Kidney cancer (KC) ranks 14th in the most common cancers with 431,288 cases in 2020 and an estimated 179,368 deaths globally (1), with incidence on the rise. Clear cell renal cell carcinoma (ccRCC) is the most common type of KC, accounting for over 75-80% of cases.
The survival of patients with RCC has improved over recent years thanks to the advent and expansion of treatment options for patients with various stages of disease. Driven by a deeper understanding of the underlying genetic mechanisms of this tumor type, the past decade has witnessed an increase in more potent therapies including targeted therapies and immune-based treatments. Despite such progress, RCC remains a highly aggressive and lethal cancer – particularly for patients with advanced/metastatic disease.
To improve outcomes for these patients, current research efforts largely focus on more precisely matching patients to treatments based on robust biomarkers, assessing the efficacy and safety profile of novel combination therapy involving tyrosine kinase inhibitors (TKIs) and other immunologic agents, and defining the optimal sequence for the systemic and personalized treatment of disease.
Co-authored by Cristina Suárez, a Clinical Investigator of VHIO’s Genitourinary, CNS Tumors, Sarcoma & Cancer of Unknown Primary Site Group (PI: Joan Carles), recently reported results of two phase 3 clinical studies could potentially lead to improved patient stratification based on biomarker analyses, and open up new treatment opportunities for these patients.
IMmotion151 molecular analyses & biomarkers of response
Building on the previously reported interim analyses (2) that met the primary end point of progression free survival (PFS), final overall survival (OS) data and results of molecular analysis of the IMmotion151 open-label, phase 3 randomized clinical trial, directed by Robert J. Motzer, Memorial Sloan Kettering Cancer Center – MSKCC (New York, NY, USA), and Brian I. Rini, Vanderbilt-Ingram Cancer Center (Nashville, TN, USA), published last month in JAMA Oncology (3).
Enrolling 915 patients with locally advanced or metastatic RCC (mRCC) from over 150 academic research centers and oncology practices in 21 countries, including VHIO and the Vall d’Hebron University Hospital (HUVH), this multicenter study was designed to compare the efficacy of PD-L1 inhibitor atezolizumab plus the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, versus the receptor tyrosine kinase inhibitor, sunitinib.
“While final results failed to demonstrate overall survival benefit with atezolizumab plus bevacizumab compared with sunitinib, our exploratory biomarker analyses provide insights into the molecular basis of different survival outcomes in these patients,” observed Cristina Suárez, co-author of this study and a Medical Oncologist of HUVH’s Medical Oncology Department, headed by VHIO’s Director, Josep Tabernero.
Specifically, findings from their analyses showed that patients with tumors characterized by T-effector/proliferative, proliferative, and small nucleolar RNA transcription profiles had improved OS with atezolizumab/bevacizumab versus sunitinib, while patients with tumors characterized by an angiogenic transcription profile responded to both regimens because each contained an angiogenetic inhibitor.
“Moving forward, our results could help to inform the development of personalized approaches for treatment with antiangiogenics, immune checkpoint inhibitors, and their combinations in metastatic renal cell carcinoma,” added Cristina Suárez, who also serves as Vice-President of the Spanish Oncology Genito Urinary Group (SOGUG).
Although these biomarker results show promise, the IMmotion151 investigators caution that further evaluation and validation of the molecular subsets in more datasets will be required to inform applicability to other anti-angiogenesis plus checkpoint inhibitor combinations, and extended to other clinical settings including adjuvant therapy.
CheckMate 9ER: the promise of a novel immune-based combination
Published this month in The Lancet Oncology (4), results of a study led by David Cella, Robert H Lurie Comprehensive Cancer Center, Northwestern University (Chicago, IL, USA), and Toni K. Choueiri, Dana-Farber Cancer Institute, Lank Center for Genitourinary Oncology (Boston, MA, USA), report patient-reported outcomes (PRO) from the CheckMate 9ER open-label, randomized, phase 3 trial.
This multicenter international study, performed in 125 cancer centers, urology centers and hospitals across 18 countries, including VHIO and the Vall d’Hebron University Hospital (HUVH), enrolled patients with previously untreated advanced clear cell renal cell carcinoma (ccRCC) who were randomly assigned (1:1), to receive first-line immunotherapy with nivolumab plus targeted therapy with cabozantinib, or sunitinib, until disease progression or toxicity.
As previously reported (5), the 323 patients who received the novel nivolumab and cabozantinib combination had significantly better progression-free survival (PFS) compared with the 328 patients who were assigned to sunitinib. This present study, also co-authored by VHIO’s Cristina Suárez, now describes results of PRO analyses from CheckMate 9ER (4).
“Our results show that patient-reported outcome scores were maintained or improved with nivolumab plus cabozantinib versus sunitinib. Compared with sunitinib, this novel combination significantly delayed time to deterioration of PROs,” noted Cristina Suárez.
She concluded, “Suggesting clinical benefit for this combination, these promising findings point to a potential new treatment option for patients with advanced renal cell carcinoma.”
Reflective of her expertise within the genitourinary cancer field, Cristina Suárez has served as a Member of the American Society of Clinical Oncology’s (ASCO) Scientific Program Committee Genitourinary Cancer – Kidney and Bladder over the past two consecutive years. She is currently appointed as Track leader of this same Committee and a Member of ASCO’s Education Committee: Genitourinary Cancer – Kidney & Bladder.
In addition, Cristina is a Member of the European Society for Medical Oncology’s (ESMO) Scientific Committee-ESMO Congresses 2022 & 2023, and an ESMO faculty member of Genitourinary Tumors, non-Prostate (2021-2025).
- Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.
- Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, Bracarda S, Stadler WM, Donskov F, Lee JL, Hawkins R, Ravaud A, Alekseev B, Staehler M, Uemura M, De Giorgi U, Mellado B, Porta C, Melichar B, Gurney H, Bedke J, Choueiri TK, Parnis F, Khaznadar T, Thobhani A, Li S, Piault-Louis E, Frantz G, Huseni M, Schiff C, Green MC, Motzer RJ; IMmotion151 Study Group. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019 Jun 15;393(10189):2404-2415. doi: 10.1016/S0140-6736(19)30723-8. Epub 2019 May 9. PMID: 31079938.
- Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, Lee JL, Suarez C, Stroyakovskiy D, De Giorgi U, Donskov F, Mellado B, Banchereau R, Hamidi H, Khan O, Craine V, Huseni M, Flinn N, Dubey S, Rini BI. Final Overall Survival and Molecular Analysis in IMmotion151, a Phase 3 Trial Comparing Atezolizumab Plus Bevacizumab vs Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma. JAMA Oncol. 2021 Dec 23. doi: 10.1001/jamaoncol.2021.5981. Epub ahead of print. PMID: 34940781.
- Cella D, Motzer RJ, Suarez C, Blum SI, Ejzykowicz F, Hamilton M, Wallace JF, Simsek B, Zhang J, Ivanescu C, Apolo AB, Choueiri TK. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jan 12:S1470-2045(21)00693-8. doi: 10.1016/S1470-2045(21)00693-8. Epub ahead of print. PMID: 35032437.
- Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, Oyervides Juárez VM, Hsieh JJ, Basso U, Shah AY, Suárez C, Hamzaj A, Goh JC, Barrios C, Richardet M, Porta C, Kowalyszyn R, Feregrino JP, Żołnierek J, Pook D, Kessler ER, Tomita Y, Mizuno R, Bedke J, Zhang J, Maurer MA, Simsek B, Ejzykowicz F, Schwab GM, Apolo AB, Motzer RJ; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. doi: 10.1056/NEJMoa2026982. PMID: 33657295; PMCID: PMC8436591.