Thai H. Ho, MD, PhD, discusses frontline treatment considerations in metastatic renal cell carcinoma, the utility of TKI monotherapy, and new combinations on the horizon.
Thai H. Ho, MD, PhD
The FDA approvals of dual immunotherapy and TKI/immunotherapy combinations for use in patients with newly diagnosed, metastatic renal cell carcinoma (mRCC) have signaled a shift away from TKI monotherapy in the frontline setting, according to Thai H. Ho, MD, PhD.
For example, the FDA granted an approval to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in April 2018 for use in patients with newly diagnosed, intermediate- and poor-risk disease based on a 37% reduction in the risk of death versus sunitinib (Sutent) monotherapy in the phase III CheckMate-214 trial (HR, 0.63; 99.8% CI, 0.44-0.89;  P  <.001).1
In April 2019, the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) was approved as frontline therapy after demonstrating a robust improvement in overall survival (OS) versus sunitinib across poor-, intermediate-, and favorable risk groups in the phase III KEYNOTE-426 trial (HR, 0.53; 95% CI, 0.38-0.74;  P  <.0001).2
Most recently, in May 2019, the FDA approved the combination of avelumab (Bavencio) and axitinib as first-line therapy based on data from the phase III JAVELIN Renal 101 trial, in which the combination showed a median progression-free survival (PFS) advantage of 13.8 months versus 8.4 months with sunitinib monotherapy (HR, 0.69; 95% CI, 0.563-0.840; 2-sided  P  = .0002) in the overall population.3
“Two major schools of thought [exist when it comes to selecting frontline therapy],” said Ho. “One school of thought is to stratify patients by their risk. Another school of thought is to not use the International Metastatic RCC Database Consortium (IMDC) risk score and give the combination of axitinib and pembrolizumab to all-comers.”
Such schools of thought should serve as guiding principles, said Ho, but they are not the only factors to consider. Selection decisions should also be based on the likelihood of complete response (CR) and tolerability profiles of these agents alone and in combination, Ho added.
“After frontline therapy, the biggest challenge is trying to identify therapies that work in immune-oncology—refractory patients,” said Ho.
In an interview during the 2019  OncLive®  State of the Science Summit™ on Genitourinary Malignancies, Ho, a consultant in the division of Hematology/Oncology, Department of Internal Medicine, and assistant professor of medicine, at Mayo Clinic, discussed frontline treatment considerations in mRCC, the utility of TKI monotherapy, and new combinations on the horizon.
: Could you discuss the results of the CheckMate-214, KEYNOTE-426, and the JAVELIN Renal 101 trials?
Ho: The earliest trial was the CheckMate-214 trial, which was a randomized study in which patients were stratified by IMDC risk criteria. The majority of the patients [enrolled on the trial] fell into the intermediate- and poor-risk groups. Patients were randomized to receive the combination of ipilimumab and nivolumab versus sunitinib as the comparator. The study was powered for PFS and OS. The FDA approved the combination based on the OS benefit observed with the combination. Another highlight of the study was the improved CR rate, which was approximately 10% in the poor- and intermediate-risk group. In terms of adverse events (AEs), about one-third of patients required high-dose steroids.
In the KEYNOTE-426 study, patients were randomized to receive the combination of pembrolizumab plus axitinib versus sunitinib. All risk groups were [included]. Investigators reported improved PFS, as well as a trend toward improved OS in all patients, including those with favorable-risk disease. These data led to the approval of the combination for use in the first-line setting. Highlights of this study include the objective response rate (ORR) of >50%, as well as the reduced grade 3/4 [immune-related] AEs versus what was seen in the CheckMate-214 trial.
The last study I highlighted was the JAVELIN Renal 101 study, which evaluated the combination of axitinib and avelumab. In this study, patients were randomized to receive avelumab plus axitinib or sunitinib. Avelumab was dosed every 2 weeks, and axitinib was dosed twice daily, similar to the KEYNOTE-426 trial. The combination demonstrated a PFS benefit, leading to its FDA approval. Notably, the toxicity profile of the combination resulted in about a 10% use of corticosteroids compared with 30% in the CheckMate-214 trial. Based on these data, sunitinib has taken on a minimal role [in mRCC].
How are you currently selecting frontline therapy?
If I’m going for a higher CR in patients with poor- and intermediate-risk, I would opt for the combination of nivolumab and ipilimumab. This is a pure immunotherapy combination with CR rates of approximately 10%, independent of PD-L1 status.
The combination of axitinib and pembrolizumab is associated with a lower incidence of grade 3/4 AEs and a higher ORR. These are the 2 most favorable combinations in terms of PFS and OS benefit.
The combination of axitinib and avelumab is less popular because OS data have not been presented yet. In addition, avelumab is given every 2 weeks, which may be less favorable to 3-week dosing, or even 4-week dosing with the immunotherapy compounds.
With these newly available combination regimens, how do you determine sequencing?
I prefer to go for a higher CR rate [with the combination of nivolumab and ipilimumab,] which also preserves the use of cabozantinib (Cabometyx) in the second-line setting in terms of antiangiogenic therapy. However, we don't have any good sequencing data yet.
Would you say there is still a role for TKI monotherapy in mRCC?
There is a role for TKI monotherapy, as we have seen from the CABOSUN data; this was a phase II ALLIANCE study in which patients were randomized to receive either cabozantinib or sunitinib. We saw an improvement in PFS and OS with cabozantinib over sunitinib. Sunitinib has been beaten by multiple agents now. As such, first-line therapy should not include sunitinib unless you have some other compelling reason [to use it]. Cabozantinib might be an option for patients who are intolerant of or ineligible for immunotherapy.
Axitinib has the shortest half-life, whereas cabozantinib has the longest half-life. These factors should also be taken into consideration when thinking about the AE profiles associated with these agents.
Data regarding the combination of telaglenastat/everolimus (Afinitor) and nivolumab/tivozanib (Fotivda) were presented at the 2019 ESMO Congress. Could you provide your thoughts on those data?
Those [combinations would be used] in later lines of therapy. The combination of lenvatinib (Lenvima) and everolimus is another combination that has already received regulatory approval based on improved PFS. The combination of lenvatinib and everolimus or cabozantinib monotherapy are poised for second-line therapy. If telaglenastat is approved, it would be used in combination with cabozantinib, which would be a great option for patients who are currently treated with cabozantinib.
What is the biggest challenge in this space?
[The biggest challenge is the management of] patients who were previously treated with and are refractory to immunotherapy—whether it be ipilimumab and nivolumab, axitinib and pembrolizumab, or axitinib and avelumab. This is where the least amount of data have been published. Some trials are looking specifically at treatment sequences where patients are given immunotherapy in the first-line setting, followed by selected TKIs in the second-line setting.
How are biomarkers and molecular signatures being used in mRCC?
Some of these molecular signatures include traditional RNA and DNA protein, or even PD-L1 immunohistochemistry. However, it's hard to exclude a patient [from treatment] using a biomarker test. For example, some of the patients in the CheckMate-214 trial were PD-L1—negative and still had a CR, which suggests that many of these tests have a poor negative predictive value. By using a predictive test with a poor negative predictive value, you may exclude a patient who may inadvertently respond to immunotherapy.