Favorable-Risk mRCC: Treatment Approaches

Martin H. Voss, MD: It gets to be very difficult once someone decides to pursue systemic therapy with a patient. We’ve seen subgroup analyses offer combination trials that speak to the uncertainty of whether there’s true benefit from adding the I/O [immuno-oncology] agent to the TKI [tyrosine kinase inhibitor] alone. Colleagues from the FDA presented data pooling data from all the pivotal trials we mentioned and showed no significant overall survival [OS] benefit. The patients in the favorable-risk group were treated across these trials and compared with sunitinib. Obviously, this is all limited by numbers, but I’m curious to hear what your individual practices are with patients who are favorable risk. Are they always considered for combination therapy based on the higher response rates? Are you more leaning toward using single-agent TKI to limit toxicity? Or is there no 1-size-fits-all approach in this patient population? Do any of you want to speak to that?

Thomas Powles, MD, MBBS, MRCP: Martin, the way I look at this is the recent adjuvant positive trial makes this a bit more confusing because I’m guessing that the adjuvant population inherently are a better risk; a good-risk group of patients who relapsed from surgery. IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] is a biological diffuse group of patients. They contain immune-sensitive and VEGF-sensitive tumors. There will be patients in that good-risk group who will respond and do well with immunotherapy. The adjuvant data suggest that there’s a DFS [disease-free survival] advantage and potentially an OS advantage in early intervention in this good-risk early population. Starting earlier may be better.

I also think the long-term survival of these patients remains somewhat unknown. You asked me previously to compare 32-month survival with 48-month survival, which is pretty irrelevant in the grand scale of things. What about comparing the 10-year survival with the 5-year survival or the 5-year survival with the 2-year survival? That means a lot more to me in the good-risk population. The number of events in this good-risk population is still really small. Maybe in 20 years’ time, having really early immunotherapy will have completely changed everything.

I agree with what was said previously. The problem with starting VEGF-targeted therapy in the good-risk population is you get initial control, they’re on this drug for a long period of time, and in the end, it goes wrong. Some of the work by a number of different groups, including the group at Crick [The Francis Crick Institute in London, England], show that there’s heterogeneity associated with VEGF-targeted therapy. You may be ultimately generating even more aggressive cancer by giving it. That may be in the end why the adjuvant trials were negative. My approach is to say in that good-risk population, observation is a great idea. I can see stereotactic radiotherapy for oligometastatic disease, and I can see immune-VEGF combinations in patients who you think require therapy. But I don’t see sunitinib as a great option for good-risk disease.

Martin H. Voss, MD: Terrific. Thanks very much, Tom.

Thomas Powles, MD, MBBS, MRCP: The same applies with pazopanib. I’m not anti-sunitinib. I’m equally anti- all the drugs in that space.

Martin H. Voss, MD: Single-agent TKI, understood. Sandy, do you want to speak to your approach in these patients with favorable-risk disease?

Sandy Srinivas, MBBS: They do have a spectrum. The problem is that it comes down to the clinical features we use. Is that the most appropriate way to prognosticate patients? That’s where the field is headed. There’s so much information coming about: What makes favorable-risk favorable? What’s the underpinning biology? To me, it feels from all these trials that they do well with the TKI. They do really well with the TKI, but is the response from a TKI enough? Clearly, we’re not satisfied with just a TKI alone for patients. They are going to have a chronic illness. That’s what we’ve seen in the last decade. We have clearly improved their PFS [progression-free survival] and OS, but we aren’t seeing cure rates.

With I/O–I/O, we don’t need an urgency for these patients with favorable-risk. Many of them are not symptomatic. I would even say giving them the dual I/O is not completely unreasonable if your goal is trying to get them to a CR [complete remission]. The only problem that I have: We do feel terrible when these patients end up having some immune-mediated adverse effects, but it would be great for them to get this drug and not have to be on any, hit that home run, and have a durable CR where they don’t need to be on any other therapy. Having said all this, it’s very confusing. You have to think through the patient who’s in front of you as to whether you’re going to offer surveillance, stereotactic radiosurgery for oligometastases, or metastasectomy, as Amishi said. Any of the I/O–TKIs are reasonable combinations, but I have to admit, I’m a fan of dual I/O with the intent to get patients a durable CR.

Transcript Edited for Clarity