Practical Considerations Regarding the Use of Combination Regimens for the Treatment of Advanced Renal Cell Carcinoma

Targeted OncologyTM: Could you review the available first-line combination treatment options for patients with advanced renal cell carcinoma (RCC)?

Chung-Han Lee, MD, PhD: Currently, there are 2 main treatment strategies that are available for patients with clear cell kidney cancer, both of which build upon a PD-1 backbone. These combinations either incorporate anti-CTLA4 therapy or an anti-TKI [tyrosine kinase inhibitor] hitting the VEGF signaling pathway. Both are currently FDA-approved as appropriate first-line therapies for the treatment of metastatic RCC.

To what extent do guideline recommendations factor into your decision-making for frontline therapy in patients with advanced RCC?

Dr Lee: The current risk stratification scheme for RCC subdivides patients into favorable-, intermediate-, and poor-risk disease, with various treatment stratification schemes. These include the Memorial Sloan Kettering Cancer Center (MSKCC) risk stratification system and also the [International Metastatic RCC Database Consortium] risk stratification system. There are some particulars [regarding] whether patients [with intermittent poor-risk disease] are designated specific treatments, but there are also treatment strategies that are available for people across all risk categories.
Currently, based [on] the NCCN [National Comprehensive Cancer Network]–preferred recommendations, there are various TKI/IO [immunotherapy] approaches that are appropriate for people across all risk stratification schemes. There, we see multiple combinations of TKIs paired with an anti-PD-1–based therapy as appropriate therapies. These regimens include the combinations lenvatinib plus pembrolizumab, axitinib plus pembrolizumab, and also cabozantinib plus nivolumab. All 3 of these regimens have been designated as preferred regimens across all risk groups based [on] improvements and objective response rate, progression-free survival, and overall survival in comparison to sunitinib monotherapy.

What are some common adverse events (AEs) observed with the different IO/TKI combinations?

Dr Lee: Whenever you talk about various AEs, they [all] often relate to mechanism of action in class-based toxicities. For example, when we talk about IO-based therapy, we always discuss the possibility of immune-related toxicities. These [are] potentially unpredictable, potentially severe, and may require the addition of steroids. Usually, when I talk to patients about potential toxicities, [they include] diarrhea, potential of pneumonitis, neuropathy, autoimmune hepatitis, or even cardiomyopathies that may result [from IO-based treatment]. We make patients very aware of these potential toxicities due to the severity in which [they] may occur and the unpredictability so that they can adequately communicate these potential toxicities. [It also helps] us make a decision about whether to start them on steroids in a timely manner.
Now, in terms of the different TKI partners, there are class-specific toxicities that relate to the TKIs, and there are also individual toxicities that can be seen. From a class-related effect, most of the TKIs will have evidence of increases in blood pressure. This needs to be closely monitored. With that increase in blood pressure, there is an increased risk of cardiotoxicity, including heart failure and stroke. This tends to be well-managed so long as the pressures are well-controlled.
The other thing that we often want people to be aware of is the potential wound healing issues. For example, we very rarely see spontaneous bleeding. However, in any sort of injury, any type of elective procedure, we often do ask people to hold the [TKI] after complete wound healing before resuming the medications.
We also see incidences of GI [gastrointestinal] distress. There are some subtleties with regard to some of the medications and the frequency in which [patients] get this GI distress. Most common out of this is probably diarrhea, [which is] an ongoing type of issue. For example, it’s a little bit more common to develop diarrhea related to the axitinib in comparison to drugs like lenvatinib.
Similarly, we [can] talk about the risk of hepatotoxicity, which is an overlapping toxicity that can happen not only with the PD-1 checkpoint inhibitor, but [also] with TKIs. [In] comparison [with] the cabozantinib-plus-nivolumab combination, the risk of liver function abnormalities is higher compared [with] things like lenvatinib, perhaps due to some of the long half-lives associated with cabozantinib. Trying to tease out attributions of whether that’s a cabozantinib effect versus a nivolumab effect becomes a bit more challenging.
Other than that, there are quite a few similarities, mainly thinking about these drug class toxicities. But the benefit of TKI toxicities is the ability to dose-reduce, and many of these TKI-related AEs do improve with dose reduction.

What has been your real-world experience regarding the tolerability of the lenvatinib-plus-pembrolizumab combination versus other IO/TKI regimens?

Dr Lee: We’ve seen fairly good concordance between the real-world experience with combinations like lenvatinib plus pembrolizumab with what was reported within clinical trials. When we talk from an efficacy perspective, one of the things that we do is hold fairly strongly to the dose—starting at full dose, and then [following] the dose-modification scheme that was reported within the clinical trial. As a result, we’ve seen fairly comparable results in efficacy. In terms of the tolerability, in the clinical trials, this [was] the percentage and frequency of grade 3 and grade 4 toxicities based upon accumulation of points, or an indication of toxicity.
What we have seen with the lenvatinib-pembro[lizumab] combination is that a lot of patients ultimately do require some degree of dose reduction. That is demonstrated when you look at the percentage and frequency of dose reduction that was necessary in the protocol. Now, what is not well-captured within the clinical trial data is the quality of life (QOL) and the experience of the patients in terms of toxicities post–dose reduction. It’s often the case that after the doses have been reduced, the tolerability of the medications significantly improve. The real-world patient experience, and [what] most of my patients have described, [is] a fairly good tolerability of the medications after the [dose of the] drug has been reduced to the [same level as that of the maintenance dose].
A question that often comes up in this sort of setting is, if we know that there’s going to be a dose reduction that’s necessary, why don’t we just go ahead and start on the lower dose? There [are] data demonstrating that, not necessarily with the lenvatinib-pembro[lizumab] combination, but with the lenvatinib-everolimus, if you take that sort of approach where you start at a lower dose and see whether or not you can dose escalate in the absence of toxicity, the overall efficacy of the regimen is actually compromised. As a result, to try to maintain the efficacy and balance that with tolerability, the general approach that I’ve taken is to start at a higher dose or start at the full dose of the medication and prepare the patients in advance that a dose modification is likely necessary so they know that in the back of their mind. Assess them carefully, make sure whether we would want to potentially dose reduce at a later time point, and, if necessary, reduce the dose.

How do dose reductions impact the efficacy of the IO/TKI regimens?

Dr Lee: We’ve always thought there’s probably a theoretical threshold for all these medications, that beyond a certain  point we’re not hitting the receptors, the various tyrosine kinases, to the same degree of effect. Some of these worries come from the provider and from the patient—that reducing the dose will limit the efficacy. However, it’s important to remember that when we talk about the clinical trial data and the efficacy results that we’re seeing, these were with mandated dose reductions. There was very little flexibility that was provided within the protocol that allowed for dose escalation. Both the patients and the providers should remember that the efficacy results that were seen within the clinical trial were based off this kind of mechanism and metric used for dose reduction. If we start treading beyond the threshold really necessary to hit the receptors, we’re getting much more in terms of off-target types of effects that could actually increase the amount of off-target AEs that the patients might experience.

Are there any instances or situations in which you would not adjust the dose?

Dr Lee: We do still want to maintain dose intensity. What we want to do is maximize not only the dose but also the supportive medications that are given. If we can resolve the toxicities based off adjustments on the supportive medications, then that’s really the optimal way to do it. For example, they’re probably rare—a class-based effect for all the TKIs is the hypertension that can result. Hypertension is an AE and toxicity; there are multiple drugs that can be used to help control people’s blood pressure. Therefore, it’s been my practice that I do my best, certainly not to dose-reduce the TKI regardless of what that TKI is for toxicity, such as hypertension, without fully maximizing the antihypertensives that the patients are on. This is to avoid having to dose-reduce for an unnecessary reason. We do know that if we dose-reduce for hypertension, the hypertension will improve. In this type of instance, it is probably more important to get [the] dose in as opposed to [avoiding the addition of] medications to treat the blood pressure.

What factors influence how you reduce the dose?

Dr Lee: I consider [when] the appropriate time for dose reduction is, when I feel that there’s nothing else that can be done to maintain patient QOL without reducing the dose. This is where the decision comes in to see to what degree I have maximized the supportive medication. If I’ve fully maximized the supportive medication, then a dose reduction is mandatory, because we’re not trying to make patients miserable.
In terms of thinking about to what degree do we dose reduce, a lot of that also comes from the severity of the toxicity. In the schema that I described before, sometimes we think about dropping just 1 dose level down. Sometimes, we may think about dropping more than 1 dose level down, because the potential toxicity that we saw or the toxicity that we did see was severe enough that I’m worried the patient will still feel rather unwell [just going 1 dose level down]. In those sorts of scenarios in which we will drop more than 1 dose level down, then I do consider dose escalation.

Are your patients concerned about the AEs they may experience with the IO/TKI combination? Are they concerned about any dose reductions or potential loss of efficacy when they reduce the dose?

Dr Lee: From the patients’ perspective, they often are very concerned about the idea of dose-reducing, and that’s a very natural response to the idea of lowering the dose. There is a very easy, coincidental relationship that can be seen—[when] they reduce the dose, then the scans don’t look good. The first question that comes to mind is, was it because I just didn’t get enough drug in, and this is why we didn’t get the result that we were necessarily hoping for? That it is important from a patient education end, to discuss the potential of dose reduction and have them understand why dose reduction is necessary. The way I often describe it to patients is, thinking [from] a QOL standpoint, could they imagine living like this for a year? Not because I know whether or not or how long these medications may necessarily be effective, but a year is an arbitrarily long enough amount of time that most people don’t tough through AEs if they know it has to be for a reasonably expected period of time. My feeling is that if you can’t live with the degree of AEs for a year’s worth of time, we really do have to consider going down on the dose, because we want to try to maintain QOL from it.
For all the TKIs, if you look at the absolute numbers—grade III, grade IV toxicity—and you look at the absolute numbers of people who have dose reduction, there is a lot of concern with regard to how these medications will be tolerated. Part of the discussion [is] understanding that these are class-related effects. Sometimes, if you talk to patients having experienced multiple different TKIs, they often have a difficult time or have contradictory views about which TKI they thought was the toughest.

What typically happens in the community setting when a patient experiences an AE, and what recommendations do you have regarding the management of those AEs?

Dr Lee: One of the things I’ve noticed is certainly when I see people with that kind of opinion, there are kind of 2 camps. There are people looking at the fact that most people require dose reduction and are already starting at a lower dose. And then there is the other side, which probably maintains the full initial dose for beyond what is actually tolerable. That’s part of getting experience with the regimen that will improve upon learning how to best titrate the TKI dosing… There [are] clinical data that demonstrate that using the full dose, or at least initially starting at the full dose, is more effective than taking a dose-reduced option.
There are preclinical data based off which of the tyrosine kinases are being inhibited at the various doses and the [pharmacokinetic-pharmacodynamic] data that say that this type of approach is probably going to be more effective. We know that so many people will require dose reduction. For people who are a little bit reluctant to start at full dose, it’s really talking to the patient and letting them know that this is an expected part of the experience of the medication, and adequate communication will allow us to appropriately go down on the dose. Similarly, for providers [who] lean a bit more toward just hanging on to the full dose and worry that going down on the dose is going to compromise efficacy, it’s important to remember that, from a clinical trial design standpoint, if you had severe toxicity, you were mandated to go down on the dose.
The efficacy results that we see from the CLEAR study are based off those mandated dose reductions. Some of the QOL data demonstrated that you can actually maintain QOL with those mandated dose reductions and see the efficacy results from the clinical trial. The advice I’d give for the community oncologist for managing AEs is management of kidney cancer and management of toxicities. Being able to incorporate and partner with the patient’s primary care providers is very critical for maintaining the efficacy of these medications and making sure that they’re also aware of these potential toxicities. It’s not only that the oncologist has expertise, but [also that they have] a support network of other physicians [who] have experience with some of the AE management.

When reviewing the subgroup analysis of the CLEAR study that assessed the QOL outcomes, how do you compare the outcomes from QOL analysis among the IO/TKI regimens?

Dr Lee: There have been multiple subgroup analyses that have been done comparing QOL between the various regimens based off the [results] of the CLEAR study. What they were able to demonstrate was that across multiple measures of patient-reported QOL, the QOL on the combination of lenvatinib plus pembrolizumab was either similar or better than what was experienced with patients on sunitinib. What that really demonstrated was that, based off the mandated dose modification scheme, we were able to provide the same QOL using a doublet therapy in which the toxicities of 2 different medications in combination with each other were fairly similar to [those of] just a single TKI. That speaks a lot to the overall tolerability of the medication and, probably, also the importance of adjusting the dose based [on] these metrics.
The other QOL metrics between the different IO/TKI combinations show fairly similar results. If you look at the data for axitinib plus pembrolizumab, again they show fairly comparable levels of QOL between the combination of axitinib and pembrolizumab versus sunitinib. The 1 study that did show improved QOL was [the one involving] the combination of cabozantinib plus nivolumab. A key difference between some of these studies is that in the cabozantinib study, cabozantinib was used at a slightly lower dose, so they were actually starting with a degree of dose reduction. Cabozantinib was given at 40 mg before moving on to nivolumab. This mandated dose attenuation did affect the overall QOL experienced by the patients. This is probably something that is to be expected. With all the TKIs, we know the toxicities are dose-related, and, with dose reduction, toxicities improve. [This was shown in the results of trials] like the CLEAR study, where the lenvatinib is [given] at 20 mg, which is a relatively high dose. In fact, the combination dose with everolimus is only 18 mg, [which] probably adds to the fact that there are some additional toxicities that come along with it.