Chung-Han Lee, MD, PhD

In this patient, the selection of lenvatinib plus everolimus was selected as second-line therapy after progression on a single-agent checkpoint inhibitor. In this patient, they had an outstanding response to TKI [tyrosine kinase inhibitor] therapy, suggesting that there’s a strong VEGF component to their disease. And in these types of patients, we may consider whether they are so antiangiogenic responsive that we would want to use a regimen that would contain some sort of anti-VEGF activity.

The combination of lenvatinib plus everolimus targets 2 different pathways: the antiangiogenic pathways with lenvatinib with targeting VEGFR 1 through 3 and FGFR 1 through 4, in combination with everolimus, which is an mTOR inhibitor. This is probably one of the first combinations that we used in kidney cancer that was quite tolerable, especially hitting 2 different pathways.

This was originally FDA approved based off a randomized phase 2 study comparing the combination of lenvatinib plus everolimus versus lenvatinib alone versus everolimus as monotherapy. They demonstrated improved progression-free survival and overall survival. In this patient who had a very strong and prolonged response to VEGF-targeted therapy, it does make sense to use something that continues to address the VEGF signaling pathway, and lenvatinib plus everolimus would be a very reasonable combination in this sort of setting.

When you think about toxicities related to combination therapy, generally speaking, you’ll end up getting toxicities that are related to both medications: toxicities related to VEGF-targeted therapy and toxicities related to the mTOR-targeted therapy. Different from what we often see with the everolimus toxicity is, everolimus, the FDA-approved dose as monotherapy being 10 mg, in this combination is given at 5 mg. The potential toxicities related to everolimus include stomatitis, peripheral edema, and a small risk related to pneumonitis. Things that we often do want to watch out for are increases in the blood glucose levels and also the lipid profile. Those are things that certainly do need to be managed. In this patient, she had underlying diabetes, although it was very mild and controlled without medications. Those are things that we want to watch out for during that everolimus type combination.

The tolerability of lenvatinib is quite similar to other VEGF-targeted therapies, with toxicities that are very much related to that class of medications: potential issues with bleeding, potential issues with wound healing, rises in blood pressure, and some diarrhea that may be related to it. Most of these toxicities are dose-dependent, and there’s a lot of room to go down on the medications. The way I usually describe it to patients is I ask them, “Could you imagine living like this for the next year?” Not because a year is how long we know the medication will work, but it gives you a sense of how tolerable is this? Sometimes patients do have this tendency to want to try to power through, but we actually, with dose reduction of lenvatinib, often see that it can be effective even at relatively low doses. It really is more dependent on the patient and their tumor. I think there is that caution we provide to patients about trying not to suffer unnecessarily.

In recent years, we’ve seen a lot of progress made in the treatment of metastatic kidney cancers with the approval of multiple agents and different treatment modalities, including the incorporation of various immunotherapies for the management of disease. Even though we’ve made significant progress, RCC [renal cell carcinoma] remains a disease that is often not curable by systemic therapy. At least as of 2020, VEGF-targeted therapy remains the backbone of metastatic kidney cancer treatment. There are multiple directions that we need to go on this. One is the development of biomarkers for better risk stratification of patients, incorporation of genomics to better understand what is the optimal treatment for patients, and also the opening of various treatment modalities, targeting different pathways to further improve the outcomes of patients and getting us closer to curing the patients that we care for.

I think that right now we definitely live in a very exciting time in the treatment of RCC. We’re seeing rapid change within the field, we’re seeing new regimens come out targeting different pathways, and we’re seeing the guidelines change on a month-by-month basis. And this is all to the benefit of all the patients that we care for and treat. I hope that we continue to see this type of progress in the field.

A 69-year-old woman presents with a 2-month history of fatigue, lower back pain and unintentional weight loss

PE: flank and lower back discomfort on palpation

Chest/abdominal/pelvic CT showed a right-sided 7.9 cm renal mass; paraaortic lymph node involvement

Percutaneous biopsy confirmed clear cell renal cell carcinoma

The patient underwent right total nephrectomy; surgery was well-tolerated

Follow-up at 3, 9, 12 months were unremarkable

At 24 months the patient developed disease with multifocal disease in her lungs; Stage IV

ECOG 0; good risk disease by IMDC and MSKCC risk

She started treatment on pazopanib; well-tolerated, achieved PR

2 year later the patient suffered progression of disease; with increasing lung nodules, largest (30 mm)

Lenvatinib 18 mg PO QD + everolimus 5 mg PO QD was initiated

Imaging at week 8 showed a 33% reduction from baseline of the largest lung lesion (20 mm);

At week 24 of treatment showed 40% reduction from baseline of largest lung lesion (18 mm); decrease in size of other pulmonary lesions noted

At 6 months she continued to have stable disease

At 12 months of treatment CT showed 2 new liver nodules

Videos

Second-Line Treatment: TKI Combination Therapy

There are triggers we would usually have in terms of frontline therapies and changing the frontline therapies. We continue these medications on an ongoing basis so long as the patients are deriving clinical benefit, defined by a lack of progression, no new lesions, no growth of the existing lesions, or very slow growth of new lesions, and also a question of tolerability. We want to have that all to be true, whereas if we notice that the disease was growing in some sort of way or patients were having difficulty from a tolerability standpoint, then that certainly would trigger us to think about switching treatments.

Right now in terms of what we would do as second-line treatment, a lot is based on what treatments they’ve had in the past and how they did on the treatments. In this patient in particular, they were started on a single-agent TKI [tyrosine kinase inhibitor] because they had favorable-risk disease, and from a time standpoint, combining immunotherapy [I-O] was not necessarily an option. However, they had an outstanding response to a single-agent TKI. Typically speaking, a long-term responder to a single-agent TKI is about 18 months, and the patient certainly exceeded that, and went on for more than double what the median progression-free survival was on a single-agent TKI, suggesting that there’s probably a strong VEGF component to their disease. We take that into consideration in whether or not to stick with additional VEGF-targeted therapy or think about switching to some sort of I-O-containing regimen.

In thinking about second-line therapy, the options for this patient after having been on a single-agent TKI include a single-agent checkpoint inhibitor, such as nivolumab, could consider cabozantinib as monotherapy, could consider lenvatinib plus everolimus as a combination therapy targeting both the mTOR and VEGF signaling pathways, or even other second-line TKI therapies.

Second-Line Therapy Decision Factors

For the initial management of patients with localized renal cell carcinoma, the standard of care at this time remains surgical therapy, if possible. There has been a lot of investigation with regard to whether doing neoadjuvant therapy or even adjuvant therapy can be beneficial.

There is the option of using adjuvant sunitinib for the treatment after surgery for patients who are at risk high risk of recurrence. This is a medication that is FDA approved, and there’s a pretty extensive discussion with the medical oncologist with regard to the risk and benefits of using such an approach. Even though this is an FDA-approved regimen, it also has to be understood in the context of the other trials with other agents that are studied in that setting. This is often a very deep and intense conversation and has to be individualized.

In patients who ultimately develop metastatic disease, one of the things that has become standard of care is clinical risk stratification. Dividing patients into people who are favorable risk or intermediate or poor risk. This has guided the various treatment regimens. A lot of the risk stratification did come from the initial clinical trial of CheckMate 214, in which patients who had intermediate- and poor-risk disease did better on the combination of ipilimumab plus nivolumab compared to sunitinib. From a progression-free survival standpoint in subgroup analyses, the reverse seemed to be true. The initial FDA approval for the IPI/NIVO [ipilimumab plus nivolumab] combination was in intermediate- and poor-risk disease.

As per NCCN [National Comprehensive Cancer Network] guidelines, there’s a multitude of potential things that we can do in the first-line setting. Part of it is dependent on risk stratification and patient preferences. The combination of IPI/NIVO is of course approved in patients who have intermediate- or poor-risk disease. The combination with various TKI [tyrosine kinase inhibitor] and I-O immunotherapy agents are also FDA approved across all risk categories, and in certain groups, single-agent TKIs may also make sense for them.

Initial Management of Advanced RCC

In thinking about the patient’s prognosis at diagnosis; she presented with stage III disease. Most people with stage III disease probably have about a 50% chance of developing metastatic disease. What that means is 50% of patients are likely cured by a surgical resection alone. Unfortunately, for people who develop metastatic disease, the treatments we have today are mostly thought of as slowing the disease. Certainly we do risk stratification, that gives us a better idea of what their prognosis is. With some of the newer therapies, we are seeing an extension of that. A lot of that is changed by how they respond to the various agents.

There are multiple risk stratification schemes for the treatment of metastatic kidney cancer. The 2 most commonly used risk stratification systems are IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] and MSKCC [Memorial Sloan Kettering Cancer Center] risk scores. There are a lot of common features between those, as both were developed in the TKI [tyrosine kinase inhibitor]-targeted therapy or the interferon eras. They include things like performance status, hemoglobin, calcium, LDH [lactate dehydrogenase], and neutrophil count. The risk stratifications are slightly different between the two, but there’s significant overlap in how the patients end up being classified.

Some of the considerations that we have in terms of management and treatment are thinking about a lot of the different risk factors patients may have. In terms of age and fitness and underlying comorbidities, this is kind of the baseline status for the patient, and it gives you a sense of what treatments they may or may not tolerate. It also gives you a sense of what types of treatments may be associated with increased adverse effects related to that therapy. We also do risk stratification, which gives us an idea about the overall prognosis of the patient. These risk stratification schemes were developed even in times in which patients do not necessarily have very many effective therapies, so it gives you an idea of what the pace of disease may end up being. This has been further validated even in the era of having active systemic therapies. So that overall risk stratification has been very useful from a prognostic standpoint.

Now that we talk about first-line therapy, risk stratification has become more useful in that certain treatment types are a little bit different depending on clinical risk stratification. Not actually incorporated into risk stratification though are things like disease burden and the number of sites of metastases. These give you an idea of what type of response you may end up needing. For people who have high disease burden and multiple sites of metastatic disease, even if they don’t necessarily fall within the poor-risk stratification groups, it does make you a little bit more worried about them, and it changes the way you think about what systemic therapies you would necessarily try.

The other thing that we often take into consideration is the use of an I-O agent, or immunotherapy agent, versus a targeted therapy or thinking about combinations. Generally speaking, immunotherapies are well tolerated. However, the toxicity profile tends to be a little bit less predictable and less dose dependent. When you think about a TKI therapy, more patients end up having some sort of toxicity related to the medication. However, there is probably a dose dependence on that type of treatment. We notice improvements in the toxicities with just withdrawal of the medication or lowering of the dose.

There is some consideration that we also make with regard to using an oral versus an IV [intravenous] agent, and some of that is more of a logistical thing and patient preference. Often we have to inform the patient that because it’s oral doesn’t mean it’s easier to tolerate, or if it’s IV, it doesn’t mean that it works better. They’re completely different, and this is based off of the way the drugs were formulated.

Chung-Han Lee, MD, PhD | Authors

Articles

Second-Line Treatment: TKI Combination Therapy

Second-Line Therapy Decision Factors

Initial Management of Advanced RCC

Advanced RCC: Prognosis and Therapy Selection