Strategies for Switching From Frontline Therapy to Second-Line Therapy in mRCC

Daniel J. George, MD: That’s right. Neeraj, I always give you the toughest questions, so I’ve got to come back to you here. I want you to think about this 1 carefully: Off-study, what are your criteria for switching somebody from frontline to second line? What constitutes real-world progression to you? Does that type of progression affect what you do in the second-line space? I’m going to follow-up on that second point, but right now, how do you call a patient a progressor in that frontline setting?

Neeraj Agarwal, MD: Obviously, this is not like what we do in clinical trials.

Daniel J. George, MD: Right.

Neeraj Agarwal, MD: That’s a straightforward, 1-line answer to begin with. I never take a patient off treatment because 1 target lesion has grown out by 30% or 20%, while other nontarget lesions are stable or mildly increase in size. The most important criteria for me in my clinic at the Huntsman Cancer Institute to take a patient off-study is the clinical progression in addition to emerging progression. It’s never emerging progression alone unless there’s a high-volume disease progression or rapid disease progression, which I’m going to come to later. Half of this answers your second question.

Yes, the patients are doing well. In fact, today I saw a patient doing well with a 30% increase in the size of the main lung lesion, but other lesions are doing pretty well. He’s tolerating the treatment well. He’s planning on going on a vacation next month. I don’t want to rock the boat. We decided to repeat the scans 3 months from now.

In this case, I decided to continue the patient on the same treatment despite objective disease progression but obvious ongoing clinical benefit. The patient is going to come back to me after 3 months, and at that point, if the patient continues to have slowly progressive disease, I may continue the patient on the same regimen if clinical benefit is still happening.

There may be other situations: The patient may show a rapid disease progression with multiple new lesions. This patient, by the way, is on ipilimumab-nivolumab combination. I will use cabozantinib or cabozantinib as second-line treatment, or maybe lenvatinib-everolimus if, hypothetically speaking, the patient was on cabozantinib with nivolumab combination. If the patient was being treated on that combination trial and a patient is having disease progression or rapid disease progression, I’ll start lenvatinib-everolimus. If there is a situation where a patient who is on a VEGF–TKI [tyrosine kinase inhibitor], such as sunitinib—I still have patients on sunitinib—and they have mild disease progression, and I see that I have already noticed the disease to have progressed over the last 2 or 3 scans, and the patient wants to continue to be on an oral pill, then VEGF-TKI still has a part to play. I will start the patient on cabozantinib in the second-line setting. It’s so nuanced in real-life compared with clinical trials.

Daniel J. George, MD: It is, and those are good, illustrative examples of how you choose 1 strategy or another. Monty, any thoughts on those? Any other examples where a certain type of disease progression leads to a certain type of management, call it second line or just a modification of frontline?

Sumanta K. Pal, MD: No, Neeraj summarized it beautifully. I have very little to add to that. I struggle if, for instance, there is CNS progression. Those are certainly challenging episodes. Oligo-progression is another. It was alluded to earlier. I try to incorporate radiation therapy or surgery where relevant. I think he gave a great all-encompassing answer.

Daniel J. George, MD: What about this other scenario, where it’s not disease progression, but it may be chronic intolerance. We talked about the patients who have these severe, immune-related AEs. But what about good old-fashioned chronic fatigue or weight loss, whether it’s the drug or the diarrhea or what have you: patients dwindling down. Maybe we lower the dose of drug down as they get a bit weaker. Then there may be some slight progression, as Neeraj said. They’re just getting a bit worse, but it’s not anything dramatic. How do you manage that? In those scenarios, do you consider that it’s then time for a treatment break? Is it a second-line treatment? Do you switch class of therapy? How do you manage those patients, Rana? What do you think about in terms of your toxicity management around time for a treatment change? There is not necessarily clear progression, but it’s more toxicity driven.

Rana R. McKay, MD: I try to maintain a strategy where I can keep the patient on the therapy as long as possible. If that means a lower dose or maybe a lower dose with a modified dosing schedule within the week, if it helps them stay on therapy longer, then that’s the strategy to maintain as opposed to that persistent grade 2 toxicity. You’re right: It can be pretty life altering for patients. Especially with the TKI regimens, it may be that every 2 to 3 weeks, you get a weekend off. You get 2 days off, and that’s enough to just reset the clock. Patients will know. especially those who have been on the TKI for a long time, or if somebody may be having progression but was dose-reduced already. It’s not a lot of progression, but they dose-reduced for toxicity, and you’re not going to challenge them back to the next dose level; maybe you’ll do alternating days. I know that’s not necessarily in the guidelines, but that’s the clinical application. For example, with cabozantinib, you may have had somebody you dose reduced down to 20 mg because of toxicity. They’re doing great on the 20 mg, but maybe they’ve got a little progression. It’s not enough to say that you want to switch gears altogether. I’m not going to take you back up to the 40 mg. But 3 days a week, we do 40 mg, and the remaining days we do 20 mg. We’ll get creative because what I want to do is this: I want to milk every ounce of goodness out of that therapy that you’re on because it’s not as if we have an infinite number of options at our disposal. I try to maximize while also being cognizant to not lose a window of opportunity where you may not be able to get them on the line.

Sites of disease also matter. I’ve had patients with pancreatic metastasis who chug along, and they’re changing over time, but there is no other disease elsewhere. We know that pancreatic metastasis behaves different from other metastatic sites. Maybe they’re having some lung progression, and those patients are biologically different, so being creative to limit toxicity and maintain efficacy is key.

Daniel J. George, MD: Those are great points. I take the same philosophy. Similar to what Neeraj said, I try to keep that frontline therapy going as long as possible even through those slow-progressing signs and things. As you said, Rana, to me the reason is this: Every time we make a treatment change, there’s a risk. There’s a risk when we’re taking a break from therapy to make that treatment change. There could be a flare, there could be trouble getting on that next regimen, and there could be insurance issues or other issues. There could be a tolerance issue with the second regimen that’s worse than the first, yet it’s tempting.

I know you said we don’t have that many treatment options, but last time I looked there were 11 drugs for renal cell carcinoma. I’m going to talk about this next: I’ve seen people who have gone through multiple lines of therapy: 5, 6, 7 lines of therapy. To me, the goal is not to use every drug in the book. That’s different from prostate cancer, where I’d like to use every drug in the book. In kidney cancer, I like to maximize each treatment line as long as I can without being pigheaded or stubborn about it. I use these creative techniques because when we either modify the dose or interrupt the dose—I like interruption more than modifications, by the way. But when we interrupt doses like that to make the drug more tolerable for patients, we’re not necessarily compromising the biologic effect. When we start at a lower dose and plan to start a drug at half its dose, we may be undermining the effectiveness of that drug. When we start at the full or near the full dose and then we modified it based on tolerance, then I feel like, because that’s a drug-driven adverse effect, then we’re still getting an adequate dose in patients. No, I don’t check pharmacokinetics on every patient, but that’s my poor-man’s pharmacokinetic: Is it a drug-related adverse effect, and if it is, I don’t mind making modifications around it. I like both of those strategies. Monty gets a pass because he agrees as well. We’re all saying the same thing on this.

Transcript Edited for Clarity