Pedro Barata, MD, MSc: Dr Garmezy, because we're talking about efficacy and about getting these agents early on, and you brought up the point about IO [immuno-oncology], these conversations involve immunotherapy in the frontline and subsequently. There's one ongoing trial that is testing tivozanib with nivolumab: TiNivo, which you mentioned briefly earlier today. You also mentioned CONTACT-03. What are your thoughts about the role of immunotherapy post-progression on a prior immunotherapy? Perhaps I'll let you comment on the TiNivo trial; tivozanib plus nivolumab, post-checkpoint inhibitors. What are your thoughts about CONTACT-03 with cabozantinib and atezolizumab with the PD-L1 inhibitor post-checkpoint inhibitors, and your thoughts about the concept in general? Feel free to share details about those studies.

Benjamin Garmezy, MD: This is the critical question that's going to be potentially practice-changing in the second or third line. I believe that we might see a benefit in patients continuing immunotherapy, because when we think about the heterogeneity of a disease and what we call progression in the frontline, we know somebody with metastatic sites across their body, and those individual metastatic sites have different microenvironments in different biologies. Some of those sites probably still are immune sensitive while others are immune resistant. While a patient may be progressing in one organ site, they may not be progressing in another organ site, and by pulling off that checkpoint inhibitor therapy, we may be doing them a disservice.

Ultimately, the data must be read out and we're going to follow it, but I'm excited for the option. In my clinic, in the real-world setting, patients are nervous when they stop immunotherapy because they've been told that immunotherapy is a chance of curing metastatic disease and they hate to give that immunotherapy up. I'm not advocating or thinking that we are going to be curing patients in subsequent-line therapy, but I am advocating that we may be able to extend progression-free survival and perhaps overall survival.

The TiNivo-2 trial is randomizing patients in the second or third line to either tivozanib as a single agent or tivozanib and nivolumab continuing immunotherapy from the frontline patients coming into that trial receiving mostly IO-TKI combinations or IO-IO combinations, having seen one of each class of medication due to some guidance from what that trial was looking for. That will be essential. We're also going to have another trial, and hopefully both will read out positive so we don't have to debate the merits of one vs the other. That's the CONTACT-03 trial, which is basically looking at a similar patient population, but randomizing patients to cabozantinib at 60 mg; not 40 mg, the dose that was used in the CheckMate 9ER study in the frontline. Sixty mg, which is the monotherapy approved dose plus or minus atezolizumab, which is a PD-L1 inhibitor. PD-L1 and PD-1 seem to potentially be different. We don't know their role in the subsequent-line setting yet, but we do know that both have NCCN guidelines attached to them, with avelumab being a PD-L1 inhibitor compared with axitinib previously being used more in the frontline setting, which hit a progression-free survival endpoint, but not an OS [overall survival] endpoint. Therefore, that one has fallen out of favor, but we don't know whether that PD-L1 inhibitor in the second line combination setting with a TKI may or may not hit.

Hopefully both will be informative for our patients. I hope they're both positive because more options is always better. Especially when you think about what you gave in the frontline setting. If you gave cabozantinib in the frontline setting, you're going to want to have an option to give a different TKI continuation with immunotherapy in that second-line setting. But if you gave something outside of cabozantinib, then you can make your choice between tivozanib or cabozantinib immunotherapy combinations if those read out. Now, of course, they may not, so we're going to follow those data. That data are going to read out soon, and then that may be practice changing for every patient with renal cell carcinoma across the country with this type of biology. What are your thoughts, Dr Barata? Are you excited about these potential combinations in the future?

Pedro Barata, MD, MSc: Yes, I agree with your thoughts completely. I'll add that as we’re enrolling for TiNivo, enrollment for CONTACT-03 has completed, and we're expecting a readout soon. I think you will depend on the patient population that we're enrolled for those studies. Meaning, because they're not mandating an X amount of time of prior checkpoint [inhibition], when we're giving a checkpoint inhibitor combined with something else, whether it's another checkpoint or a TKI, and we are including patients who have a primary resistance to a checkpoint, for whom checkpoint doesn't work at all. We’re also including patients who are having this secondary progression or secondary resistance, where it works for a while and then it stops working.

Perhaps you’re also including patients who have a unique responsiveness to immunotherapy, definitely less than 50%. Whether that number is 20% or so remains to be proven definitively. You’re enrolling patients with a different chance of success with the checkpoint. The more of the primary resistant patients that we get on those trials. How do I know that? Well, if they progress on frontline in a shorter period of time, they're more likely to not benefit from a checkpoint-based approach. It’s more likely that the trials are going to be negative because it's more unlikely that there's a synergistic effect with an IO, with a TKI in the second-line agent compared with the TKI alone. Whether it's tivozanib or cabozantinib, there's no biological thought process to think that the synergy between one TKI and checkpoint will be different.

I don't know what to make out of the PD-1 vs PD-L1. Certainly, in GU, PD-L1 have been suggested to potentially be less effective than PD-1s. We don't know if that's the case, but I think it has to do with the patient characteristics enrolling the studies. If we’re enrolling and considering a lot of patients who are progressing more than a year, a year and a half being on a one checkpoint, potentially, there's a synergistic effect. The reason why we say that is based on phase 2 data, and we have the example of lenvatinib-pembrolizumab combination in the refractory space where response rates are over 50% with that combination, I believe 51% in an institutional study from Memorial Sloan Kettering Cancer Center. There's something there that you don't get with lenvatinib alone. You must have something else helping you out. There are a lot of no nuances, and the baseline characteristics of patients and the disease will impact the outcomes. These are definitely interesting studies that have the potential to change practice and definitely settle the question regarding the role of a checkpoint inhibition in the salvage setting for patients with metastatic RCC.

Benjamin Garmezy, MD: Yes, I think those are great points. I want to thank you for those comments because I think that's right. When we look at those patients who get enrolled, it's going to influence the trial. It's the same patients whom we're now thinking about who were progressing on adjuvant pembrolizumab prior to frontline metastatic therapy. How much can we still use those immune targets to our advantage in metastatic disease? That's a great point. That's another question that we're going to have to solve, as well as a community of researchers.

Transcript edited for clarity.