Key Takeaways

• Adjuvant therapy with pembrolizumab should be considered for patients with RCC at intermediate/high or high risk of recurrence (pT2, grade 4 or sarcomatoid differentiation; pT3 or pT4, any grade; or any pT with node-positive disease) following nephrectomy or nephrectomy and complete resection of metastatic lesions based on results from the phase III KEYNOTE-564 study
• Current guidelines recommend selecting first-line therapy for advanced RCC based on risk assessment: ICI plus VEGFR TKI for patients with favorable risk and ICI plus VEGFR TKI or ICI plus ICI combinations for patients with intermediate or poor risk; which of the available combination regimens to use depends on patient preference or disease characteristics
• The optimal sequence of therapy for progression after first-line therapy depends on what regimens the patient has already received and then considers what other options remain

In this commentary, Katy E. Beckermann, MD, PhD; Naomi B. Haas, MD; and Eric Jonasch, MD, provide insight on the available treatment regimens in renal cell carcinoma (RCC) across the adjuvant, first-line, and second-line settings. In addition, they discuss management of adverse events (AEs), particularly for patients receiving combination therapy. These key learning points were discussed during a recent live Clinical Care Options satellite symposium held during the American Society of Clinical Oncology annual meeting.

Adjuvant Therapy

Naomi B. Haas, MD:
Historically for patients with earlier stage RCC, the standard of care was resection and then observation; however, there have been 2 FDA approvals for adjuvant therapy for those patients at higher risk for recurrent disease: sunitinib and pembrolizumab. Six trials have assessed VEGFR tyrosine kinase inhibitors (TKIs) as adjuvant therapy in RCC, but only the S-TRAC trial with sunitinib showed an improvement in disease-free survival vs observation, and none showed an overall survival benefit. In addition, the phase III EVERST trial assessed 1 year of adjuvant everolimus vs placebo in patients with pathologically intermediate/high-risk or very high–risk RCC after nephrectomy but did not meet the primary endpoint of recurrence-free survival. 

Currently, adjuvant therapy with pembrolizumab should be considered for patients with RCC at intermediate/high or high risk of recurrence (pT2, grade 4 or sarcomatoid differentiation; pT3 or pT4, any grade; or any pT with node-positive disease) following nephrectomy or nephrectomy and complete resection of metastatic lesions based on results from the phase III KEYNOTE-564 study. This study has shown an improvement in disease-free survival vs placebo as well as a trend towards an improvement in OS in an interim analysis. Median OS is still immature and additional follow-up is planned.

Does the use pembrolizumab as adjuvant treatment of RCC preclude use of immune checkpoint inhibitor (ICI)-based therapy in the metastatic setting?

Naomi B. Haas, MD:
This is a very important question, and the answer depends on where a patient is in their treatment course at the time of disease recurrence. Clearly, patients who experience disease progression while receiving pembrolizumab likely have primary resistance to immunotherapy and should not receive additional ICI-based therapy as their next line of treatment. However, there is more of a gray area for patients who have completed adjuvant pembrolizumab and recur after 6 or 12 months. We can extrapolate from what we know about patients who receive second-line ICI after previously receiving ICI-based therapy first line. Arguably, the biology of a relapsed primary kidney tumor may be slightly different from what you see in metastatic disease, so we still need more data to answer this question definitively.

Katy E. Beckermann, MD, PhD:
I agree, and it does depend on the timing of the recurrence. Although more research is needed to answer this question, I think retreatment with frontline ICI-based combination therapy for RCC is reasonable, particularly if the patient has relapsed more than 1 year after adjuvant therapy, whether you are considering an ICI and VEGFR TKI or ICI plus ICI therapy.

Naomi B. Haas, MD:
Yes, and this can also be patient specific. For example, I had a patient on KEYNOTE-564 who relapsed about 6 months after completing adjuvant treatment. He requested to be unblinded and noted that his cancer started regrowing right when he was done with the course of pembrolizumab and wanted to resume ICI therapy. We restarted therapy with pembrolizumab plus axitinib, and he did respond. That said, I had the same situation with another patient who continued to progress after restarting with an ICI plus VEGFR TKI. Based on the anecdotal cases, it is reasonable to consider ICI-based combination therapy after recurrence, but patients should be monitored carefully for continued progression.

Katy E. Beckermann, MD, PhD:
Of note, patients with preexisting autoimmune disease often are not considered candidates for ICI therapy and have been generally excluded from clinical trials. However, when we looked at clinical data retrospectively, it seems that immunotherapy is relatively safe (with close monitoring) in patients with autoimmune disease, provided they do not require systemic management with steroids. 

Are there any biomarkers to help predict response to immunotherapy in RCC?

Naomi B. Haas, MD:
Currently, no one biomarker helps predict response to ICIs in RCC. However, a recent paper by Motzer and colleagues in Cancer Cell looked at clusters of immunotherapy signatures (molecular subsets) that might predict responsiveness to immunotherapy or VEGF-targeted therapy in the metastatic setting. Results showed 7 molecular subtypes, including those with associations of angiogenic/stromal clusters and clusters of T-effector/proliferative, proliferative, and stromal/proliferative that may help predict which subtypes would respond better to VEGFR TKIs or to ICI-based therapy.

Eric Jonasch, MD:

Another important goal in RCC treatment is to be able to assess measurable residual disease (MRD) in the adjuvant setting, but to date none of the available assays is sensitive enough. Once we can determine MRD status for these patients, questions to address include: Is MRD status predictive of the need for adjuvant therapy, and does the biology of RCC predict for response to ICI-based therapy?

First-line Therapy

Naomi B. Haas, MD:
Accurate risk assessment is crucial to selecting optimal first-line systemic therapies for patients with advanced RCC. Multiple risk criteria are employed today to predict survival, including the Memorial Sloan Kettering Cancer Center criteria and the International Metastatic RCC Database Consortium risk score. The National Comprehensive Cancer Network clinical practice guidelines provide recommended treatment based on the risk assessment: ICI plus VEGFR TKI for patients with favorable risk and ICI plus VEGFR TKI or ICI plus ICI combinations for patients with intermediate or poor risk. These recommendations are based on a series of clinical trials comparing combination regimens with sunitinib, including KEYNOTE 426 with pembrolizumab plus axitinib, CheckMate 9ER with nivolumab plus cabozantinib, CLEAR with lenvatinib plus pembrolizumab, and CheckMate 214 with nivolumab plus ipilimumab. 

How do you decide which of these regimens to select for individual patients with advanced RCC?

Naomi B. Haas, MD:
Which of these 4 regimens to use often can depend on patient preference or disease characteristics; for example, patients who do not want to be on a pill regimen may prefer nivolumab plus ipilimumab, whereas patients whose disease is progressing rapidly may instead benefit from axitinib plus pembrolizumab, cabozantinib plus nivolumab, or lenvatinib plus pembrolizumab.

Katy E. Beckermann, MD, PhD:
I agree. I evaluate patients individually, taking into account their preferences and specific disease characteristics. As Dr Haas mentioned, I consider ipilimumab plus nivolumab for a patient whose pace of disease or disease burden does not require a quick response to try for the prolonged treatment-free interval we have seen with this regimen, even if a patient has favorable-risk disease. That said, this is not FDA indicated for favorable-risk patients, who often receive a combination of ICI plus VEGFR TKI. We also know the biology of favorable-risk RCC can be driven by angiogenic signatures, so considering one of the ICI plus VEGFR TKI regimens is a reasonable approach. 

Eric Jonasch, MD:
Ipilimumab plus nivolumab has a greater chance of complete response vs sunitinib, even in favorable-risk patients; however, there is also a higher rate of primary progressive disease with this regimen (18% vs 11% with axitinib plus pembrolizumab, 6% with cabozantinib plus nivolumab, or 5% with lenvatinib plus pembrolizumab). In my clinic, if I have a fit, younger patient who wants to try the ICI plus ICI regimen, I will do so, but there is a good likelihood they will not achieve a cure and will need additional therapy.

Overall, I think it is reasonable to consider the ICI plus VEGFR TKI regimens for many patients, including those who require a rapid response and those who may not be able to tolerate the potential increase in immune-related AEs (irAEs) associated with ipilimumab plus nivolumab.

Are there any differences in the mechanism of action of VEGFR TKIs or ICIs that can influence the choice of first-line combination regimen for patients with RCC?

Eric Jonasch, MD:
For me, there is not an appreciable difference in the ICIs available for advanced RCC, and I consider pembrolizumab and nivolumab interchangeable in the available first-line regimens. However, there are some differences in axitinib, cabozantinib, and lenvatinib that we can consider for individual patients.

Katy E. Beckermann, MD, PhD:
When choosing between the ICI plus VEGFR TKI combinations for first-line immunotherapy, I extrapolate data from other phase III trials of the VEGFR TKI agents. Cabozantinib is a pan-TKI, which inhibits MET and AXL, among other targets. Lenvatinib is a multikinase inhibitor and targets VEGFR1, VEGFR2, and VEGFR3, as well as FGFR1, 2, 3, and 4, among other targets. These broad TKI options have shown high overall response rates (ORRs) and impressive progression-free survival (PFS) data in the CheckMate 9ER and CLEAR trials. I often recommend the combination of lenvatinib plus pembrolizumab as my preferred first-line regimen based on the CLEAR trial results showing a high ORR and the longest PFS to date, particularly for a patient with aggressive RCC.

Axitinib is a more selective inhibitor but has a very short half-life. For patients who may have difficulty tolerating combination therapy, axitinib plus pembrolizumab can be a good choice. For some AEs, like colitis or hepatitis, holding axitinib can help us quickly determine if these toxicities are related to the VEGF TKI or the ICI component and act accordingly.

Naomi B. Haas, MD:
I agree, but because axitinib targets VEGF receptors, it also can increase blood pressure, so I might not recommend axitinib for a patient with difficult-to-control high blood pressure. In addition, cabozantinib has shown promising efficacy in patients with bone metastases, which may make cabozantinib plus nivolumab a good choice for them.

It also is hard to predict how patients will feel on each of these combination regimens. Feeling bad while receiving one of the ICI plus VEGFR TKI regimens does not necessarily mean patients will feel bad on all of these regimens. I also have switched from one ICI plus VEGFR TKI regimen to another for patients who are not tolerating their initial therapy well.

Do you use single-agent VEGFR TKIs or single agent ICIs as first-line therapy in RCC?

Naomi B. Haas, MD:
Yes, I will consider single-agent treatment for patients who may not be able to tolerate combination therapy. For example, I used single-agent pazopanib to treat an older woman with severe arthritis who let me know that she was not sure if she wanted to be on treatment at all. I have other patients with heart conditions that may preclude treatment with a VEGFR TKI or the ipilimumab plus nivolumab combination, so I recommended single-agent nivolumab to start, with the option to add another agent later if the treatment is well tolerated.

Katy E. Beckermann, MD, PhD:
I try to use an ICI-based first-line combination in most of my patients. However, if tolerating these regimens is a concern, I do sometimes use an ICI alone and add on a VEGFR TKI if they tolerate therapy well. The only area where I consistently use VEGFR TKI monotherapy is in patients who are receiving solid organ transplants; these patients receive VEGF TKIs but not an ICI due to the risk of transplant rejection.

Second-line Therapy and Beyond

Katy E. Beckermann, MD, PhD:
Now that most patients with advanced RCC typically receive first-line treatment with either an ICI plus VEGFR TKI combination or an ICI plus ICI combination, the standard of care for treatment after disease progression is shifting. Currently, patients who progress on dual immunotherapy such as nivolumab plus ipilimumab should receive second-line treatment with VEGFR TKI, with many options available including cabozantinib, everolimus plus lenvatinib, or axitinib. Patients whose disease progresses after combination ICI plus VEGFR TKI therapy might benefit most from single-agent cabozantinib or combination lenvatinib with everolimus. In addition, the phase Ib/II KEYNOTE-146 study of lenvatinib and pembrolizumab included a cohort of patients with metastatic RCC after ≤2 lines of previous therapy, including ICIs in most patients, and showed an ORR of 56% and median PFS of 12 months. The phase III TIVO-3 study also has demonstrated PFS improvement with tivozanib vs sorafenib in patients with advanced RCC after VEGFR TKI therapy, with previous ICIs allowed. 

Numerous novel agents are being investigated as treatment for patients with RCC who failed frontline therapy. These include belzutifan, an HIF-2α inhibitor that produced exciting responses and PFS in a small phase I/II study in patients with clear-cell RCC and ≥1 prior therapy. Several important phase III trials are evaluating novel combinations for advanced RCC in the postimmunotherapy setting, including MK-6482-005 (belzutifan vs everolimus after PD-1/PD-L1 and TKI therapy), CONTACT-3 (atezolizumab plus cabozantinib vs cabozantinib after PD-1/PD-L1 therapy), and TiNivo-2 (tivozanib plus nivolumab vs tivozanib after immunotherapy). 

How should the optimal sequence of therapy be chosen after frontline ICI and/or VEGFR TKI treatment?

Eric Jonasch, MD:
The optimal sequence of therapy typically depends on what regimens the patient has already received and then considers what other options remain. For example, if a patient received cabozantinib plus nivolumab as first-line therapy, lenvatinib plus everolimus or lenvatinib plus pembrolizumab may be the best option as second-line therapy. Subsequently, I would consider a single-agent VEGFR TKI like tivozanib. For a patient who received axitinib plus pembrolizumab as first-line therapy, you could consider second-line therapy with cabozantinib before moving on to the other regimens already mentioned. In addition, it is always ideal to consider clinical trials, if they are available, for any patient with advanced RCC.

Katy E. Beckermann, MD, PhD:
I agree. To add on to that, Dr Haas, do you ever consider continuation of ICIs after progression on first-line therapy?

Naomi B. Haas, MD:
For me, it depends on the situation. If a patient has had a mixed response to frontline therapy, with most of their disease shrinking but a few clones that are progressing, I would consider continuing the current ICI therapy and either treat the oligometastases with radiation therapy and/or switch to a different VEGFR TKI.

It can be more complicated for a patient whose disease is benefitting from therapy, but the patient is not tolerating their treatment well. We generally will try VEGFR TKI dose reductions or dose holds to start, but I may continue the ICI without the VEGFR TKI if necessary. Also, if a patient insists on staying on ICI-based therapy a bit longer, I generally go with their preference, because it is important for patients to feel they have control over their health and some power in controlling their disease.

Managing irAEs

Eric Jonasch, MD:
As is now widely understood, the benefit from ICIs in RCC comes at the cost of a novel spectrum of irAEs that can involve different organs with diverse presentations (biology, time to onset, severity). These agents can cause symptoms such as hypophysitis, uveitis, pneumonitis, cardiotoxicity, hepatitis, pancreatitis, loss of β-cell function leading to diabetes, adrenal insufficiency, chronic toxicity such as arthralgias, cutaneous manifestations, and diarrhea. VEGFR TKIs use in RCC are commonly associated with AEs such as fatigue, hand–foot syndrome, rash, stomatitis/mucositis, and hypertension. In short, this array of potential AEs represents a varying challenge in clinical practice and a steep learning curve for oncologists and others used to managing toxicities of more traditional chemotherapies. 

The goal in managing irAEs is to control the symptoms early and effectively to minimize recurrence. If irAEs are well controlled, the patient may be eligible for rechallenge with ICI therapy depending on the type and grade of the AE. Corticosteroids such as prednisone are commonly used to manage irAEs, with a taper once the AE is controlled to limit duration of steroid therapy and resulting immunosuppression. For steroid-refractory disease, biologic agents can be added to corticosteroid therapy, including abatacept (targets CTLA4), rituximab (targets CD20), infliximab (TNFα blocker), tocilizumab (targets IL-6), and vedolizumab (α4β7 integrin inhibitor). In addition, mycophenolate (a selective inhibitor of T-cells and B-cells) is particularly useful in patients with hepatotoxicity, as it avoids the concerns around infliximab exacerbating hepatic inflammation. 

If a patient with RCC is receiving an ICI and a VEGF TKI and develops an AE, which component of the treatment is the likely culprit?

Eric Jonasch, MD:
It can be difficult to know for some AEs whether the culprit is the ICI or the VEGFR TKI. For a situation where a patient is receiving pembrolizumab and axitinib and develops diarrhea, for example, it is recommended to hold therapy to observe the AE. Because axitinib has a short half-life, if the diarrhea is related to axitinib, the symptoms should abate in 1-2 days; if symptoms continue, it can be attributed to the ICI.

For a patient receiving nivolumab and cabozantinib who experiences an increase in liver function tests (LFTs), you can have a similar approach. You can hold both agents and recheck LFTs in 1 week to see if the AE is resolving. In addition, single-agent cabozantinib can cause increases in LFTs in the high double digits, but for a rapid rise into the low to mid hundreds, it is more likely associated with the ICI. In that case, I would involve a hepatologist and obtain a liver biopsy to rule out other causes, such as viral hepatitis. Patients with very high LFTs (ie, >5x upper limit of normal) should stop the ICI and receive corticosteroid therapy.

Will you rechallenge a patient with RCC with immunotherapy if they have had a severe irAE?

Eric Jonasch, MD:
I do rechallenge patients with immunotherapy following an irAE, but only if it was grade ≤3 and we have been successful at fully controlling it. One caution is that in about one third of such patients, there is a recrudescence of irAEs, highlighting the need for careful monitoring while continuing the ICI.

Naomi Haas, MD:
Other situations where I would consider immunotherapy rechallenge are where the severe irAE was diabetes or hypophysitis, as rechallenge will not change the situation once the patient is stabilized and responding.

Your Thoughts?
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