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Keeping Pace in RCC
Keeping Pace With Rapid Changes in the Management of RCC

Released: July 19, 2023

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Key Takeaways
  • Adjuvant treatment with pembrolizumab is most appropriate for patients with T2 grade 4 or T3 or higher disease and patients with M1 NED within 1 year of surgery based on results from the KEYNOTE-564 trial.
  • Patients with newly diagnosed advanced clear cell RCC and poor/intermediate-risk disease based on International Metastatic RCC Database Consortium risk factors are good candidates for an IO/IO or IO/TKI combination. An IO/TKI may elicit a faster response if a patient requires that for disease symptoms.
  • Available data indicate that VEGF inhibitors are beneficial in the second-line setting following ICI frontline therapy. Continuation of immune checkpoint inhibition is not beneficial and adds toxicity in the refractory setting.

The treatment of patients with renal cell carcinoma (RCC) has evolved dramatically over the past several years. Historically, the initial treatment for advanced RCC was VEGFR tyrosine kinase inhibitors (TKIs) or mTOR inhibitors. Currently, most patients with advanced clear cell RCC, the most common subtype, receive immunotherapy-based combination therapy for first-line treatment consisting of an immune checkpoint inhibitor (ICI) plus a TKI or 2 ICIs. With multiple treatment options available and no head-to-head data comparing recommended agents, healthcare professionals need to consider various disease- and patient-related factors when selecting therapy. Immunotherapy also is used now in early-stage RCC as adjuvant therapy for selected patients after nephrectomy. The following discussion adapted from an ASCO 2023 satellite symposium on RCC provides practical insight on how to best manage patients with RCC in the context of these rapid changes in the field. 

Adjuvant Treatment for RCC

Toni K. Choueiri, MD:
Based primarily on data from the KEYNOTE-564 study, adjuvant treatment with pembrolizumab is most appropriate for patients with T2 grade 4 or T3 or higher disease and patients with M1 NED within 1 year of surgery. Of importance, this should be a multidisciplinary discussion with the urologist, medical oncologist, and patient. Counseling and collaboration are definitely warranted because many of these patients may not need therapy or even may not be eligible for pembrolizumab.

We hope to have answers for some questions not addressed by the KEYNOTE-564 study in future trials. These include: Should you use adjuvant therapy in non‒clear cell histology? Is adjuvant therapy for >1 year beneficial, especially in patients with M1 NED? Is <1 year of adjuvant therapy appropriate for other patients? What is the optimal choice for first-line therapy in a patient who received adjuvant pembrolizumab and experienced disease progression? Regarding the latter question, I personally may rechallenge with an ICI if the progression-free interval is >1 year.

First-line Therapies in Advanced or Metastatic RCC

Stephanie A. Berg, DO:
One of the biggest questions in advanced RCC currently is when to use initial immuno-oncology (IO)/IO combination therapy and when to use initial IO/TKI combination therapy, because both options are recommended in the National Comprehensive Cancer Network (NCCN) guidelines. We know that these agents from different classes have complementary mechanisms of action and work synergistically, but the combination may not be appropriate for all patients. Fortunately, the most recent version of the NCCN guidelines recommends therapies according to risk (favorable vs intermediate/poor risk), so this helps in deciding which combination therapy to choose. However, the options are very similar, and ipilimumab plus nivolumab and cabozantinib monotherapy are the only options recommended for patients with poor/intermediate-risk disease that are not also recommended for patients with favorable-risk disease. Beyond this, patients with tumors that are actively bleeding should not receive TKIs because they are associated with an increased risk of hemorrhage and impaired wound healing. In addition, patients who have poor/intermediate-risk disease based on International Metastatic RCC Database Consortium risk factors are good candidates for an IO/TKI combination to elicit a faster response and control symptoms due to the cancer. 

Regarding combining these 2 classes of therapies, it should be noted that both overlapping and separate toxicities may arise, so knowing what to monitor for and how to manage these differing toxicities is important. Fortunately, we do have guidelines to help us manage these toxicities, which are based on the grade of the abnormality. Lower-grade abnormalities typically warrant only monitoring, whereas higher-grade toxicities may warrant holding one or both agents and altering dose schedules. Timing and type of toxicity may help healthcare professionals distinguish between IO- or VEGFR-mediated events. For instance, VEGFR toxicities, such as diarrhea or hand‒foot skin reactions, usually occur early in a treatment course, whereas IO-mediated toxicities such as hypothyroidism may occur later. However, elevated liver enzymes can occur after a few days with either treatment, and therefore the etiology may be difficult to distinguish. Finally, we know that fatigue is a common toxicity for both treatments, and evaluation of adrenal insufficiency is extremely important. For more severe toxicities attributed to ICI therapy, high doses of steroids are often required and work very successfully. Although not performed in clinical trials, an ICI rechallenge is often common practice in the clinic if the patient was benefitting from therapy, but this is always a dilemma, especially in the case of a grade 3 or 4 adverse event. Overall, the risk‒benefit ratio always must be considered. 

Toni K. Choueiri, MD:
There has been some question of whether corticosteroids affect the efficacy of IO therapy. Hypothetically—and based on some preclinical data—steroid therapy could lead to a decrease in lymphocyte activity, but to date there are no clinical data in RCC to suggest that this is the case. 

Post-ICI Therapy: Second-line Therapy and Beyond

Katy E. Beckermann, MD, PhD:
It is important to note that the NCCN guidelines changed this year in the refractory setting to recommend agents based on whether the patient received prior IO therapy and, if they did receive prior IO, how therapy should be sequenced. Although there are no preferred regimens, all recommended regimens for patients with prior IO therapy contain a TKI component. 

Should ICI Therapy Be Continued in Patients Refractory to IO Frontline Combination? 

Katy E. Beckermann, MD, PhD:
Data from the CONTACT-03 trial on whether to continue ICI therapy with either the same or a different ICI in patients refractory to an IO frontline combination were presented at ASCO 2023. In this trial, patients with advanced or metastatic RCC who had progressive disease during or following first- or second-line ICI therapy were randomized to receive cabozantinib plus atezolizumab or cabozantinib alone. Investigators showed that cabozantinib plus atezolizumab did not improve clinical outcomes vs cabozantinib alone in these patents, with overall response rate (ORR) and progression-free survival (PFS) similar at 10.6 months and 10.8 months, respectively (stratified HR: 1.03; P = .784). Of importance, the combination arm had increased toxicity compared with TKI monotherapy.

Also of importance, the ongoing TiNivo-2 trial has a similar study design and is investigating tivozanib plus nivolumab (PD-1 inhibitor) vs tivozanib alone in patients progressing on an IO therapy. Data from CONTACT-03 suggest that continuing an ICI does not provide benefit for patients and comes at the cost of substantial toxicity.

Activity of VEGF TKIs Following Frontline ICI Therapy  

Katy E. Beckermann, MD, PhD:
Regarding patents who received prior ICI combination therapy, we currently have limited data on sequencing therapy. However, the phase I/II KEYNOTE-146 study specifically looked at the efficacy of lenvatinib plus pembrolizumab in patients who were IO naive (n = 17) or who had prior IO (n = 104). Patients could have received 0-2 lines of prior therapy. Investigators showed an ORR at 24 weeks of 55.8% and a PFS of 12.2 months in the prior IO group. Therefore, these data suggest efficacy of lenvatinib plus pembrolizumab in the refractory setting. This combination is now being investigated in a multiarm study specifically in the ICI refractory population, and we look forward to those data. 

Another study, CaboPoint, looked at the efficacy of cabozantinib in ICI-refractory clear cell RCC in 2 different cohorts: prior IO (ipilimumab/nivolumab; n = 60) and prior IO/VEGF TKI (n = 28). The ORR in the prior IO group was 31.7%, which is favorable considering that an ORR of only 17% was achieved in the METEOR trial with cabozantinib after prior VEGF TKI therapy. This study therefore raises additional questions, such as whether there is continued benefit of the ICI in the frontline setting and whether cabozantinib performs better in the post-ICI era. I certainly will be curious to see what the follow-up data for this trial show. 

Tivozanib, the most recently approved TKI in kidney cancer, is indicated for the treatment of adult patients with relapsed/refractory advanced RCC following ≥2 prior systemic therapies. Approval was based on the randomized phase III TIVO-3 study, where patients who had ≥2 prior lines of therapy were randomized to receive either tivozanib or sorafenib. The ORR was 18% with tivozanib vs 8% with sorafenib, with a median PFS of 5.6 months vs 3.9 months, respectively. Of note, because this was a more recent trial, 26% of patients had received a prior ICI, signifying that tivozanib also appears to have benefit in the post-ICI setting. 

Novel Therapeutics: Targeting HIF

Katy E. Beckermann, MD, PhD:
Belzutifan is a potent, selective, oral small-molecule HIF-2α inhibitor with antitumor activity in clear cell RCC that is approved for patients with von Hippel-Lindau (VHL) syndrome but does not yet have an indication in the refractory setting for patients with nongermline clear cell RCC. However, recent data from a single-arm phase I/II trial showed an ORR of 25% with belzutifan in a multiple-refractory setting, with a median PFS of 14.5 months. More recently, investigators showed an ORR of 30.8% with a PFS of 13.8 months for belzutifan plus cabozantinib in patients treated with ≥1 previous therapy. We know from our patients who have VHL syndrome that belzutifan has a very specific on-target adverse event. Indeed, when you inhibit HIF-2α, you downregulate epoetin α production, and by downregulating epoetin α production, you cause anemia. It is manageable—but something to be aware of to monitor and treat appropriately. Overall, I think these data are very promising, and there is a lot of excitement around this novel mechanism.       

Patient-Reported Outcomes

Stephanie A. Berg, DO:
A question in RCC clinical trials that recently has become more of a focus, especially with combination therapy, is whether patient quality of life improves or gets worse on these therapies. As such, the FSKI-19 score, a quality-of-life indicator specific for kidney cancer, has been measured in many of the pivotal RCC clinical trials. Overall, we see improvements in the FSKI-19 total score for comparator arms vs sunitinib, and often we see that this score improves over baseline. From a clinical counseling perspective, it is nice to be able tell our patients that they can live a relatively normal life while receiving treatment.

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