BACKGROUND: The extent of tumor shrinkage has been deemed a predictor of survival for advanced/metastatic renal cell carcinoma (RCC), a disease with historically poor survival. OBJECTIVE: To perform an exploratory analysis of overall survival (OS) by tumor response by 6 mo, and to assess the efficacy and survival outcomes in specific subgroups. DESIGN, SETTING, AND PARTICIPANTS: CLEAR was an open-label, multicenter, randomized, phase 3 trial of first-line treatment of advanced clear cell RCC. INTERVENTION: Patients were randomized 1:1:1 to lenvatinib 20 mg orally daily with pembrolizumab 200 mg intravenously once every 3 wk, lenvatinib plus everolimus (not included in this analysis), or sunitinib 50 mg orally daily for 4 wk on treatment/2 wk of no treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Landmark analyses were conducted to assess the association of OS with tumor shrinkage and progressive disease status by 6 mo. Progression-free survival, duration of response, and objective response rate (ORR) were analyzed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk subgroup and by the presence of target kidney lesions. Efficacy was assessed by an independent review committee as per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS AND LIMITATIONS: Landmark analyses by tumor shrinkage showed that patients enrolled to lenvatinib plus pembrolizumab arm with a confirmed complete response or >75% target-lesion reduction by 6 mo had a 24-mo OS probability of ≥91.7%. A landmark analysis by disease progression showed that patients with no progression by 6 mo had lower probabilities of death in both arms. Patients with an IMDC risk classification of intermediate/poor had longer median progression-free survival (22.1 vs 5.9 mo) and a higher ORR (72.4% vs 28.8%) with lenvatinib plus pembrolizumab versus sunitinib. Similarly, results favored lenvatinib plus pembrolizumab in IMDC-favorable patients and those with/without target kidney lesions. Limitations of the study are that results were exploratory and not powered/stratified. CONCLUSIONS: Lenvatinib plus pembrolizumab showed improved efficacy versus sunitinib for patients with advanced RCC; landmark analyses showed that tumor response by 6 mo correlated with longer OS. PATIENT SUMMARY: In this report of the CLEAR trial, we explored the survival of patients with advanced renal cell carcinoma by assessing how well they initially responded to treatment. We also explored how certain groups of patients responded to treatment overall. Patients were assigned to cycles of either lenvatinib 20 mg daily plus pembrolizumab 200 mg every 3 wk or sunitinib 50 mg daily for 4 wk (followed by a 2-wk break). Patients who either had a "complete response" or had their tumors shrunk by >75% within 6 mo after starting treatment with lenvatinib plus pembrolizumab had better survival than those with less tumor reduction by 6 mo. Additionally, patients who had more severe disease (as per the International Metastatic Renal Cell Carcinoma Database Consortium) at the start of study treatment survived for longer without disease progression with lenvatinib plus pembrolizumab than with sunitinib.

Centre René Gauducheau Centre de Lutte Contre Le Cancer Nantes Saint Herblain France

Eisai Inc Nutley NJ USA

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Italy

Hospital de la Santa Creu i Sant Pau Barcelona Spain

Hospital Universitario Ramón y Cajal Madrid Spain

Interdisciplinary Genitourinary Oncology Clinic for Urology Clinic for Medical Oncology University Hospital Essen Essen Germany

Keio University School of Medicine Tokyo Japan

Kyushu University Fukuoka Japan

Memorial Sloan Kettering Cancer Center New York NY USA

Merck and Co Inc Rahway NJ USA

Palacký University Medical School and Teaching Hospital Olomouc Czech Republic

Seoul National University Hospital Seoul Republic of Korea

State Budgetary Health Care Institution Novosibirsk Regional Clinical Oncology Dispensary Novosibirsk Russia

State Institution of Healthcare Regional Clinical Oncology Dispensary Omsk Russia

Texas Oncology Dallas TX USA

The Royal Free NHS Trust London England UK

University of Bari 'A Moro' Bari Italy

University of Western Ontario London Ontario Canada

Western Health VIC Australia

See more in PubMed

National Cancer Institute. Surveillance, Epidemiology, and End Results Program (SEER). Cancer stat facts: kidney and renal pelvis cancer https://seer.cancer.gov/statfacts/html/kidrp.html.

International Agency for Research on Cancer (IARC). GLOBOCAN 2020. Cancer Today. https://gco.iarc.fr/today/home.

Padala SA, Barsouk A, Thandra KC, et al. Epidemiology of renal cell carcinoma. World J Oncol 2020;11:79–87. PubMed PMC

Li P, Wong YN, Armstrong K, et al. Survival among patients with advanced renal cell carcinoma in the pretargeted versus targeted therapy eras. Cancer Med 2016;5:169–81. PubMed PMC

Choueiri TK, Motzer RJ. Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med 2017;376:354–66. PubMed

Choueiri TK, Kaelin WG Jr. Targeting the HIF2-VEGF axis in renal cell carcinoma. Nat Med 2020;26:1519–30. PubMed

Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2021;384:829–41. PubMed PMC

Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–90. PubMed PMC

Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med 2021;384:1289–300. PubMed

Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380: 1103–15. PubMed PMC

Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116–27. PubMed

Rassy E, Flippot R, Albiges L. Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma. Ther Adv Med Oncol 2020;12:1758835920907504. PubMed PMC

National Comprehensive Cancer Network clinical practice guidelines in oncology (NCCN Guidelines®). Kidney cancer. Version 3. 2022. http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf.

Bedke J, Albiges L, Capitanio U, et al. Updated European Association of Urology guidelines on renal cell carcinoma: nivolumab plus cabozantinib joins immune checkpoint inhibition combination therapies for treatment-naïve metastatic clear-cell renal cell carcinoma. Eur Urol 2021;79:339–42. PubMed

Powles T, Albiges L, Bex A, et al. ESMO clinical practice guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma. Ann Oncol 2021;32:1511–9. PubMed

Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 2015;16:1473–82. PubMed

Pal SK, Puente J, Heng DYC, et al. Phase II trial of lenvatinib (LEN) at two starting doses + everolimus (EVE) in patients (pts) with renal cell carcinoma (RCC): results by independent imaging review (IIR) and prior immune checkpoint inhibition (ICI) [abstract]. J Clin Oncol 2021;39(6 Suppl):307.

Larkin JMG, Tykodi SS, Donskov F, et al. First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): updated follow-up for KEYNOTE-427 cohort A. Ann Oncol 2019;30(Suppl 5):v381–2, Abstract 949P.

Lee J-L, Ziobro M, Gafanov R, et al. KEYNOTE-427 cohort B: first-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (NCC-RCC). J Clin Oncol 2019;37(15 Suppl):4569.

Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol 2021;22:946–58. PubMed PMC

Grünwald V, McKay RR, Krajewski KM, et al. Depth of remission is a prognostic factor for survival in patients with metastatic renal cell carcinoma. Eur Urol 2015;67:952–8. PubMed PMC

Motzer R, Porta C, Alekseev B, et al. Health-related quality of life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib: a randomized phase 3 study (CLEAR trial). Lancet Oncol 2022;23: 768–80. PubMed PMC

Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol 2020;21: 1563–73. PubMed

Motzer RJ, Escudier B, McDermott DF, et al. Survival outcomes and independent response assessment with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma: 42-month follow-up of a randomized phase 3 clinical trial. J Immunother Cancer 2020;8:e000891. PubMed PMC

Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol 2021;39(15 Suppl):4500.

Haanen JBAG, Larkin J, Choueiri TK, et al. Efficacy of avelumabaxitinib (AAx) versus sunitinib (S) by IMDC risk group in advanced renal cell carcinoma (aRCC): extended follow-up results from JAVELIN Renal 101. J Clin Oncol 2021;39(15 Suppl):4574.

Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open 2020;5:e001079. PubMed PMC

Leary A, Larkin JM, Pickering LM. Cytokine therapy for renal cell cancer: the evolving role of immunomodulation. Therapy 2011;8: 347–58.

Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000;6(Suppl 1):S55–7. PubMed