Dr. Brian Rini:
Hi. Welcome to the ASCO Post Roundtable Series on Treatment Considerations in Renal Cell Carcinoma. I'm Dr. Brian Rini. I'm the Chief of Clinical Trials at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. And joining me today are two of my colleagues who will introduce themselves.
Dr. Katy Beckermann:
Hi, everyone, my name is Katy Beckermann. It's wonderful to be here and discuss kidney cancer today. I'm a GU medical oncologist at Vanderbilt University Medical Center.
Dr. Pedro Barata:
Hey, there, I'm Pedro Barata, I'm also a GU Oncologist Associate Professor of Medicine at Case Western University at University Hospital Seidman Cancer Center in Cleveland, Ohio. Also, a pleasure to be here with you both.
Dr. Rini:
Thanks to both of you for joining. Today, we're going to discuss recent updates in the treatment of kidney cancer and integrate new developments including new data from ASCO this year into patient case studies. And our last installment will focus on immunotherapy-refractory advanced kidney cancer. This case is a 65-year-old female who has been on axitinib plus pembrolizumab for the past 4 years. As you know, this IO/TKI doublet is a standard of care for the initial treatment of kidney cancer. She originally presented with pulmonary lymph node metastases within a year after a nephrectomy for a T3a clear cell RCC, was then placed on axitinib/pembrolizumab and had a nice PR after six cycles, tolerated treatment fairly well with just some mild fatigue and diarrhea and hoarseness. Unfortunately, now after this nice and fairly durable response, now 4 years later, her imaging shows new liver lesions and new pulmonary and mediastinal lesions. Still has a good performance status, Karnofsky 80%, slightly anemic with a hemoglobin of 10.8, but other labs within the normal range.
So what therapy would you choose now? Katy, let's start with you. These are really common patients in our clinic now and as we've discussed, we think pretty much every patient without an absolute contraindication should be getting some form of immune-based therapy upfront. Also, patients are now getting it in the adjuvant setting. So immune-refractory kidney cancer is a very growing population of patients. So, how would you approach this patient?
Dr. Beckermann:
Yeah, so I see we've got a list of options here. I'm going to mention one on this list and then maybe some other alternatives that I would think about for this particular patient. So essentially they've progressed on frontline IO/TKI and we certainly have data for sequencing of TKIs. So for this patient, based on the list provided to us, I think I would consider second line of cabozantinib, we can base that on the, going back to the METEOR trial, those patients got sunitinib or pazopanib upfront and then had a nice objective response rate and improvement in PFS and improvement in overall survival.
So I think here cabozantinib is a great second line option. And I think we're going to discuss the new data that was presented at ASCO. So the one thing I would not give this patient based on recent data is an IO/TKI without any evidence of that's beneficial in the second line setting.
Dr. Rini:
Didn't that data in one second. So cabo as a standard of care, I think it's probably the most commonly used. Most of the others had immune therapy and we'll talk about the CONTACT data. How about tivozanib? Where do you use that drug?
Dr. Beckermann:
Yeah, so I definitely lean on tivozanib approved in patients who've had two or more prior lines of therapy. So they're looking at third and fourth line agents. Again, similar, great objective response rate improvement in PFS in comparison to sorafenib in that line of setting.
Dr. Rini:
Pedro, what do you think? How would you approach this patient?
Dr. Barata:
I agree with the thought process. I just want to highlight that this patient has been on axitinib therapy for 4 years. So patient completed 2 years of pembro and continued on axitinib monotherapy. So actually yes, CONTACT-03 data was presented and I think it established a new way of practice, which is probably going to going to give a lot of the providers some reluctance I guess, or revisit their practice because there are a lot of folks out there doing IO in a salvage setting. I can only imagine that for a patient has completed 2 years of pembro, being on axitinib, progressed 2 years later on axitinib, right? It is possible that folks will still revisit IO in that setting, which it's not clear, it is not quite what CONTACT-03 tried to answer just by the way it was designed.
So I wouldn't discard completely the role of IO, but with that said, I probably, my go-to would probably be cabozantinib, but I was just going to make that point. And also I think tivo would be appropriate. There's two lines of therapy, at least one TKI, as based on TIVO-3, that really helped with lead. And so I don't think it would be inappropriate. I think it has advantages in terms of tolerability. Patients do remarkably well, we manage. And so I don't think it would be unreasonable.
Dr. Rini:
Yeah, reasonable. So let's go over that CONTACT data. And I want to revisit the role of immune therapy. And Pedro, you brought up a really good point this, and I didn't mention it during the case. This patient would've stopped, and I do this in my practice, stopped pembro at 2 years, which we don't know what the role of just reintroducing pembro. That's never been studied. I've not had to do it. I don't even know of anecdotal or case series. So we're starting to get into sort of new waters with this, but let's talk about CONTACT-03. I think this was the most important study presented at ASCO this year, even though negative, I think it was very clinically impactful. So again, this was advanced clear cell or non-clear cell kidney cancer, but predominantly clear cell. And they had progression on or after a prior immune checkpoint inhibitor–containing regimen.
They did allow adjuvant, although only one patient in each arm actually had adjuvant therapy just based on the timing of the study. And importantly, and this gets to your point, Pedro, immune therapy had to be the immediately preceding line of therapy. And I don't know if there was a time gap, I assume there was, but I'm guessing that patient's probably finished immune therapy within 3 months of starting study, probably even closer than that, stratified by IMDC risk group, histology, and whether, you know, where they got their most recent ICI, and then randomized to cabozantinib monotherapy, which I think we'd all agree is certainly a standard of care in this setting. Or the combination of cabo plus the PDL1 inhibitor atezolizumab. And that combination had been studied in various studies in cohorts across many diseases and has presented a lot of data and clearly has activity but had never been studied in a randomized study.
And what we saw again, presented at ASCO, published in Lancet same day, was that the PFS was no different. It was very good in both arms, about 10 1/2 months. That's very good for cabo in this setting. And these curves are entirely overlapping. And of course the hazard ratio is 1. And then not surprisingly, no difference in overall survival, again with overlapping curves. And importantly, combination therapy does have more toxicity here, including three deaths related to treatment. So higher number of SAEs and AEs in general and some treatment-related deaths. So the addition of atezolizumab in this case added no efficacy and certainly added toxicity and I think gives us pause about the role of sequential immune therapy. So having gone over the data, Katy, you wrote an excellent editorial in the Lancet, I remember, for this article. And what do you think explains these results? Why wouldn't IO/TKI work? What's going on here?
Dr. Beckermann:
I think there's a lot of details to go into. First of all, I think one of the questions that we'll hopefully have some more answers to is the partners here that were chosen. So testing atezolizumab, which has previously not been shown to have that overall survival benefit in the metastatic setting, in the adjuvant setting, no benefit. So TIVO-2 is another study that will look at what if we, instead of combining PDL1, what if we combine a PD1 with again, a very useful TKI (tivozanib) there. So that's one of the questions that's kind of still left in my mind after seeing this CONTACT-03 data.
Dr. Rini:
Maybe mechanism of the IO.
Dr. Beckermann:
Yeah.
Dr. Rini:
Okay.
Dr. Beckermann:
Yeah, and I do think it answered a good question. I think it gave us valuable data to say there is more toxicity and we're not seeing any improvement by adding the IO.
Dr. Rini:
Yeah. And Pedro, what do you think? Why is it negative? Why did the cabo arm do so well? Where do we go from here?
Dr. Barata:
Yeah, I think, yeah, that's a great question. I think based on the pre-specified calculations, in reality, I think it was over 40% or so patients treated with ipi/nivo, meaning TKI-naive patient population, in CONTACT-03. And so definitely we would expect patients on cabo on the control arm, cabo 60mg, which by the way is a high bar, is a very effective TKI, to do better because it’s their first TKI and not their second TKI, right? So for some patients we could use METEOR to kind of guide us what to expect in terms of progression-free survival as the endpoint and in other cases will be better than that. We could look at cabozan and so forth. So I think that might be one of the reasonings. The other one is the fact that they allow patients progressing while on IO frontline or within 6 months of completion of prior IO.
I think that was the language in the eligibility criteria. Basically you're taking to consideration possibly the checkpoint lingering effect as we know there's occupancy of the receptors. It's definitely a few months afterwards. I want to quote around 75% 3 months later. And it's about that. And so it is possible there's some effect that comes from prior line of therapy in IO that could help the control arm to do well. And so we didn't see a difference. I think we have now definitely lack level 1 data to support the use of salvage checkpoint inhibition in the refractory setting. We definitely have some cases of success. The data from Sloan is definitely provocative, phase II from Lee. But it is quite an interesting story because we also thought we had an opportunity for CTLA-4 in the refractory setting a few years ago.
And a number of studies kind of made us be not as excited as before, let me put it that way. And so now I think we've set on the question that if we want to do it still before we do it upfront, and it sounds like it might be the case for PD-1s and PD-L1s, although to Katy's point, right now we only know that for PD-L1 and that at least the meta-analysis that I know in GU that suggests that PD-1s might be in fact more effective. We don't know that for a fact. So I do believe trials like TiNivo-2 are important to be conducted and they're just complete accrual. So it'll be very relevant to see that's the same message going to come out of that knowing that we're keeping the same control, the same TKI in both arms, which I think that's unique of CONTACT-03 with cabozantinib in both arms. And I think that allows us to interpret the data and apply it to clinical setting. So long answer to basically agree with Katy about what we're going to-
Dr. Rini:
Yeah, I think the cabo monotherapy arm probably did well for the reasons you mentioned, lingering IO, the drug itself, or the T cells. And so it was in essence IO/TKI vs IO/TKI. So not surprising, the curves are overlapping. Also, if you think about it, all the patients who do really well on immune therapy didn't make it to the study. They're either cured or still on their immune therapy. So you're going to enrich for probably an angiogenic-driven population of patients as you alluded to. I don't remember if they presented data based on receipt of prior TKI or not. I don't remember if that was in the forest plot. I remember that patients who responded to prior IO, it looked like that hazard ratio was lower within the limitations of subsets, but I don't remember. And again, parsing out subsets of a negative trial is always dangerous.
But as you both said, really important practice impacting data. We've been fooled by phase II studies before, right? Phase II studies with nice shiny response rates are appealing and we start doing it. But randomization is the great equalizer, right? It's the sobriety test for whether we should be using this. And in my practice, in my opinion, I do not think people should be using sequential immune therapy until and unless there's actually data that shows benefit, randomized data that shows benefit. The one question that we'll have to leave unanswered is what about the gap? What about if you got adjuvant therapy 3 years ago and now you recur? Or to your point, Pedro, what if you had stopped pembro on your IO/TKI and now it's 2, 3 years later? We don't know. You can imagine you'll start seeing those case reports and those case series and stuff.
I don't know that a trial will ever be done, but we'll have to see how it plays out in practice. And then I think maybe my last comment on the data is, as you alluded to Pedro, CTLA-4, which we know is a great drug, ipi’s a great drug, but it's not a great salvage agent. So I'm moving more and more to the opinion that we need to study novel immune therapy and novel combinations upfront. That this refractory setting is not a great setting to really decipher the activity of immune therapy in general or novel immune therapy.
So just to wrap up with the key clinical takeaways from this case, there's no proven benefit to sequential checkpoint blockade in kidney cancer pending further data and there is increased toxicity. Whether immune therapy after immune therapy with a longer time in between that we just talked about probably most likely in the adjuvant setting will require further studies. An initial IO may be the most effective approach, and importantly, insight into mechanisms of resistance to IO, which we have very little insight now, that knowledge base is sorely needed.
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.
