Transcript: Daniel J. George, MD: Let me bring up 1 other scenario because I think you brought this up earlier about these treatment breaks and this idea that these patients might get to a complete response or near response or they might have toxicity that requires a break from therapy, a significant colitis or what not. Patients recover, patients have no evidence of disease recurrence, but then at some later point they start recurring. How do you manage that patient, do you go back to the original regimen? Do you then say, “Well, we can’t go back to that, we should try something different.” Is that different therapy now an IO [immune-oncology] therapy or is it a TKI [tyrosine kinase inhibitor]? That’s some of the context of what’s happening in the frontline setting that I think could have impact on how we treat the second-line setting. What would be your thoughts on this? Nizar, you had experience with this. What do you think here?

Nizar M. Tannir, MD, FACP: I think it depends what they received in the first-line of IO therapy that produced a toxicity. If they received nivolumab-ipilimumab and they had colitis, for example, grade 3, obviously we treat that colitis with immunomodulating agents, corticosteroids, maybe you add vedolizumab, the anti-integrin antibody, or maybe the anti-TNF [tumor necrosis factor] alpha, infliximab. Once that colitis resolves, I follow them without therapy as long as they’re progression-free.

Once they have progression, I would not go back to nivolumab-ipilimumab again because I’m really concerned about the immune system still being fired up and them ending up with a worse toxicity. But it is possible, if the toxicity was just colitis and nothing else, it is possible to go back to nivolumab alone. And in parallel, as you give nivolumab, what we do at MD Anderson Cancer Center is do a colonoscopy and see what the colon looks like, and if we need to do a biopsy, we’ll do a biopsy and treat in parallel with nivolumab. As we give nivolumab, give vedolizumab—the anti-integrin—to try to keep the colitis from recurring and see if they’ll respond. But I wouldn’t go back to nivolumab-ipilimumab if they had bad toxicity with nivolumab-ipilimumab because I think that would be alarming. There is really a risk of having a worse AE [adverse event].

Daniel J. George, MD: And we’ve got these other treatment options.

Nizar M. Tannir, MD, FACP: And we have these other treatment options.

Daniel J. George, MD: It would be one thing if that’s all we have, right?

Nizar M. Tannir, MD, FACP: Exactly.

Daniel J. George, MD: But now you’ve got all these other options. You’d hate to end up with a complication that’s irreversible.

Nizar M. Tannir, MD, FACP: That’s where you go to TKI. And like I said, we have lenvatinib-everolimus as an option, you have cabozantinib as an option, you have axitinib if they never received axitinib in the frontline. Then it becomes which agent you’re comfortable with. You’re very comfortable with lenvatinib-everolimus because you’ve done the trial.

Chung-Han Lee, MD, PhD: Yes.

Nizar M. Tannir, MD, FACP: I have been impressed with lenvatinib-everolimus lately and have given it to patients. And we’re participating with pembrolizumab-lenvatinib for the HOPE 111 trial post-IO. So I think you have many options. It’s a good thing for patients that we have all these options.

Robert S. Alter, MD: When patient toxicity may be grade 3, they actually taper off steroids quite well. And let’s say you use hepatitis as your grade 3 toxicity, we’ve had the opportunity of rechallenging patients with nominal toxicities, not even having patients on a low dose of prednisone. The rechallenge in some patients can be quite well, especially if you have the previous responses that some may have achieved based upon their disease in and of itself. But patients sometimes drive us to consider treating them longer where we have to recognize that even by stocking these therapies and giving them this drug holiday, which may be a very durable holiday, that rechallenging them too fast may be inappropriate.

Chung-Han Lee, MD, PhD: I think a lot of it does come down to the potential subsequent therapies that are available, and of course mechanism of action is very important, whether it’s a VEGF/IO combination that’s available, whether it’s lenvatinib-everolimus and looking at VEGF plus mTOR [mammalian target of rapamycin] inhibition as an option. The other part of it is how bad was the IO toxicity that they experienced. Certainly, anyone who’s had a very severe one, are things that have the opportunity of progressing very quickly, we’re probably a lot more cautious about that. But the ones in which they reverse very quickly, there is the ability to rechallenge with a more narrow spectrum of therapy, even with an IO.

Transcript Edited for Clarity