New Data and Treatment Sequencing in Renal Cell Carcinoma

Zita Lim

What are your thoughts about the potential new addition of combination cabozantinib/nivolumab to our regimen of immunotherapy (IO)/tyrosine kinase inhibitor (TKI) therapies vs. IO/IO therapies for renal cell carcinoma (RCC)?

Emily Lemke

In the past 2 to 3 years the market has been happily flooded with a lot of options that have made the question of treatment sequencing a really important one, and one that we don't necessarily have a best answer to. But looking at these new combinations—specifically nivolumab/ipilimumab and pembrolizumab/axitinib, and now the newer data with nivolumab/cabozantinib, which hasn’t yet been approved—brings up a lot of questions.

I approach these newly diagnosed metastatic patients by looking at their burden of disease and how they're feeling, and of course thinking about their IMDC [International Metastatic RCC Database Consortium] risk category. So a patient who comes in with a lower-volume disease, specifically lung-dominant or lymph node–dominant metastases, that's the patient we start with nivolumab and ipilimumab, just because we know that that combination therapy can take a little bit longer to work, and the objective response rate isn't as high as the TKI/IO combinations. But the pathological complete response (CR) rate, which to me is the golden ticket, is similar among all of these. So if you feel like you have time to allow for a response from a dual immunotherapy combo, nivo/ipi is my preference. Whereas if somebody comes in and they're "on fire"—more visceral metastases, bony disease—and they’re symptomatic, that’s the patient I'm going to want a quicker response for, and the option of the IO plus a TKI is going to be more attractive. I lean toward doing more pembrolizumab/axitinib, as opposed to cabozantinib/nivolumab, because I still like to save cabozantinib as a nice salvage option. Although if somebody was at risk of dying within the next 2 to 3 weeks, you can really pull them from the jaws of death with nivolumab/cabozantinib. And that might be the unique patient who would benefit from using everything we have right from the get-go.

But what about you, Zita? How do you approach those intermediate/poor-risk, on-fire type RCC patients?

Zita Lim

What you said is spot on. We do very carefully try to risk-stratify patients based on their IMDC criteria: Does the patient present with metastatic disease at the onset, or within a year of their nephrectomy? Do they have other factors such as anemia, hypercalcemia, thrombocytosis, or elevated white counts? And then, of course, what’s their performance status? Those are the factors we lean on to determine different treatment regimens.

Ideally, we like to treat patients with IO/IO therapy in the intermediate- and poor-risk setting. I think we will probably switch to nivolumab/cabozantinib once it's approved for that group of poor-risk patients who you fear may not have enough time for the immunotherapy to work and their decline will be too precipitous. Giving them a TKI up front, especially one like cabozantinib that blocks several other pathways in addition to VEGF, makes sense.

Treatment decisions seem relatively straightforward for the intermediate/poor-risk patients; the cases I actually find more tricky are the good-risk patients. How do you approach those patients with all the potential treatment options?

Emily Lemke

Good-risk RCC patients really have every option in the book, especially since the CheckMate 214¹ data presented at the 2020 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, showed that sunitinib and nivolumab/ipilimumab actually had similar responses in the good-risk category. I think it's a tough question. And is there still a role for single-agent pazopanib or sunitinib in these patients?

The other million-dollar question is, what is the role of active surveillance? Because thoughtfully using active surveillance in some of these really good-risk patients whose disease has proven itself to be indolent is also an interesting option. So looking at their disease history, if they had a nephrectomy 12 years ago and are now coming in with less than 1-cm pulmonary nodules, that might even be a patient you could consider observing, or doing pazopanib or sunitinib up front. But for anybody who is coming in with good-risk disease and more than one site of metastatic disease, I think you have to do nivolumab/ipilimumab. Everybody deserves the chance at the CR that that regimen allows and the usually favorable toxicity profile. If you can make it to the maintenance nivolumab phase without having any of those immune-mediated side effects, the schedule is nice, the side-effect profile is nice, and the chance for a CR is really nice.

I mentioned active surveillance, but tied in with that is the question of whether or not you could treat a patient like this with a metastasectomy approach or stereotactic body radiation therapy (SBRT). Is that something you're doing for your patients?

Zita Lim

There are patients like this who can still benefit from just very minimal interventions like that. Just today I had a patient with kidney cancer who had a nephrectomy more than 5 years ago and had a solitary, biopsy-proven recurrence in the lung, who we ended up treating with SBRT. That patient is now disease-free over a year later. We were able to spare him any of the toxicities of these other therapies, and we can reserve them to use in the future, if necessary. So I think in select patients, there are still other options on the table as well.

Emily Lemke

In these good-risk patients who have potentially a long treatment trajectory ahead of them, what do you think about treatment-free survival as a metric, and how do you incorporate TKI/IO combination therapy for these patients when we know that the treatment could become more toxic than the cancer itself?

Zita Lim

That's an interesting question and something I think most patients wonder about. The first thing patients ask you is, “How long am I going to be on this treatment?” And this is an interesting, evolving question. We have some data answering this question based on the CheckMate 214 trial, which you mentioned. In a post hoc subgroup, non-prespecified analysis, survival was as good or even better in the patients on the nivolumab/ipilimumab arm of the trial who developed grade 3 or 4 toxicities compared with patients who completed the treatment.²

Interestingly, I have a number of these patients who after either just three or four cycles of induction nivolumab/ipilimumab had to come off the trial for toxicity and we ended up just monitoring them. The OMNIVORE trial, which was presented at the 2020 ASCO Annual Meeting, looked at patients treated up front with nivolumab and those who achieved stable disease or progressed had ipilimumab added to their regimen to see if it would boost the response.³ Anecdotally, there were several patients who did not complete all four ipilimumab infusions who achieved a durable response. Ultimately, we need better biomarkers to stratify which patients would benefit most from immunotherapy. I hope to be able to offer more patients treatment-free periods, ideally permanent ones.

Emily Lemke

When you have known these patients for a couple of years, and their cancer biology has proven itself, making those decisions is a lot more comfortable because for any patient with stage IV cancer, the thought of not being on any therapy can be a bit anxiety provoking. But when you can look back at the history of their disease and talk about how they’ve had six scans without any change, and they’ve been off therapy, that's a really lovely opportunity patients have to maximize their quality of life.

And that brings me to my next question about salvage therapy. When you burn your first-line bridges and you've got progression, what is your preferred regimen? Mine is usually cabozantinib or lenvatinib/everolimus, but how do you incorporate those regimens in your practice?

Zita Lim

I advocate for different clinical trials at that point. That is the risk we have when we use an IO/TKI therapy up front: What do you go to next? I agree with you; we use some of these salvage regimens. If a patient progresses on IO/IO therapy, there are some interesting clinical trials going on looking at restoring the microbiome and seeing if that can help reactive a patient’s immune system. But off protocol, we're fortunate that we have several different tyrosine kinases that block different pathways, and we'll try to rotate and then maximize those as well.

Looking beyond currently approved therapies, what are your thoughts about treatments on the horizon for clear-cell kidney cancer?

Emily Lemke

I think that understanding treatment sequencing is going to be more important in upcoming clinical trials and, along with that, making the comparator arm in future trials more appropriate than sunitinib. That will help guide further clinical decisions. I'm personally really excited about some of the trials that are combining SBRT and immunotherapy: the RADVAX trial⁴ and the CYTOSHRINK trial⁵. We’ve been chasing the ever-elusive abscopal effect for a long time, and looking at how those two modalities work with each other is going to be really interesting in a disease that was historically a little bit more radiotherapy-resistant.

And as with all cancers, I think biomarker-driven therapy is going to continue to evolve, especially in the non–clear cell cohort, but in the clear cell cohort as well, as we have more molecular testing on patients, and we have more databases to draw some conclusions from. Tailoring patients' treatment to their specific profiling really is the wave of the future.