Combination IO TKI Therapy in Patients With Metastatic Renal Cell Carcinoma


Focused discussion on combination IO-TKI therapy and its role as first-line therapy in patients diagnosed with metastatic renal cell carcinoma.


Hans Hammers, MD, PhD:Lenvatinib-pembrolizumab [Lenvima/Keytruda] is the latest hit on the blood when it comes to PD-1 TKI [programmed cell death protein 1 tyrosine kinase inhibitor] combinations. There are now 3 of those [that are] FDA [Food and Drug Administration] approved and commonly used [combinations]. One of them is axitinib [Inlyta] and pembrolizumab—that was the first combination of a PD-1 and a TKI.

What stands out for those regimens is the increased response rate. If you look at intermediate-risk patients, intermediate-poor risk patients, response rates for nivolumab-ipilimumab [Opdivo/Yervoy] is [approximately] 42%. If you look at good-risk patients, it’s [approximately] 30%. If you mix those 2 together, it’s [approximately] 40%. If you add a TKI, essentially, you get another 20% response rate. If response rate is everything, then a PD-1 TKI is hard to beat. We still have to see the long-term benefits. Is there a tail formation that we like to see on the progression-free survival curve with CheckMate 214 [NCT02231749]? Some of the regimens have a little longer to wait before we get the additional data sets, but clearly, some of those are very effective regimens. Response rates for axitinib-pembrolizumab is [approximately] 60%—similar for cabozantinib-nivolumab [Cometriq]. The lenvatinib-pembrolizumab is a little unique, [as] this regimen really doubled down on the VEGF [vascular endothelial growth factor] inhibitory pathway. Lenvatinib is a little unique [because] it doesn’t cause liver toxicity. They did need to be careful with the dose of the TKI. We do see some synergy there [regarding] liver toxicity with some TKIs and PD-1 inhibitors. They really doubled down on the pathway. The starting dose is 20 mg, which is really high. On the upper end of a VEGF inhibitor, the response rate with this regimen is [approximately] 70%, with a 16% CR [complete response] rate. That doesn’t mean we cure those patients, but clearly we are shrinking the disease very effectively. And the chance for progressive disease as best response, meaning patients progress on the first scan, is only 5%, [which is] similar to the cabozantinib-nivolumab regimen. The disease progression’s best response [is] only 5%. Of the 3, cabozantinib is probably the more liver-toxic agent, so the starting dose actually is not 16 mg, it’s 40 mg. This is probably one of the reasons why it might be a better tolerated [agent] with less need for antihypertensive management, for example. Axitinib-pembrolizumab is a good starting regimen. The disease progression’s best response is [approximately] 11%, so not as potent as if you have a combination with one of the clastic salvage TKIs, if you will.

One of the things I do in clinical practice before I start someone on lenvatinib is really pay attention to the blood pressure and make sure the blood pressure is well controlled. That’s the earliest [adverse] effect, and often it’s a very significant increase. So here, we often work with cardiologists who focus on patients [with cancer] to get the blood pressure under control, especially if a patient is already on 1 or 2 blood pressure medications. Or we get their primary care physician involved, or we deploy our own regimen, but it’s really important. So I tend to already optimize the blood pressure, because otherwise, within 5 days, the patient’s going to call you with very high blood pressures.

Other [common adverse] effects are certainly fatigue and diarrhea. Hand-foot syndrome is less common on this regimen but certainly can happen and can be managed with emollients, urea-based creams, and topical steroids, for example. Diarrhea can be managed with [loperamide (Imodium)]. If needed, we can escalate to something like [Lomotil/atropine (Lomotil)], for example, opium tincture, etc. For those [patients], it’s really more like trying to find the right dose and schedule.

In my own practice, I try to stay at the higher dose and work more with dose interruptions rather than aggressive dose reductions. There [are] some data to support that, from the student experience. I tend to work more with regular dose interruptions if necessary and try to give the patient the higher dose. Dose reduction would go down to 14 mg. However, you may have an individual where you are worried about [adverse] effects and the decreased performance status, so you don’t want to hit the patient too hard up front. You may start with a lower dose, then escalate. But in my practice, I frequently use the dual immune checkpoints because of the long-term outcome that we now have available. If I go to the PD-1 TKI combinations, I tend to go with a potent regimen because, for me, the response rate is everything, and then I tend to be aggressive with the dose and administering that. However, other colleagues are living more on the side of PD-1 TKI combinations. For example, they may choose axitinib-pembrolizumab for the average patient, then go to something more aggressive if they’re really worried about disease progression or response.

There [are] also some quality-of-life data with the lenvatinib-pembrolizumab that was presented—really no surprise here. The quality of life is at least not worse than sunitinib [Sutent] when you combine lenvatinib with pembrolizumab. And clearly, the time to definitive deterioration, which is also reflected or has a component of disease progression, is certainly much longer than when on the sunitinib.

Vitaly Margulis, MD: Dr Hammers, maybe you can enlighten us. In this specific case, why did you choose the IO [immuno-oncology]-TKI combination vs IO-IO?

Hans Hammers, MD, PhD:IO-IO would have been a choice. In fact, I proposed it to him, but [the patient] loved the idea of a 70% response rate and just get it under control. And the truth is I don’t have long-term follow-up data for lenvatinib-pembrolizumab. So if I talk to a patient [who] has good-risk disease, [the] response rate that I can quote [them] officially is 29% for nivolumab-ipilimumab. That sounds very different than a 70% and 16% CR rate. It’s a difficult sell. It takes more time to try to explain to patients why it might be a bad idea to consider that still, even with good-risk disease. But I would say the classic recommendations for good-risk disease is a PD-1-TKI combination. Although, again, I use nivolumab and ipilimumab frequently in this space. So in this case, that’s what [they] chose and that’s what we gave [them]. I offer my patients choices; I typically give them 2 things to choose from, then they pick 1.

Transcript edited for clarity.

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