Professor Albiges began by discussing where we currently stand in the systemic treatment of patients with metastatic RCC. Per the European guidelines, IO-based combination therapy is currently standard of care in all IMDC risk groups. Following the results of pivotal phase III RCTs evaluating combination therapy in the first line setting for metastatic RCC patients, currently approved agents in this setting include:
- Checkpoint inhibitor (CPI) – CPI combination:
- Nivolumab + ipilimumab (ChecKMate 214)1
- CPI - Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) combination:
- Pembrolizumab + axitinib (KEYNOTE-426)2
- Avelumab + axitinib (JAVELIN 101)3
- Nivolumab + cabozantinib (ChecKMate 9ER)4
- Pembrolizumab + Lenvatinib (CLEAR)5
As demonstrated in the table below, there are some differences between the outcomes observed in these combination trials that are worth highlighting:
- Long-term OS was longest in patients receiving the CPI-CPI combination of ipilimumab/nivolumab (median OS: 55.7 months) in the ChecKMate 214 trial
- Overall response rates (ORR) were conversely highest in the trials evaluating a CPI/VEGFR-TKI combination
- Regardless of OS or ORRs, all such combinations in all the trials had a similar OS HR benefit compared to the control arm of sunitinib (HRs 0.70 to 0.73).
With doublet therapy firmly established as superior to sunitinib in this disease space, the next question was: can we improve outcomes by further intensifying therapy with an additional agent? COSMIC-313 evaluated the combination of cabozantinib + nivolumab + ipilimumab versus ipilimumab/nivolumab in the 1st line metastatic setting for patients with intermediate or poor risk IMDC clear cell RCC.
Final analysis of the PFS outcome, presented at ESMO 2022, demonstrated that patients receiving the triplet therapy had superior PFS outcomes (median: NR versus 11.3 months; HR: 0.73, 95% CI: 0.57 – 0.94, p=0.013).
Notably, tumor response was underwhelming in both trial arms, which raised the question of drug exposure (43% in triplet versus 36% in ipilimumab/nivolumab, which are both lower compared to the ORRs observed in the prior doublet trials).
Further triplet combination regimens are being evaluated in this setting with the MK6482-012 trial (NCT04736706) study design as below evaluating anit-PD-1 + VEGFR-TKI +/- HIF2 +/- CTLA4.
What about new agents in this setting? The HIF2 inhibitor Belzutifan has demonstrated impressive objective response rates of 49% in patients with von Hippel-Lindau-related renal cell carcinomas. As such, this agent is now being evaluated in a phase 3 trial randomizing patients with unresectable locally advanced/metastatic clear cell RCC who previously received 3 or less systemic regimens that must have included a PD-1/PD-L1 inhibitor and a VEGFR-TKI to either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily.
What about implementation of biomarkers in this setting? There is a plethora of available biomarkers, including sarcomatoid differentiation, PRBM1 mutations, tumor mutational burden (RMB), RNA expression, PD-L1 immunohistochemistry, etc. Can such agents be used to predict cohorts of patients who are more likely to benefit from one combination regimen versus the other?
For patients with sarcomatoid features, it is quite clear that these patients benefit from combination CPI-CPI therapy, with a confirmed ORR of 57% in IMDC intermediate/poor risk patients, compared to 42% ORR in overall IMDC intermediate/poor risk patients.
This is reflected in significant OS benefits for such sarcomatoid patients receiving ipilimumab/nivolumab versus sunitinib as demonstrated below:
Are transcriptomic tools ready to be utilized for prediction of best response to therapeutic agents? The BIONIKK study stratified patients with previously untreated metastatic clear cell RCC into one of four molecular groups with treatment assigned based on the molecular group, as demonstrated below.
Similarly, the OPTIC RCC trial (NCT053561720) is a phase II, open-label, parallel single-arm study that will use tumor RNAseq cluster to assign protocol treatment.
Given that CPIs form the basis of doublet therapies in this space, PD-L1 positivity has been evaluated as a biomarker in this setting. As summarized in the table below, patients with PD-L1 positive status had a better OS HR estimate effect with a HR of 0.45 (95% CI: 0.29 to 0.71), compared to 0.73 in PD-L1 negative patients (95% CI: 0.56-0.96), compared to sunitinib.
CARE-1 RLT will randomize patients with treatment-naïve, IMDC intermediate/poor risk disease, stratified by PD-L1 status, to either ICI-ICI combination therapy or ICI-VEGF TKI combination, with an a priori hypothesis of superior outcomes for ICI-ICI in PD-L1 positive patients and ICI-VEGFR TKI in PD-L1 negative patients.
Finally, Professor Albiges touched upon the use of adjuvant/perioperative immunotherapy in patients with high-risk RCC. As summarized in the table below, PFS benefits have only been observed with pembrolizumab, with OS benefits pending as this outcome gains further maturity. Subgroup analysis suggests that this PFS benefit is most pronounced in patients with high-risk disease (HR: 0.60; 95% CI: 0.33 – 1.10) and M1 NED (HR: 0.28, 95% CI: 0.12 – 0.66).5
Based on the results of the KEYNOTE-564 trial of adjuvant pembrolizumab, the ESMO released the following recommendation in 2022: “Adjuvant pembrolizumab should be considered optional for patients with intermediate- or high-risk operable clear cell RCC after careful patient counselling regarding immature OS and potential long-term adverse events. Further data are required in the future including positive OS data. Treatment should start within 12 weeks of surgery and continue for up to 1 year”.Professor Albiges summarized her presentation with the following take home messages:
- Where do we stand?
- IO is the cornerstone of all combinations in the first line
- Moving to triplets?
- Safety may limit full exposure to IO-based triplets
- New agents?
- Stay tuned for HIF in VHL disease and beyond
- Implementation of biomarkers?
- Not routinely performed but increasingly being implemented in trials
- The open chapter of adjuvant IO?
- The challenge is in selecting the patients
- Professor Alberto Briganti, MD, PhD, Professor of Urology, Department of Urology, Università Vita-Salute San Raffaele, Milan, Italy
- Professor Laurence Albiges MD, PhD, Professor, Medical Oncology, Vice chair of the Department of Cancer Medicine at the Gustave Roussy Institute, Villejuif, France
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 European Association of Urology (EAU) Annual Meeting, Milan, IT, Fri, Mar 10 – Mon, Mar 13, 2023.
References:- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carinoma. N Engl J Med 2018;378(14):1277-1290.
- Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1116-1127.
- Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1103-1115.
- Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841.
- Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300.