DR MAEVE HENNESSY,1 Medical Oncology Specialist Registrar; and DR EMMET JORDAN,1 Consultant Medical Oncologist. 1Department of Medical Oncology, University Hospital Waterford
In the last three years, there has been a rapid shift in the treatment landscape for newly diagnosed metastatic RCC.
Renal-cell carcinoma (RCC) represents 2-to-3 per cent of all cancers and most commonly occurs between the sixth and seventh decades of life.
Approximately 15 per cent of patients with RCC present with locally advanced or metastatic disease and the prognosis for long-term disease-free survival in this patient cohort is generally poor. RCC is comprised of several histological subtypes, with clear-cell carcinoma being the most frequent, representing 75-to-80 per cent cases of RCC.
The optimal management approach to metastatic RCC has evolved over the last two decades – therapies from high-dose bolus treatment with interleukin-2 to the use of interferon alpha, to molecularly targeted agents targeting vascular endothelial growth factor (VEGF) receptor and mammalian target of rapamycin (mTOR). The recognition of the VEGF pathway as an important therapeutic target led to the development of the anti-VEGF tyrosine kinase inhibitors (TKIs), such as sunitinib, pazopanib, and sorafenib. These agents were the first new therapies approved for advanced RCC and have been available in the European Union since 2006. Targeted therapy with VEGF-TKIs in the first-line treatment of metastatic RCC has been the standard of care over the last 10 years, with newer agents, such as cabozantinib and lenvatinib, also emerging.
|TRIAL||MEDIAN F/U (MO)||TREATMENT ARMS||PFS (MO)||OS (MO)||ORR|
|CheckMate 214 N=1096||67.7||Nivolumab/ ipilimumab vs sunitinib||12.3 vs 12.3 (HR 0.86; 95% CI 0.73-1.01; P=0.06)||55.7 vs 38.4 (HR 0.72; 95% CI 0.62-0.85; P<0.0001)||39 per cent vs 32 per cent|
|KEYNOTE-426 N=861||42.8||Pembrolizumab/ axitinib vs sunitinib||15.7 vs 11.1 (HR 0.68; 95% CI 0.58- 0.8; P<0.0001)||45.7 vs 40.1 (HR 0.73; 95% CI 0.6-0.88; P<0.0001)||60.4 per cent vs 39.6 per cent|
|CheckMate 9ER N=651||23.5||Nivolumab/ cabozantinib vs sunitinib||17 vs 8.3 (HR 0.52; 95% CI 0.43-0.64; P<0.0001)||NR vs 29.5 (HR 0.66; 95% CI 0.50-0.87; P=0.003)||54.8 per cent vs 28.4 per cent|
|JAVELIN Renal 101 N=886||13||Avelumab/axitinib vs sunitinib||13.3 vs 8 (HR 0.69; 95% CI 0.57-0.83; P<0.0001)|
|CLEAR N=1069||26.6||Lenvatinib/ pembrolizumab vs sunitinib Lenvatinib/ everolimus vs sunitinib||23.9 vs 9.2 (HR 0.39; 95% CI 0.32-0.49; P<0.001) 14.7 vs 9.2 (HR 0.65; 95% CI 0.53-0.83; P<001)||(HR 0.66, 95% CI 0.49- 0.88, P=0.005) (HR 1.15, 95% CI 0.88-1.5, P=0.3)||71 per cent vs 36.1 per cent 53.5 per cent vs 36.1 per cent|
In the last three years, there has been a rapid shift in the treatment landscape for newly diagnosed metastatic RCC, with combination immune checkpoint inhibitor therapy demonstrating improved efficacy over single agent TKI in several phase 3 clinical trials. In addition, the combination of a checkpoint inhibitor with a VEGF inhibitor has been evaluated. These combination regimens typically include treatment with a programmed death protein 1 (PD- 1) inhibitor combined with either a VEGF-TKI or an anti-cytotoxic T-lymphocyte-associated (CTLA-4) agent and have shown improved clinical outcomes as compared with sunitinib, thus establishing a new standard of care for first-line treatment of patients with metastatic RCC.
The choice of therapy for a patient with advanced RCC is informed by assessment of risk factors. The International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) prognostic model classifies patients into favourable-, intermediate-, and poor-risk categories, using the following six parameters:
1. Karnofsky Performance Status Scale (KPS) <80 per cent.
2. Time from diagnosis to treatment <one year.
3. Haemoglobin concentration less than the lower limit of normal.
4. Serum calcium greater than the upper limit of normal.
5. Neutrophil count greater than the upper limit of normal.
6. Platelet count greater than the upper limit of normal.
Favourable-risk patients have none of these riskfactors, intermediate risk have one or two factors, and those with three or more factors are classified as poor risk.
In general, systemic treatment with targeted therapy and/or immunotherapy is initiated at diagnosis and the recent evidence supporting frontline combination therapy is discussed further on. It is important to note that active surveillance can be considered in selected individuals who have low-volume indolent disease, and there is also a role for cytoreductive surgery, including nephrectomy and metastasectomy in certain scenarios.
Frontline systemic therapy – immunotherapy-based combination therapy Dual immunotherapy approach
The CheckMate 214 trial examined the combination of nivolumab (anti-PD-1 antibody) and ipilimumab (anti-CTLA-4 antibody) versus sunitinib in patients with untreated advanced clear-cell RCC. Initial results were published in the New England Journal of Medicine (NEJM) in 2018. A total 1,096 patients were randomised 1:1 to receive nivolumab at 3mg/kg with ipilimumab at 1mg/kg every three weeks for four cycles, followed by nivolumab monotherapy 3mg/kg every two weeks, or standard dosing of sunitinib (50mg orally daily for four weeks of a six-week cycle).
Updates from the trial with five years minimum follow-up duration continued to show improved outcomes for intermediate- and poor-risk patients treated with dual immunotherapy as compared to sunitinib. Progression-free survival (PFS) with ipilimumab/ nivolumab as compared to sunitinib was 12.3 months versus 12.3 months, (HR 0.86; 95% CI 0.73-1.01, P=0.06). Median overall survival (OS) was improved in the combination immunotherapy arm; 55.7 months versus 38.4 months, (HR 0.72; 95% CI 0.62-0.85, P<0.0001). The overall response rate was 39 per cent. Higher rates of grade III/IV adverse events were observed in the ipilimumab/nivolumab arm, however, this most frequently occurred in the first six months of therapy.
An exploratory analysis of patterns of progression in CheckMate 214 was presented at the American Society for Clinical Oncology Genitourinary meeting (ASCO GU) in February 2021. Findings identified that ‘new lesion only’ progression was more commonly observed
in patients who received combination therapy with ipilimumab/nivolumab as compared with sunitinib, and in particular in those patients who progressed post-response to treatment. This may have important therapeutic implications going forward, for example, in the selection of patients who may benefit from focal metastasis-directed therapy.
Immunotherapy plus targeted therapy approach
The KEYNOTE-426 trial examined the combination of pembrolizumab plus axitinib (VEGF-TKI) versus sunitinib in previously untreated metastatic clear-cell RCC. In total, 861 patients were stratified according to IMDC risk and were randomised in a 1:1 ratio to pembrolizumab 200mg thrice-weekly for up to 35 cycles plus axitinib 5mg orally twice-daily or sunitinib on standard dosing schedule.
The results of extended follow-up were recently published in The Lancet. The pembrolizumab plus axitinib arm continued to show an improved objective response rate (60.4% vs 39.9%; P<0.0001), PFS 15.7 months versus 11.1 months (HR 0.68; 95% CI 0.6–0.84; P<0 .0001), and OS 45.7 months versus 40.1 months (HR 0.73; 95% CI 0.6–0.85; P<0.0001) compared with sunitinib.
A total 37.6 per cent of the patients who received axitinib/pembrolizumab remained progression free at two years, and longer-term follow-up will reveal whether these results will be durable. A subgroup analysis of those with favourable-risk disease did not yet demonstrate differences in OS (HR 1.06; 95% CI 0.60–1.86, P=0.58) or PFS (HR 0.79; 95% CI 0.57–1.09; P= 0.078).
> CheckMate 9ER
Another checkpoint inhibitor plus anti-VEGF was evaluated in CheckMate 9ER and results published in the NEJM in March 2021. This multinational phase 3 trial randomised 651 patients with untreated advanced clear cell RCC 1:1 to nivolumab at 240mg every two weeks plus oral cabozantinib at 40mg daily versus sunitinib at standard dosing. The lower dose of cabozantinib was chosen on the basis of a phase 1 dose-finding study of nivolumab plus cabozantinib in patients with advanced genitourinary cancers, where the 40mg dose demonstrated similar efficacy, but less toxicity compared to the standard 60mg daily dose.
Improvements in PFS were seen for the nivolumab/ cabozantinib arm, 17 versus 8.3 months, (HR 0.52; 95% CI 0.43-0.64; P<0.0001). OS results appeared to favour the combination arm, however, longer term follow-up is needed. In terms of response rate, ORR was 54.8 per cent for nivolumab/cabozantinib versus 28.4 per cent for sunitinib (P<0 .0001), and complete response rates were doubled at 8 per cent versus 4.6 per cent in favour of the combination. Although the overall rate of serious adverse events was similar between the two arms, liver toxicity was more common with nivolumab and cabozantinib. Elevation in liver enzymes was noted in 25 per cent versus 6 per cent with sunitinib.
> JAVELIN Renal 101
The JAVELIN Renal 101 study adds further evidence that combination treatment and targeting multiple pathways is an effective strategy for treatment of advanced RCC. In this phase 3 trial by Motzer et al, 886 patients with metastatic RCC were randomised 1:1 to receive first-line systemic therapy with avelumab (anti-PD-L1) at 10mg/kg intravenously every two weeks plus axitinib 5mg orally twice daily or sunitinib. At the second interim analysis, the avelumab/ axitinib group had a significantly improved PFS at a median follow-up of 13 months, 13.3 versus eight months (HR 0.69; 95% CI 0.57–0.83; P<0.0001), and the benefit was demonstrated across all subgroups including all IMDC risk groups. The lack of an OS benefit demonstrated to-date perhaps makes this combination less appealing.
The phase 3 CLEAR trial was published in the NEJM in February 2021 and explored further combination approaches for advanced RCC. This was a three-arm study, which randomly assigned treatment-naïve patients to lenvatinib 20mg orally once-daily plus pembrolizumab 200mg intravenously once every three weeks, lenvatinib 18mg orally once-daily plus everolimus 5mg orally once daily, or standard dose of sunitinib. A significant OS benefit was noted for the lenvatinib/pembrolizumab arm as compared with sunitinib alone (HR 0.66, 95% CI 0.49-0.88, P=0.005) [median OS not reached (NR)]. PFS and ORR was also improved for the lenvatinib/ pembrolizumab arm [RR 71% versus 36%; PFS HR 0.39 (95% CI 0.32-0.49; P<0.001)], median PFS 23.9 months versus 9.2 months. The combination of lenvatinib/ everolimus did result in improved PFS compared with sunitinib [HR 0.65, 95% CI 0.53-0.80, P<0.001, median PFS 14.7 months (95% CI 11.1-16.7) versus 9.2 months (95% CI 6.0-11.0)], however, there was no improvement in OS (HR 1.15, 95% CI 0.88-1.50).9 Although cross-trial comparisons must be interpreted cautiously, the 23.9 month PFS, ORR of 71 per cent and complete response of 16.1 per cent noted in the lenvatinib/pembrolizumab arm are impressive when compared to other recent trials in this field. The lenvatinib/pembrolizumab combination received US FDA approval for the first-line treatment of advanced RCC in 2021 on the basis of the CLEAR trial. Lenvatinib/everolimus should not be considered as a standard treatment for metastatic RCC in the first-line, however, it may have a role in later lines of therapy.
Choice of therapy
The aforementioned studies provide evidence for the introduction of an array of new combination therapies in the frontline treatment of advanced RCC. However, none of these approaches have been directly compared with each other in prospective clinical trials, thus the optimal first-line therapy remains undetermined as of yet.
On the basis of the published data, for the 20-to-25 per cent of patients falling into the favourable risk category, treatment with either pembrolizumab/axitinib or single agent sunitinib are reasonable options. For those with intermediate- or poor-risk disease, options include nivolumab plus ipilimumab, pembrolizumab plus axitinib or nivolumab plus cabozantinib. All of these combinations have demonstrated improved OS and good tolerability (as compared with sunitinib) in randomised phase 3 trials. Of note, the combination of avelumab plus axitinib has not yet demonstrated an OS benefit. For patients who are not suitable for immunotherapy, single agent antiangiogenic treatment with a VEGF inhibitor is an option.
The potential benefits of a dual immunotherapy approach with nivolumab plus ipilimumab include the ability to achieve durable responses, an ability to avoid chronic toxicities associated with TKI therapy, and the availability of mature follow-up data demonstrating an OS benefit. However, this is countered by higher rates of immune-related adverse events (irAEs), particularly in the first six months of treatment. In addition, PFS and response rates are lower as compared to IO/VEGF combination therapies. In Ireland, nivolumab in combination with ipilimumab was approved and reimbursed for the first-line treatment of adult patients with intermediate/poor-risk advanced RCC in February 2021. Pembrolizumab in combination with axitinib for the first-line treatment of advanced RCC in adults is not yet reimbursed.
The immunotherapy/TKI combinations have also shown improved PFS, OS, and ORR and are associated with a lower rate of irAEs. When adverse events do occur, it can be difficult to ascertain whether they are related to the targeted therapy or the immunotherapy and this can pose management challenges. Longer follow-up data is needed to determine durable response to treatment. Other questions relate to the optimal sequence of therapy and whether or not a similar survival benefit could be achieved by giving immunotherapy and targeted therapy sequentially as opposed to concurrently.
At the ASCO GU Symposium 2021, the results of outcomes of first-line combination therapy in advanced RCC from the IMDC database were presented. Patients treated with immunotherapy/VEGF inhibitors were compared with those treated with dual immunotherapy and a subgroup analysis of those with intermediate-/poor-risk disease was performed. The conclusion was that no significant OS difference was detected between groups, serious irAEs were associated with improved OS, and that dual immunotherapy or immunotherapy/targeted therapy were both appropriate options in this setting.
Future directions for advanced RCC
Based on the above results, future clinical trials will likely move away from the use of sunitinib as a suitable control arm. The phase 3 COSMIC 313 study is attempting to shed further light on the optimal regimen by evaluating a TKI plus immunotherapy combination versus an immunotherapy control arm. Patients with untreated advanced RCC will be randomised to either the experimental arm of cabozantinib, nivolumab, and ipilimumab followed by cabozantinib and nivolumab or the control arm of nivolumab plus ipilimumab followed by nivolumab monotherapy.
The currently recruiting PDIGREE trial aims to address the question of how to sequence therapies and is examining a ‘response adapted approach’. Patients will receive combination ipilimumab/nivolumab initially and then based on response, cabozantinib will be added. Patients with progressive disease on ipilimumab/ nivolumab will commence cabozantinib, patients with a complete response will stop treatment for a certain period of time, while patients with stable disease or a partial response will be randomised to maintenance treatment with either nivolumab or cabozantinib.
In terms of novel therapies, an oral small molecule inhibitor of hypoxia inducible factor (HIF)-2alpha has shown efficacy in patients with von Hippel-Lindau (VHL)-associated RCC, with a manageable toxicity profile. Currently, a phase 3 trial is ongoing looking at the HIF 2 alpha inhibitor belzutifan versus everolimus in patients with advanced RCC that has progressed following treatment with immunotherapy and VEGF-targeted therapies.
In summary, we have seen rapid advances in the management of RCC over the last few years, with combination therapy emerging as the new standard of care. Ongoing studies are needed to further inform treatment selection and determine the optimal combination approach for patients with advanced RCC. Additionally, while much progress has been made in frontline therapy, questions remain regarding how to sequence therapy and the approach to treatment upon progression of disease.
References on request
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