CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 07, 2023
Expiration: April 06, 2024
There has been so much advancement in frontline therapy that now it becomes even more challenging to make a second-line treatment decision for patients with refractory disease who have progressed. There are numerous options in treatment guidelines17 for regimens in the second-line or refractory setting, including VEGF TKI, IO, VEGF TKI/IO, VEGF TKI/mTOR inhibitor, IO/IO, and mTOR inhibitor therapy. Enrollment on a clinical trial is also a recommended treatment option, as the field still is attempting to understand what the next best step is for patients who have failed frontline therapy.
I will review historic data that show the benefit of sequencing TKIs (before the era of IO combinations), as well as some of the more contemporary clinical trials that are reading out as frontline IO combinations have become more standard of care. Lastly, I will review some of the novel mechanisms that are being investigated in clinical trials.
Delving into some of the historical data with the highest level of evidence from the METEOR trial,25 this was a randomized phase III study of patients who had been previously treated with sunitinib or pazopanib and were randomized to receive either cabozantinib 60 mg daily or everolimus 10 mg daily. At the time of this study, everolimus was considered the standard of care in the second-line setting. In this study, only 5% of patients had received prior immune checkpoint inhibition, so this truly was testing sequencing of TKIs. There was an improvement in the ORR with cabozantinib (17%) vs everolimus (3%). The median PFS also was longer in the cabozantinib arm (HR: 0.51; 95% CI: 0.41-0.62; P <.0001). Median OS was 21.4 months with cabozantinib vs 17.1 months with everolimus (HR: 0.7; 95% CI: 0.58-0.85; P = .0002).26
We also have data from a randomized, multicenter phase II study of combination everolimus/lenvatinib vs single‑agent lenvatinib and single‑agent everolimus in the refractory setting.27 Similar to the previous study, a minimal number of patients (3%) had received prior immune checkpoint inhibition. Again, this study was aiming to assess sequencing of TKIs.
This study showed a benefit of lenvatinib with everolimus, yielding an ORR of 43% compared with 6% in patients who received everolimus alone. The combination therapy also showed improvement in OS compared with single-agent everolimus (HR: 0.51; 95% CI: 0.30-0.88; P = .024).
Both of these trials support that if you give a TKI in the frontline setting, subsequent sequencing of TKIs in the refractory setting can be beneficial for patients.
Moving into trials of patients who have had prior IO treatment, we have the TIVO-3 study, which used another VEGF TKI, tivozanib.28,29 This was a randomized phase III study of patients who had received multiple prior lines of therapy for metastatic kidney cancer. Patients were randomized to receive either oral tivozanib 1.34 mg once daily (3 weeks on, 1 week off) or sorafenib 400 mg twice daily. Approximately one quarter of patients in this study had received prior treatment with an IO/TKI combination. Treatment with tivozanib showed an improvement in the third- and fourth‑line settings by extending PFS compared with sorafenib; median PFS was 5.6 months with tivozanib vs 3.9 months with sorafenib (HR: 0.73; 95% CI: 0.56-0.94; P = .016). The ORR even in that late‑line refractory setting was 18% with tivozanib vs 8% with sorafenib. These results led to the FDA approval of tivozanib for the treatment of R/R advanced RCC following ≥2 prior systemic therapies.30
The CaboPoint31 study is an ongoing, randomized, open-label phase II study assessing cabozantinib in patients who have experienced disease progression with therapy containing an immune checkpoint inhibitor. Cohort A (n = 60) consisted of patients who received ipilimumab/nivolumab prior to progression, and cohort B (n = 28) consisted of patients who progressed on a prior TKI (excluding cabozantinib) in combination with an immune checkpoint inhibitor.
Data for this study were presented at ASCO GU 2023 and showed an ORR of 31.7% in cohort A and 25.0% in cohort B.
This is one of a few studies that truly has investigated RCC in the refractory setting after frontline combination therapy with immunotherapy. It shows that you can sequence and use a TKI in the second‑line setting.
The phase Ib/II KEYNOTE‑146/Study 111 trial32 sought to understand if combination lenvatinib 20 mg once daily with pembrolizumab 200 mg IV every 3 weeks could be administered after receipt of prior IO therapy. In other words, this study is continuing to look at not only sequencing with a TKI, but also if continuation of PD‑1 blockade is beneficial. Although this study was performed in multiple solid tumors, there was a metastatic RCC cohort that consisted of 145 patients. Of the RCC cohort, only 17 patients were IO naive but 104 patients had prior IO exposure. Those with prior IO exposure had an ORR rate of 55.8% at 24 weeks.
We always want to have as many options as possible for those with refractory disease. Belzutifan33 is a hypoxia-inducible factor (HIF) inhibitor that is approved by the FDA for patients with VHL disease who require therapy for associated RCC but is now being studied in all phases of somatic mutated kidney cancer. The general biology or targeting mechanism of belzutifan comes about because the majority of patients with clear cell RCC have lost function of VHL, which is normally there to degrade HIF α in normal oxygen content.34-36 Because VHL is lost, HIF α can become unregulated, and downstream signaling pathways such as vascular angiogenesis (which we have been targeting for years with VEGF TKIs) and cell-survival signals also become unregulated. Belzutifan is used to directly inhibit the HIF complex. This phase I/II clinical trial investigated oral belzutifan 120 mg once daily in patients who received ≥1 previous treatment for clear cell RCC
On the waterfall, patients who received prior IO/TKI therapy are denoted by small asterisks. In the most recent data presented by Jonasch and colleagues36 at the ASCO 2022 Annual Meeting, ORR was 25%, and 1 patient achieved a CR in the refractory setting.
Belzutifan is being compared with everolimus in a phase III trial of patients with advanced RCC, which has completed enrollment (NCT04195750).
There are data to say that sequencing of TKIs can be effective. I think there is still an ongoing understanding of what the next best regimen is after upfront IO‑based combination therapy. I hope that some novel mechanisms will be included in our armamentarium of treatment options for our patients.
Thinking about what to do next for a patient, in my own clinical practice, I look at the strength of evidence of the clinical trials available, and I ask what prior treatment the patient received. I will use a different TKI from what the patient received in the first-line setting, knowing they each have slightly different targeting modalities. What toxicities either were not acceptable to the patient or have not fully resolved from their prior therapy? I also consider potential financial toxicities for the next line of therapy. Overall, it is not a one-size-fits-all approach and is truly an individualized patient treatment decision for subsequent therapy.
I am hopeful that we will have phase III data soon to help answer the question of immune checkpoint inhibitor continuation after frontline failure. The CONTACT‑03 trial is randomizing patients after previous PD-1/PD-L1 therapy to receive cabozantinib with or without atezolizumab (NCT04338269). CONTACT‑03 has accrued, and a recently issued press release suggested that the addition of atezolizumab to cabozantinib did not improve PFS after prior immune checkpoint inhibition. We look forward to seeing the complete data presented at an upcoming meeting.
TiNivo‑2 is nearing accrual (NCT04987203). This is a phase III trial of tivozanib with or without nivolumab in advanced RCC after prior IO therapy. Both of these trials will be helpful to understanding if continued IO therapy after frontline failure is helpful.
As previously mentioned, the novel mechanism with belzutifan is being investigated in a phase III trial of belzutifan compared with everolimus (NCT04195750).
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