Targeted Oncology

 The RCC [renal cell carminoma] treatment space has rapidly evolved over the last 5 to 10 years. We have multiple regimens that are FDA approved, broadly falling into 1 of 3 categories of drugs: immune checkpoint inhibitors, multitargeted tyrosine kinase inhibitors, and mTOR inhibitors. Historically, we had always used this as monotherapy but more recently we’ve seen the transition to using combination therapy with improved outcomes. What I do expect to see going forward is that we’ll probably become a lot more adept at using these combinations together.

One thing that remains an active question is, what’s the optimal to sequence these patients? The other question is, how do these drugs interact with one another? Is there is some temporal relationship between the 2 medications or the combinations that should be used? Those are studies that probably do need to be done. The other thing is related to monoclonal agents. Most recently, there was the FDA approval of belzutifan, which is an HIF2 inhibitor for patients with VHL [von Hippel–Lindau]disease. As you all know, clear cell kidney cancer has high rates of mutation and loss of VHL, so belzutifan is another drug that may become very interesting for us to understand whether there’s a role for HIF2-directed therapy.

Historically speaking, kidney cancer is also been a malignancy of altered metabolism. Although telaglenastat, which was recently studied in a large randomized phase 3 trial, did not show improved efficacy when using combination with cabozantinib over cabozantinib alone. That doesn’t necessarily mean that there’s not a wolf we’re looking at, metabolic inhibitors in the future. Whether it’s a drug with telaglenastat in a more selected population or if it’s other metabolic inhibitors, it remains to be seen.

Also, when we think about immunotherapies, there are multiple immune checkpoint inhibitors or immune checkpoints available. Targets such as LAG3 and TIM3 and agonists like LT4 all play a significant role in altering immune responses. As we better understand the biology and the attraction of the medications, that will do a lot more in terms of tailoring the specific treatments to the disease state of the patients.

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Next steps investigating novel-based therapies for newly diagnosed metastatic renal cell carcinoma.

Tailoring Therapy for Patients With mRCC

 Nurses play a crucial role in the management of patients with advanced RCC [renal cell carcinoma]. They help connect patients to certain resources, such as social work, nutrition, and sometimes even psychiatry. What’s important for the community of oncology nurses managing patients with advanced renal cell carcinoma is to do a thorough assessment on patients with these treatment regimens, specifically lenvatinib-pembrolizumab, because we’ve seen that these adverse events can affect a patient’s quality of life significantly. It’s very important to fine-tune assessments so that these adverse events are caught in advance, so treatment regimens may not necessarily need to be interrupted or discontinued but rather may just need some modifications.

Patients often express their concerns to the nurses. There’s some hesitance from patients to open up to their physicians because they may be afraid that their treatment may be held or stopped. Establishing a good rapport with your patients. Let them know that if they experience any adverse events, have questions, or feel that something isn’t right, they should reach out. Enforcing good communication with the clinical oncology team and the nurse, and having those open discussions related to adverse events, is really important.

That being said, oncology nurses are also very important in managing patients who have advanced renal cell carcinoma because they’re managing the disease but also helping patients cope with the disease itself. Have referrals placed to support groups, to other communities and community groups that are available to patients, so that they feel that they’re being managed not just for physical symptoms but also for mental health issues that may come up.

The role of the oncology nurses is multifactorial. We are the front line in managing patients because they come to us first with their questions, concerns, and adverse events. We help guide the next steps in conjunction with the physician. It’s very important to have a good rapport and an open patient relationship and to let them know that we’re here for them. We want them to continue this treatment regimen and, of course, have a good quality of life.

Advice to oncology nurses who manage patients with metastatic renal cell carcinoma receiving novel-based therapies, including lenvatinib and pembrolizumab.

mRCC: Role of Oncology Nurses in Managing I/O–TKI Adverse Events

Since the initial presentation of the CLEAR study at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] 2021, there have been several subgroup analyses to further understand the regimen. At ASCO GU, looking at the quality-of-life data that were absent from the original CLEAR study, the authors noted that the quality of life on lenvatinib plus pembrolizumab was fairly similar to what was seen with sunitinib. This has waged some of the initial concerns about the absence of the data at the initial presentation. It also fills in some of the knowledge gaps and counters some of the reputation that lenvatinib is a relatively difficult regimen, which it gained during the earlier phase 2 study of lenvatinib plus everolimus. It was reassuring for us to see that when people were treated on lenvatinib plus pembrolizumab, the quality of life was quite similar to sunitinib in that phase 3 study.

Furthermore, there was also a separate analysis looking at depth of response and overall survival. What the authors had seen is that the depth of response did correlate with improved overall survival, meaning people who had deeper responses overall did better. For patients who were treated on the CLEAR study on the sunitinib arm, now that we’ve gone further out, it remains a matter of debate on what they would be necessarily receiving next. A lot of that depends on access to drugs. For patients who are on single-agent TKIs [tyrosine kinase inhibitors], there’s broad access to immune checkpoint inhibitors. Immune checkpoint inhibitors, either as monotherapy or combination, would be very appropriate next choices. However, in certain countries, in which immune checkpoint inhibitors are not yet available, a lot of those patients would be receiving secondary TKIs.

An overview of data demonstrated by other investigational studies of lenvatinib plus pembrolizumab as frontline therapy for metastatic renal cell carcinoma.

Subgroup Analyses of the CLEAR Study in mRCC

 The CLEAR study is a positive phase 3 clinical trial for patients with treatment-naïve metastatic kidney cancer. Based on the results of the CLEAR study, the combination of lenvatinib plus pembrolizumab received regulatory approval for this treatment population. When we think about postregulatory approval, then there are guideline recommendations. Lenvatinib plus pembrolizumab is a category 1 preferred agent for patients with either favorable intermediate or poor risk, so essentially all the risk categories for RCC [renal cell carcinoma]. Putting that in the broader context of the NCCN [

] Guidelines, for patients with favorable-risk disease, most of the regimens that have a category 1 designations and for favorable risk in the preferred category are TKI [tyrosine kinase inhibitor]–I/O [immuno-oncology] combinations, including lenvatinib plus pembrolizumab, axitinib plus pembrolizumab, and cabozantinib plus nivolumab. For intermediate and poor-risk patients, regimens that have category 1 preferred designations include the TKI–I/O combinations, including lenvatinib plus pembrolizumab, axitinib plus pembrolizumab, cabozantinib plus nivolumab, but also anti CTLA4plus PD-1 with the combination of ipilimumab plus nivolumab. This forms strong evidence for each approach.

Thinking about how we stratify patients to these approaches, we really have to do some degree of clinical stratification and try to tailor the efficacy we see for each regimen to the patients’ own goals. The data are never as complete as we would want because the trials were designed and the results are what they are. As we get further, we’ll get more information about some of the long-term effects. However, based on the need to treat patients now as opposed to waiting for long term data to be available, the way we often make a treatment decision is going to be based on the available data and prioritizing things like response rates vs known vs unknown durability of response.

In terms of determining specific adverse effects with the TKI–I/O combinations of lenvatinib-pembrolizumab, axitinib-pembrolizumab, and cabozantinib-nivolumab, it can be difficult because the adverse events are nonspecific to each regimen. In general, we expect to see some adverse events with the TKI medications—axitinib, lenvatinib and cabozantinib—and also adverse events related to immunotherapy with pembrolizumab and nivolumab. There really is no comparison to say that certain adverse events will occur with this regimen; the adverse events are quite broad. What I have seen most commonly in our clinical practice is that there are some adverse events that are across the board with these regimens. That includes diarrhea, high blood pressure, fatigue, mouth sores or mucositis, and decreased appetite. To provide a comparison is really hard. These regimens are related to the adverse events of TKIs or the adverse events of immunotherapies, but not specific to 1 regimen.

Implications for treating patients with metastatic renal cell carcinoma with frontline lenvatinib plus pembrolizumab, based on the regimen’s performance in the CLEAR study compared with other options.

Implications of the CLEAR Study in mRCC to Clinical Practice

 The CLEAR study was a randomized phase 3 clinical trial looking at 3 arms. Patients were randomized with lenvatinib plus pembrolizumab, lenvatinib plus everolimus, or sunitinib. This trial was designed to look at and compare the efficacy outcomes of these 3 regimens. The study population included patients with treatment-naïve clear cell kidney cancer that had resisted measurable disease. The key efficacy end point that they looked at was progression-free survival with key secondary end points, including objective response rate and overall survival. This study was a positive clinical trial with the evaluation of over 1000 patients. It demonstrated that the combination of lenvatinib plus pembrolizumab showed improvements in progression-free survival of about 24 months’ median progression-free survival compared with 9 months for sunitinib. And it showed an objective response rate of 71% with a 16% CR [complete response] rate compared with sunitinib. This was found to be statistically significant, along with an improvement in overall survival. For overall survival, the follow-up on this study was short enough that the medians were not reached. But even at the data cutoff, they demonstrated that the combination of lenvatinib plus pembrolizumab had a hazard ratio of 0.61 with a significant 

Safety outcomes from the CLEAR trial do indicate that almost all patients did develop some degree of adverse events. Specifically, with the lenvatinib-pembrolizumab arm, 99.7% of the patients did develop some degree of adverse events. When we talk about a grading system for adverse events, grade 1 to 2 adverse events are considered mild to moderate from the treatment regimen, and grade 3 or more are considered severe. Specifically, with lenvatinib-pembrolizumab, 82.4% of the patients did experience grade 3 or higher adverse events. The most common adverse event identified was diarrhea, and the secondary adverse event was hypertension.

For management of diarrhea, we assess patients and their frequency of bowel movements. It’s important to always get a baseline of how often they do have bowel movements, and then you set it as a comparison. Usually, 3 or more loose, watery stools above your baseline would be considered a grade 2. If it’s more frequent, then it’s grade 3 or higher. But in terms of management, with the lenvatinib-pembrolizumab, we do expect dose modifications with the lenvatinib specifically. In general, we start patients on lenvatinib 20 mg. We reduce the dosing or, if the diarrhea is quite severe, we hold the medication altogether and manage further. Those would be our interventions.

That being said, diarrhea can also occur from pembrolizumab, from the immunotherapy. Patients present with diarrhea, we also always obtain a stool sample to confirm that there’s no active infection going on. We would also prescribe Imodium once they were cleared for any active infection. But our goal is to achieve a dose of medication with the lenvatinib, so they have a good quality of life and are able to not have to use the bathroom and have bowel movements very often.

Another common adverse event that was identified was high blood pressure, or hypertension. This can be challenging when we start patients on this regimen. On lenvatinib-pembrolizumab specifically, we’ve seen that lenvatinib does increase blood pressures. And if patients already have a history of hypertension, we have to be very diligent in managing their blood pressure. One intervention that we start with when patients start this regimen is to have them obtain a blood pressure log and go over how to take their blood pressures every day and how to take them correctly. And then have that identify blood pressure perimeters, when we would ask the patients to call us if their blood pressures were over a certain number or if they were symptomatic. With the adverse events that are identified, we initially do face some challenges to adjust dosing. But once we can manage the adverse events and keep them at a dose that improves their quality of life, we find that does work. It just may take some time to get to that.

Reactions to efficacy and safety data demonstrated by the CLEAR study of lenvatinib plus pembrolizumab as first-line treatment for metastatic renal cell carcinoma.

Design and Key Takeaways of the CLEAR Study in mRCC

 Lenvatinib plus pembrolizumab was a very interesting combination to use together. As you all know, lenvatinib is a multi–tyrosine kinase inhibitor targeting the VEGF signaling pathway. So it inhibits VEGFR receptor 1-3 and also FGF receptor 1-4. Along with some other more minor tyrosine kinases.

This was originally studied in combination with everolimus and is FDA approved for metastatic kidney cancer in patients who have progressed on at least 1 prior VEGF-targeted therapy. Pembrolizumab is a very well-known PD-1 inhibitor that works by inactivating 1 of the key immune checkpoints. Pembrolizumab has been studied in multiple malignancies and demonstrated all levels of clinical efficacy. There are some preclinical data that demonstrated that the combination of VEGF-targeted signaling plus immune checkpoint inhibitor leads to enhanced immune responses. It was hypothesized that the combination of these 2 compounds would lead to at least a positive interaction to see whether this could be translated clinically. This combination was originally studied in RCC [renal cell carcinoma] in HOPE–Study 111, which was the phase 1B/2 study of lenvatinib plus pembrolizumab, originally in multiple diseases and then in a separate analysis. There were subcohorts of diseases, including bladder, endometrial, lung, and kidney. In that study, they showed very high levels of efficacy for the patients. That study was later expanded to study patients who right previously progressing immune checkpoint inhibitors and formed the key data that was used for the design of the CLEAR study.

The rationale for investigating the combinations of lenvatinib plus pembrolizumab and lenvatinib plus everolimus as frontline therapy for metastatic renal cell carcinoma.

Targeted Oncology | Authors

Articles

Tailoring Therapy for Patients With mRCC

mRCC: Role of Oncology Nurses in Managing I/O–TKI Adverse Events

Subgroup Analyses of the CLEAR Study in mRCC

Implications of the CLEAR Study in mRCC to Clinical Practice

Design and Key Takeaways of the CLEAR Study in mRCC

Combining I/O and TKI in Frontline mRCC