CARMENA: Practice Changing Strategies for Kidney Cancer
Charles Ryan and Dan George reflect on the dramatic changes clinicians have seen over the last 12 years in treating kidney cancer. Dan reviews the highlights of the CARMENA trial and the impact that the results have made to treatment strategies for patients, stressing the value of collaborative care and patient selection.
Daniel George, MD
Charles J. Ryan, MD
CARMENA: Cytoreductive Nephrectomy Followed by Sunitinib vs. Sunitinib Alone in Metastatic Renal Cell Carcinoma - Results of a Phase III Noninferiority Trial
A Phase 3 Randomized Study Comparing Perioperative Nivolumab vs. Observation in Patients With Localized Renal Cell Carcinoma Undergoing Nephrectomy: PROSPER RCC
Dr. Charles Ryan: You're the discussant for the big session on kidney cancer. Do you want to tell us a little bit about what's going on in kidney cancer?
Dr. Daniel George: Yeah, my pleasure. You know, I think this has been a field that has really dramatically changed over the last 12 years or so with the advent of targeted therapies and now, most excitingly, immunotherapy's coming into the field. But over the last 12 years, we've been, for the most part, been using VEGF targeted TKIs like sunitinib and others to manage these patients up front with metastatic disease.
But a key part of managing metastatic renal cell carcinoma has been a nephrectomy. We've done that, even in the metastatic setting, to cytoreduce, to kind of decrease the tumor volume. That's based on some really old data back probably 20 years ago in the interferon era, where it was really an ineffective systemic therapy. In that setting, this sort of debulking nephrectomy of metastatic disease really improved survival in two independent studies. That has been our entrenched standard of care. I think rightfully so.
But what we haven't known is in this TKI era of active systemic therapy, does that still hold true? The CARMENA study was a study sponsored in France, actually an international study with Belgium and the UK, and what they looked at was in patients in a non-inferiority structure, getting nephrectomy followed by sunitinib versus just sunitinib alone for this exact population. This study took twice as long to accrue and actually never met its full accrual. It was stopped at an interim analysis because the results overall for intention to treat looked like, in fact it did not benefit, to have a cytoreductive nephrectomy. There was a slight trend in favor of sunitinib alone, and overall, the confidence intervals, how we judge noninferiority studies, is by the confidence intervals. The upper limit of the confidence interval was 1.10. We mean, there's less than a 5% chance that there's a 10% difference in survival in favor of nephrectomy.
The study was stopped. It was read out as positive. It really is a practice-changing study, because it helps us recognize that for patients that have particularly poor risk features, intermediate risk features, or bulky metastatic disease, we don't need to do that nephrectomy, we can go right to systemic therapy.
What was not represented well in CARMENA are the patients with very low volume metastatic disease, where a debulking nephrectomy probably still can make sense. What remains questionable, though, is do you need to do that or could you start with systemic therapy? The CARMENA study allows for patients starting on sunitinib arm to get a debulking nephrectomy, kind of a consolidation surgery if you will, at some point if they got a near CR or if there were symptoms. Probably around 15% of patients had that done, and the average time to that surgery was 11 months. These are patients that were probably responding well to sunitinib.
We know from our larger phase III studies with Checkmate 214, an exciting immunotherapy of nivolumab plus ipilimumab, that in patients with or without prior nephrectomy, they benefited. There's reason to believe that we can extrapolate this data to other systemic therapies, that we don't need to do debulking nephrectomy in everybody. We can be super selective. We may even have equipoise in those low metastatic patients to study that further, and that it's okay to start patients right out of the gate on systemic therapy. So I think this is going to change how we practice in kidney cancer. It's no longer a surgery handoff to a medical oncologist. It should be a multi-disciplinary consult up front. Should be collaborative care. Should be personalized to that individual patient's situation to figure out, not should we do nephrectomy or not, but what's the right order? Can we start with a biopsy and go from there?
Dr. Charles Ryan: Yeah, yeah. So there's a lot to unpack there, of course. One, I think, is the issue of the biopsy. It's long been held that the nephrectomy was the biopsy, right? And so, there's been a bias against doing percutaneous biopsies of the kidney. Should that change, number one? Number two, is the headline, 'nephrectomy not needed', or 'nephrectomy not needed except in certain circumstances'? Then of course, the issue of you say systemic therapy, but is this a sunitinib specific issue? Does this apply to immunotherapies, et cetera, et cetera?
Dr. Daniel George: So first off, the biopsy. You know, that's what we do in almost every solid tumor when you have metastatic disease. Prostate cancer mets, what do we do? We biopsy the prostate. We confirm the Gleason score. I think we're going to want to do that, we want to know, we're going to core biopsy. We want to be able to do genetic profiling, we want to be able to see if there're sarcomatoid elements. We're going to want a good tissue sample in these patients, and we can do it. It's not ... The risks of bleeding and everything, I think, are overblown. We can absolutely biopsy these patients.
Dr. Charles Ryan: But this bias against doing a percutaneous biopsy in kidney cancers is like 30 years old.
Dr. Daniel George: And it's mostly because we're going to take the kidney out anyway. But if we're not going to start there, we can start with a biopsy. I think the second point that you bring up is the headline. I don't think the headline is 'surgery not needed'. I think the headline is, you know what, it's a multidisciplinary approach. There's a lot of solid tumors where we start with systemic therapy: head and neck cancers, esophageal cancers, or whatnot, anal cancers. We can start with systemic therapies, and then we can consolidate with surgery, and it may actually make for an easier surgery in some circumstances.
And then I think the third question here is really how do you extend this, as you said, into other settings? Right now we have to go with what the data tells us. What the data tells us is that with VegF TKI, sunitinib, we can do that. I think it's really worth doing future studies around surgery with the timing of immunotherapy. I think we can learn a lot from that. In fact, there is, right now, an adjuvant study that's under-accruing, that needs to accrue, would love to have a multidisciplinary approach to this approach, where we would give in stage II and stage III kidney tumors pre-operative nivolumab followed by surgery followed by more nivolumab. This is the Prosper RCC study, and we really need collective group help on this in the US. If the French can do this, we can do it, and I think this is our opportunity to learn more about immunotherapy in kidney cancer.
Dr. Charles Ryan: Yeah, good, great. Really exciting ASCO for you and Duke. It's always a pleasure talking to you, Dan.
Dr. Daniel George: My pleasure, too. Thanks, Chuck.