Ulka Vaishampayan, MD: The next question is the consideration of second-line treatment after progression on initial immunotherapy, whether it is ipilimumab-nivolumab or the combination of an anti-VEGF TKI [tyrosine kinase inhibitor] with an immune checkpoint inhibitor. Post immunotherapy, what is your thinking about optimal second-line treatment? Tian?

Tian Zhang, MD: This is a really important question, Ulka. We’ve thought about sequencing after immune checkpoint inhibitors in the frontline setting. Dr Daniel Heng presented some interesting data from the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] database about this at GU ASCO [Genitourinary Cancers Symposium] 2019. But largely, the sequencing question has been unstudied. The VEGF-I/O [immuno-oncology] combinations really have been studied, mostly in the early first-line setting and without refractory disease data. We really don’t have randomized trials, I think, to test each of these sequences separately. And so in that setting, real-world data as well as registry data—some of the ongoing studies that are currently in development—will really help us understand what the different sequences allow in terms of overall survival for these patients.

We’re also studying the sequencing question in an ongoing Alliance for Clinical Trials in Oncology phase III trial called PDIGREE—we’ll talk about this a little more soon—but we’ll have data on the patients who undergo ipilimumab-nivolumab up front and then follow it with cabozantinib. So it really is a data-free zone. It’s going to be difficult to think about which patients benefit from immunotherapy after initial immunotherapy and whether we should switch mechanisms right away—to a VEGF-targeted therapy after the early immunotherapy combinations.

Ulka Vaishampayan, MD: Those are excellent thoughts. Do you think that the response to the initial immunotherapy should factor in? If so, how does it factor into our second-line decisions?

Tian Zhang, MD: Sure. We certainly are seeing some great responses from immune checkpoint combinations—so ipilimumab-nivolumab. We now have some data on treatment-free survival. These patients who are coming off ipilimumab-nivolumab up front have a certain time off treatment. Do they progress 9 months after they’ve discontinued treatment? I think those are the perfect candidates for rechallenging therapy. They’ve had an initial great response, and now they should probably be rechallenged.

In terms of early response or even early progression of disease, if they have been treated with 3 months of ipilimumab-nivolumab, for example, and then progress right away, immunotherapy is probably not doing very much in that setting. And so they definitely need another mechanism of action. In that instance, we have a lot of data on cabozantinib, for example, in the METEOR study, as well as other VEGF TKIs. Certainly, the duration of the frontline treatment, length of response, and depth of response really matters in terms of sequencing.

Ulka Vaishampayan, MD: How do immune-related adverse events that occur during frontline immunotherapy impact the second-line treatment decision?

Matthew T. Campbell, MD, MS: That’s a great question, and our group is giving this a lot of thought right now. In fact, many groups around the country are giving this thought right now. With nivolumab and ipilimumab, there’s a high toxicity rate. There are patients who have to come off therapy because of autoimmune colitis, autoimmune hepatitis, pneumonitis. In our practice, if patients have myositis or myocarditis and survive, we will not rechallenge them with immunotherapy. If they have severe pneumonitis, we will not likely rechallenge them with immunotherapy.

If they have colitis, we’re starting to play around with some of these patients as they recover because our sense is that it’s largely driven by the ipilimumab. We’re working, along with 1 of our fantastic gastroenterologists, at this. They’re started on vedolizumab. And so she’s studying that right now to see how well patients do on rechallenging with treatment, in terms of if their colitis flares back up or if we can keep them on therapy.

But as Tian said, some patients who develop these adverse effects don’t progress. It’s fine to just watch them. But other patients start progressing quickly off therapy. Then you have to decide what to do. That’s a problematic area.

When I’m thinking about what to do for second-line therapy, I am again thinking about the rate of progression. A lot of times in the community, they’re kind of basing progression off what the radiologist is saying. Sometimes these are just very small, millimeter changes among nodules, lymph nodes, or an adrenal metastasis, or pancreas metastasis. These are often patients who can be contained on the same therapy and don’t even warrant a switch. But for those patients, I would probably think about using a drug such as axitinib if they have not received that as their initial therapy. If they’re really progressing rapidly, particularly in the bone or in the liver, and if you really need to get a response, I think either cabozantinib or lenvatinib-everolimus are very reasonable options at that point.

Transcript Edited for Clarity