randomized trials in the era of interferon.
And then we had the CARMENA trial, which is an imperfect trial, which took patients and randomized them to upfront nephrectomy followed by sunitinib or sunitinib alone. And what that trial showed, with the caveat that patients that chose to enroll in this trial are probably sicker, maybe favor more towards the more intermediate- and poor-risk disease, is that there was no benefit to upfront systemic therapy.
Now, I think that doesn't say that there's no role for upfront cytoreductive nephrectomy, but what it does tell us is that highly effective systemic therapy is really important. And now we have much more highly effective systemic therapy. So in this situation, we have a 10-cm, asymptomatic renal masses, bone brain met lung masses. I agree that going right to a systemic therapeutic option is critical. That's not to say that a cytoreductive nephrectomy in the future, wouldn't be beneficial. If you start systemic therapy and you have a great response in the lungs and the bone, and you still have pretty significant disease in the kidney, which is what we would expect to see based on all the data we've seen from the different trials, that the response in the primary seems to be slightly less than we see elsewhere.
It's not to say that 3 or 6 months down the line we wouldn't want to think about cytoreductive nephrectomy. The ongoing PROBE trial is trying to answer this very question. Is starting systemic therapy if you have response randomized patients to get nephrectomy or to continue on systemic therapy. But I think in this situation, I would echo everything said, I would not pursue a nephrectomy right now. I think systemic therapy is important. I tend to agree, I think that if a patient can tolerate progressive disease where the rate of disease for nivolumab/ipilimumab is around 20%, I do like the durability that's offered by nivolumab and ipilimumab, which we haven't yet seen with the other regimens. But if we really feel that if the patient is going to become significantly sick, if they were to progress with targeted second line therapy, then we need to go for the upfront response where TK/IO combinations heavy responses approaching 70%.
I think one of these types of considerations we're always thinking about is the presence of brain mets. Should that affect our management anyway? We don't have any nice large prospective data. We do have some pretty compelling data in cohort series for cabozantinib in close to 100 patients, patients who have untreated brain mets or brain mets that treated with radiation and cabozantinib. Response rates in the intracranial approaching 50% with cabozantinib monotherapy. So if I do have a patient who has asymptomatic multiple small brain mets, that may be a situation where I would think about like a cabozantinib plus nivolumab approach in that front-line setting to try to get CNS control, while minimizing the need for extensive radiation. So again, systemic therapy extracranially and intracranially.
Dr. Xu: Thanks. Those are great thoughts. I think this is a good chance to review some of the data on the first-line therapies in RCC. And we've had several important trials in the last few years as mentioned by Dr. Braun, Dr. McGregor. The combination first-line immunotherapy currently approved is ipilimumab and nivolumab, which was investigated in CheckMate 214 and showed a PFS and overall survival benefit specifically in the intermediate- and poor-risk population.
We have several trials investigating combinations of checkpoint inhibitors, plus VEGF receptor TKIs, nivolumab/cabozantinib, pembrolizumab and lenvatinib, avelumab and axitinib, pembrolizumab and axitinib. Among these VEGF receptor TKI and checkpoint inhibitor combinations, it's very important to point out that only nivolumab plus cabozantinib, pembrolizumab plus lenvatinib, and axitinib plus pembrolizumab have shown overall survival benefit, although all four showed progression-free survival benefit. And so the trials and regimens that demonstrate overall survival benefit compared to sunitinib should be prioritized.
And finally cabozantinib monotherapy in the intermediate- to poor-risk population demonstrated a progression-free survival benefit vs sunitinib, and can be considered in patients who have some contraindication to immunotherapy.
So that brings us to the IMDC risk criteria. Some patients may have greater risk for progression, maybe have risk factors that make us worry about worse overall survival or faster disease-related symptoms. So Dr. Braun and Dr. McGregor, how should we use the IMDC risk criteria in choosing first-line systemic therapies?
Dr. Braun: That's a wonderful question. And I'm curious about Dr. McGregor’s answer. I think the data’s in flux, and honestly, I don’t know if there’s a perfect answer. If we went back to 2018 in the CheckMate 214 days, the media answer then, would've been nivolumab/ipilimumab or immunotherapy alone in a favorable-risk population is not the right answer. You use a TKI. And then as we went into the IO/TKI era, those seemed to have pretty good responses across the board, really sort of independent of IMDC risk status. And so either an IO/TKI or a TKI monotherapy, and truly that's the way I've practiced. I've probably done an IO/TKI combination for most favorable risks recently.
I think the thing that's given me a little bit of pause about that is as we follow CheckMate 214 longer term, the curves have crossed. So while upfront nivolumab/ipilimumab didn't do as well, that durability, that potential for durability with that combination IO/IO is still there.
And so I think while it's not an approved regimen to give that in the favorable-risk population, I think it's really not an unreasonable thing again, given that durability. Lastly, if we look at more recent data from, for instance, the Hoosier Cancer Research Network trial from Dr. Atkins, which looked at upfront nivolumab monotherapy with the addition of salvage ipilimumab if needed, the response rate in the favorable risk population was somewhere around 50%.
And so I think in light of these more recent data, it's not unreasonable to consider pure IO-based therapy for that favorable risk, but still at least in my mind where the data's probably the strongest is still for the IO/TKIs. And so I think for most patients, I'd probably still lean towards IO/TKI for favorable risk. And otherwise it's still a conversation. For the intermediate/poor, again, with the exception of someone with really needs an urgent response, I'll tend to favor IO/IO.
Dr. McGregor: Yeah. I mean, it's a great discussion, I think, favorable risk, we have no idea. I mean, sure. I mean, it's really the area that in clinic, I think is the longest discussion with the patient because as Dr. Braun alluded to, the data is just in so much flux. It's very clear for intermediate- and poor-risk disease, combination therapy is imperative—be that IO/TKI or IO/IO—when you have that discussion with the patients. I think for the favorable-risk patients, it is really, really unclear As Dr. Braun alluded to, with extended follow-up in the favorable-risk population in CheckMate 214, there's actually a numerical improvement in overall survival for those with favorable-risk disease. Now, again, subgroup analysis. Then with extended follow-up of all the IO/TKI, again, explorative analysis, all those hazard ratios cross over 1 for the IO/TKI. So it really is a complicated, complicated situation.
I think the data would tell you that for upfront favorable risk, an IO/TKI is the preferred option, given the approvals as they are indicated in the trial designs. But I think this is truly an area where we can do better. And I think it really highlights that IMDC is an amazing clinical tool, and it's probably the best thing we have right now, but we need more. And I think really smart people like Dr. Braun or in the lab, trying to help us figure out this exact thing. What are those biomarkers? Is there something beyond clinical factors that we can look at and say, Hey, this is a patient where we need IO. This patient needs VEGF. And can we sort of do something beyond clinical criteria? Because we know that not all favorable risk are the same. In CheckMate 214, about 10% to 12% of favorable-risk patients got a CR with nivolumab/ipilimumab. And if we could find out who those patients are and give them that therapy and potentially cure them, that would be amazing.
So I think trials looking at transcriptomic signatures and different things are going to be really critical as we try to move forward and try to figure out how can we best determine what makes sense. I think right now, IMDC or MSKCC prognostic factors based on clinical features and labs are the best we have. And there's something we have to use in clinic every day.
Dr. Xu: And speaking of biomarkers, this is not part of the IMDC or MSKCC criteria, but sarcomatoid features are something that we see in kidney cancers. Does that change your first-line treatment selection?
Dr. Braun: Yeah, I just first want to echo Brad, I totally agree. I think we need better ways to sort of select among favorable-risk patients who are going to be, the tumors that are bad actors and what are the tumors that are really acting in a more indolent fashion? I think we kind of know intuitively that something might be technically favorable risk, but if it is a brain and a bone and a liver met, that's probably not acting in an indolent way. Similarly, if we have a favorable risk, but we have sarcomatoid features, that's something that's probably not going to act in a particularly indolent way.
For sarcomatoid specifically, I think the data from CheckMate 214 where the complete response rate is really around, hovering around that 20% mark, that's something I think in general, sarcomatoid needs in IO-based therapy. And there's good response with IO/TKI, but it's that 20% complete response rate with. IO/IO that when I see sarcomatoid in general, it really pushes me towards dual IO therapy.
Dr. McGregor: Yeah. I would echo that. I think when we look at all the different trials, it’s clear that patients with sarcomatoid histology do better with an IO-based regiment IO/TKI or IO/IO vs VEGF monotherapy. What separates me with nivolumab/ipilimumab apart is that sarcomatoid does better than those patients without sarcomatoid. I mean, again, small numbers, exploratory, but as Dr. Braun alluded to, I mean, a 20% CR rate, a 60% objective response rate. I mean, it really suggests that there's something there.
So yeah, I agree, for those patients that have sarcomatoid histology, if possible I really do like to double down on an IO/IO combination with a caveat that their PD rate for those patients is still around 20%, even with IO/IO so certainly that's where we have that's if you respond, it’s the best response, but we certainly need to continue to do better and try to improve outcomes for all these patients.
Dr. Xu: So we're having this conversation at the end of August, right before ESMO. And we know from the press release that COSMIC-313, which investigated triplet therapy with cabozantinib, ipilimumab, and nivolumab, compared to ipilimumab and nivolumab, met its progression-free survival primary endpoint, although overall survival is not yet mature. What do you think about triplet therapy? Is there a place in this in the first line?
Dr. McGregor: Yeah, I think I want to commend the investigators for running this trial, right? We've had all these different trials of the combinations vs VEGF monotherapy. But COSMIC-313 was the first trial to try to go against a modern comparator arm. So every patient got nivolumab and ipilimumab as the standards per CheckMate-214, and they randomized to receive cabozantinib at dose of 40 mg daily, or a placebo. And the trial did meet its primary endpoint. And there was an improvement in progression-free survival with the triplet therapy vs doublet. But as you alluded to, to date, the overall survival data is immature. So I think very, very exciting data to have head-to-head with a modern comparator. I think longer-term follow up and toxicity profile are going to be really important as we consider how to implement this into our practice, with the caveat that this trial only included those patients with intermediate- and poor-risk disease given that sequelae for nivolumab/ipilimumab.
Dr. Braun: Yeah. And I would completely agree. I think we were in the era of monotherapy frontline, then combination therapy with two agents, and this might really be the beginning of a triplet era. And we're seeing this in other trials now, but this is really sort of breaking the ground. And it met its primary endpoint, which is prolongation of progression-free survival. I really think the key will be those longer-term outcomes. So looking at overall survival, I think there's two factors there. One is the classic looking at hazard ratios and is it improved? But I think the second thing, perhaps just as meaningfully, is where does that PFS curve kind of flatten out? We know that for nivolumab/ipilimumab alone from CheckMate 214, that really flattens out at maybe 25% or 30%, those patients are getting really durable responses. Are we seeing that flatten out now at 35% or 40%, some meaningfully increased rate where it might be worth some increased upfront toxicity?
And the other point I'd sort of think about as well is we've sort of had this discussion about IO/IO maybe being durable and IO/TKI being a little bit less risky because less primary progressive disease rate. So does this triplet in some ways de-risk dual IO therapy? Can you maybe get the dual IO sort of benefit of durability, but not such a high primary progressive disease rate? And we'll have to wait for some longer-term outcomes and all the data, but I think that's sort of an appealing idea as well: de-risking the possibility of a durable IO response.
Dr. McGregor: And sort of adds, I mean, we have that data, but there's still unanswered questions from trials that are ongoing. PDIGREE is looking to start with nivolumab/ipilimumab and try to intensify with cabozantinib in addition to nivolumab at earlier points. I think that's a different approach where we get double upfront and then maybe do a cabozantinib, nivolumab approach earlier, patients have only a PR or stable disease. And then we have ongoing trial looking at different triplets. So we have the ongoing large Merck trial looking at lenvatinib/pembrolizumab background, looking to add in a HIF-2 inhibitor on that pembrolizumab or another CTLA-4 inhibitor at a lower dose for longer duration.
So I think this is the hope is that similar to maybe lymphoma or testicular cancer, with more therapies we're able to achieve a cure. Is that possible with intensification of therapy, are we going to get, as Dr. Braun alluded to, more patients to get that durable response? And can we raise that tail to the curve significantly with intensification? I think we made a lot of progress in the past 5, 6 years, and this is really the next wave of trials and in COSMIC-313 is the first of those for us to sort of dissect and really start thinking about.
Dr. Xu: So here are some key clinical takeaways from this case. Most patients who need first-line systemic therapy for metastatic clear cell renal cell carcinoma should receive doublet therapies in 2022, and doublet therapies have shown progression-free survival and overall survival benefit over sunitinib across multiple trials.
However, when choosing between doublets, treatment selections should take into account patient factors, tumor locations, symptom burden, performance status, comorbidities, and potential for toxicities as well. In general, VEGF receptor TKI plus checkpoint inhibitor combinations have higher objective upfront response rates compared to combination immunotherapy with ipilimumab and nivolumab. However, combination ipilimumab/nivolumab remains an important front-line option, especially for intermediate- or poor-risk clear cell kidney cancer or patients with sarcomatoid features. And this combination of immunotherapy regimen has many patients who comprise an important subset with long-term response and survival.
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.
