Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study).

Abstract

269 Background: In pts with advanced RCC, second-line treatment with LEN + EVE prolonged progression-free survival (PFS) compared with EVE alone. LEN + PEMBRO, also showed preliminary efficacious evidence in a phase 1/2 RCC study. Here, we describe the investigational study results of first-line LEN + PEMBRO or LEN + EVE versus SUN in pts with advanced RCC. Methods: Pts were randomized (1:1:1) to receive LEN 20 mg orally once daily + PEMBRO 200 mg IV every 3 weeks (wks); or LEN 18 mg + EVE 5 mg orally once daily; or SUN 50 mg orally once daily (4 wks on/2 wks off). Eligible pts had advanced RCC with no prior systemic therapy. Randomization was stratified by geographic region and MSKCC prognostic group. The primary endpoint was PFS by Independent Review Committee per RECIST v1.1. Secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. A sequential approach was used to test PFS first, then OS and ORR. PFS and OS were compared across arms by a stratified log-rank test; hazard ratios (HRs) were estimated by a stratified Cox regression model. Results: 1069 pts were randomized (Table). After a median follow-up of 27 months (data cutoff August 28, 2020), PFS was significantly improved with LEN + PEMBRO (median 24 months [mos]) vs SUN (median 9 mos; HR 0.39, 95% CI 0.32–0.49) and LEN + EVE (median 15 mos) vs SUN (HR 0.65, 95% CI 0.53–0.80). OS was significantly longer with LEN + PEMBRO vs SUN (HR 0.66, 95% CI 0.49–0.88), whereas OS with LEN + EVE vs SUN was not statistically different (HR 1.15, 95% CI 0.88–1.50). ORR was significantly greater with LEN + PEMBRO (ORR 71%; complete response [CR] 16%) vs SUN (ORR 36%; CR 4%; odds ratio 4.35, 95% CI 3.16–5.97) and LEN + EVE (ORR 54%; CR 10%) vs SUN (odds ratio 2.15, 95% CI 1.57–2.93). Grade ≥3 treatment-related adverse events occurred in 72% of pts in the LEN + PEMBRO arm and 73% of pts in the LEN + EVE arm compared with 59% of pts in the SUN arm. Conclusions: LEN + PEMBRO demonstrated significant improvements in PFS, OS and ORR vs SUN. LEN + EVE demonstrated significant improvements in PFS and ORR vs SUN. Safety was manageable and consistent with the known single-agent profiles. Clinical trial information: NCT02811861 . [Table: see text]

Multi-Omics Analysis of the Anti-tumor Synergistic Mechanism and Potential Application of Immune Checkpoint Blockade Combined With Lenvatinib

“…We identified 412 original articles and 56 meeting abstracts during our electronic searches. After screening, four original articles and 12 conference abstracts met the criteria for inclusion in the meta-analysis ( Supplementary Figure 2 ; Fernandez et al, 2020 ; Finn et al, 2020 ; Haugen et al, 2020 ; Kawazoe et al, 2020 ; Kudo et al, 2020 ; Lee et al, 2020 ; Li et al, 2020 ; Lin et al, 2020 ; Lwin et al, 2020 ; Makker et al, 2020 ; Taylor et al, 2020 ; Chung, 2021 ; Gomez-Roca et al, 2021 ; Motzer et al, 2021 ; Villanueva, 2021 ). The key characteristics of the 15 included studies are presented in Table 1 .…”

Management of advanced kidney cancer: Kidney Cancer Research Network of Canada (KCRNC) consensus update 2021

“…The CLEAR study was a randomized, open-label, phase 3 study, that assessed the efficacy and safety of the two drug combinations of lenvatinib + pembrolizumab or lenvatinib + everolimus (mTOR inhibitor) compared to sunitinib as therapy in advanced RCC. 13,14 The 1069 patients (33% favorable-, 55% intermediate-, 10% poor-risk) enrolled in this study had clear-cell mRCC (including sarcomatoid features), no previous systemic therapy for mRCC, and any IMDC risk group. Patients were randomized (1:1:1) to receive either lenvatinib (20 mg orally daily) + pembrolizumab (200 mg IV every three weeks for up to 35 cycles) (n=355), lenvatinib (18 mg orally daily) + everolimus (5 mg orally daily) (n=357) or sunitinib (n=357).…”

“…Most participants felt that further maturity of the data was required to potentially recommend this as a firstline treatment and, at this time, lenvatinib + everolimus could not be recommended as a first-line option. 13,14 In the opinion of the participants at the consensus meeting, an initial period of observation (active surveillance) also remains a reasonable option in select patients, given that all available treatments can be associated with side effects, and that some patients may experience an indolent clinical course with stable or slow-growing, low-volume, and/or asymptomatic metastases or in patients with competing risks from other comorbidities. This is supported by prospective, observational data presented by Rini and colleagues.…”

“…The overall data are reported above. 13,14 On subgroup analysis, there was improved PFS and OS in the lenvatinib + pembrolizumab arm for IMDC intermediate-(HR 0.44 and 0.72) and poor-risk groups (HR 0.18 and 0.30), respectively, vs. sunitinib. 13…”

“…Two exceptions are the late addition of data from the CLEAR and PAPMET studies, which were presented at the ASCO Genitourinary Cancers Symposium on February 13, 2021 and concurrently published. [13][14][15][16] The results of these trials were reviewed by all co-authors and there was agreement to include the findings in this publication to ensure the most contemporary document and recommendations possible. As new data become available, treatment options will invariably change, and members of the KCRNC intend to update these recommendations on a regular basis moving forward.…”