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KOL Pulse — Trial Profile

CLEAR / Study 307 / KEYNOTE-581 Trial

1L advanced renal cell carcinoma (aRCC) — Merck / Eisai partnership

1L advanced renal cell carcinoma (aRCC)Lenvima + KeytrudaASCO GU 2021 / ASCO 2024 long-term update✓ FDA Approved (2021-08)
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At a Glance

CLEAR / Study 307 / KEYNOTE-581 Key Takeaways

Design - Multicenter, open-label, randomized Phase 3: lenvatinib + pembrolizumab (with a separate lenvatinib + everolimus arm) vs sunitinib in first-line advanced RCC across all IMDC risk groups (ASCO GU 2021 primary; ASCO 2024 long-term update).

Progression-free survival (primary) - Median PFS 23.9 months with lenvatinib + pembrolizumab vs 9.2 months with sunitinib (HR 0.47, 95% CI 0.38-0.57; final analysis; primary NEJM 2021 HR 0.39). ORR 71% vs 36%, with benefit across all IMDC risk categories.

Overall survival - Final OS analysis: median OS 53.7 vs 54.3 months, HR 0.79 (95% CI 0.63-0.99); 36-month OS 66.4% vs 60.2%. The counterintuitive medians reflect high crossover from the control arm; PFS and ORR remain the most robust efficacy signals.

Safety - Grade >=3 treatment-related AEs 72% vs 62% with sunitinib; most common were hypertension, diarrhea, and fatigue. Lenvatinib dose modifications were commonly required; no new safety signals in extended follow-up.

Regulatory / sponsor - FDA approved August 10, 2021: lenvatinib (Lenvima) + pembrolizumab (Keytruda) for first-line advanced RCC. Lead sponsor: Eisai, in partnership with Merck. 1L standard of care across all IMDC risk groups.

Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated August 19, 2026.

Influence Leaders

Top KOLs Discussing CLEAR / Study 307 / KEYNOTE-581

Yüksel Ürün
Yüksel Ürün
@DrYukselUrun
10.3K impressions
Sumanta K. Pal, MD, FASCO
Sumanta K. Pal, MD, FASCO
@montypal
4.1K impressions
The ASCO Post
The ASCO Post
@ASCOPost
1.4K impressions
Barts Experimental Cancer Medicine Centre
Barts Experimental Cancer Medicine Centre
@BartsECMC
1.2K impressions
HemOnc Today
HemOnc Today
@HemOncToday
633 impressions
Cristiane D Bergerot
Cristiane D Bergerot
@crisbergerot
562 impressions
Conference Presentations

CLEAR / Study 307 / KEYNOTE-581 Key Slides & Visuals

Official trial slides and relevant visuals shared by KOLs at ASCO GU 2021 / ASCO 2024 long-term update. Click any image to expand.

Yüksel Ürün
Yüksel Ürün @DrYukselUrun
CLEAR / Study 307 / KEYNOTE-581 Data
10.3K impressions · 79 likes · Apr 9, 2024
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CLEAR / Study 307 / KEYNOTE-581 conference slide — trial design schema and Kaplan-Meier survival data: Check for updates
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CLEAR / Study 307 / KEYNOTE-581 conference slide — trial design schema and Kaplan-Meier survival data: OS (probability)
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CLEAR / Study 307 / KEYNOTE-581 conference slide — trial design schema and Kaplan-Meier survival data: Intermediate
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CLEAR / Study 307 / KEYNOTE-581 conference slide — trial design schema and Kaplan-Meier survival data: Median DOR
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[Slide 1] Check for updates Clinical Trial Updates a Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study Robert J. Motzer, MD1 ID ; Camillo Porta, MD²,³; Masatoshi Eto, MD4; Thomas Powles, MD5 ID ; Viktor Grunwald, MD6 ID ; Thomas E. Hutson, MD7 ID Boris Alekseev, MD8; Sun Young Rha, MD9 ID ; Jaime Merchan, MD¹⁰ ID ; Jeffrey C. Goh, MD¹¹ ID ; Aly-Khan A. Lalani, MD¹² ID ; Ugo De Giorgi, MD¹³ ID ; Bohuslav Melichar, MD¹⁴; Sung-Hoo Hong, MD 15 ID : Howard Gurney, MD¹⁶ ID ; Maria Jose Méndez-Vidal, MD¹⁷ ID ; Evgeny Kopyltsov, MD¹⁸; Sergei Tjulandin, MD¹⁹ ID ; Teresa Alonso Gordoa, MD²⁰ ID ; Vadim Kozlov, MD²¹; Anna Alyasova, MD²²; Eric Winquist, MD²³ ID ; Pablo Maroto, MD²⁴; Miso Kim, MD25 ID : Avivit Peer, MD²⁶; Giuseppe Procopio, MD27 ID ; Toshio Takagi, MD,28; Shirley Wong, MD²⁹; Jens Bedke, MD³⁰ ID ; Manuela Schmidinger, MD³¹; Karla Rodriguez-Lopez, MD³²; Joseph Burgents, PhD³³; Cixin He, PhD³⁴; Chinyere E. Okpara, PhD³⁵ ID ; Jodi McKenzie, PhD³⁴ ID; and Toni K. Choueiri, MD³⁶ ID ; for the CLEAR Trial Investigators DOI https://doi.org/10.1200/JCO.23.01569. --- [Slide 2] A 1.0 0.9 80.4% 0.8 0.7 66.4% 69.6% OS (probability) 0.6 60.2% LEN + PEMBRO 0.5 0.4 Median OS, Months (95% CI) LEN + PEMBRO 0.3 53.7 (48.7 to NE) SUN SUN 54.3 (40.9 to NE) 0.2 HR (95% CI) 0.79 (0.63 to 0.99) 0.1 Nominal P .0424 0 + Censored 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) No. at risk: 355 338 313 296 269 245 216 158 117 34 5 0 357 308 264 242 226 208 188 145 108 33 3 0 B 1.0 0.9 0.8 Median PFS, Months (95% CI) LEN + PEMBRO 23.9 (20.8 to 27.7) 0.7 SUN 9.2 (6.0 to 11.0) PFS (probability) 0.6 HR (95% CI) 0.47 (0.38 to 0.57) 49.0% 0.5 Nominal P < .0001 37.3% 0.4 0.3 LEN + PEMBRO 23.4% 0.2 17.6% SUN 0.1 0 + Censored 0 6 12 18 24 30 36 42 48 54 60 Time (months) No. at risk: 355 276 213 161 128 99 81 49 25 4 0 357 145 85 59 41 30 23 12 7 1 0 --- [Slide 3] A Favorable Intermediate + Poor 1.0 1.0 91.3% 0.9 0.9 0.8 80.7% 0.8 75.5% 87.0% LEN + PEMBRO 0.7 0.7 OS (probability) 0.6 77.2% OS (probability) 0.6 60.1% 61.5% LEN + PEMBRO 0.5 0.5 0.4 SUN 0.4 49.0% Median OS, Months (95% CI) Median OS, Months (95% CI) 0.3 SUN LEN + PEMBRO NR (NE to NE) 0.3 LEN + PEMBRO 47.9 (40.5 to NE) 0.2 SUN 59.9 (58.8 to NE) 0.2 SUN 34.3 (26.3 to 54.3) 0.1 HR (95% CI) 0.94 (0.58 to 1.52) 0.1 HR (95% CI) 0.74 (0.57 to 0.96) 0 + Censored 0 + Censored 0 6 12 18 24 30 36 42 48 54 60 66 0 6 12 18 24 30 36 42 48 54 60 66 Time (months) Time (months) No. at risk: No. at risk: 110 106 101 98 92 83 76 57 42 11 2 0 243 230 210 196 176 161 139 101 75 23 3 0 124 115 107 102 98 95 88 65 46 15 2 0 229 190 155 138 127 112 99 79 61 18 1 0 B Favorable Intermediate + Poor 1.0 1.0 0.9 Median PFS, Months (95% CI) 0.9 Median PFS, Months (95% CI) LEN + PEMBRO 28.6 (17.2 to 37.0) LEN + PEMBRO 22.1 (16.6 to 27.6) 0.8 0.8 SUN 12.9 (11.1 to 18.4) SUN 5.9 (5.6 to 7.5) 0.7 HR (95% CI) 0.50 (0.35 to 0.71) 0.7 HR (95% CI) 0.43 (0.34 to 0.55) PFS (probability) 0.6 55.8% 0.5 42.2% PFS (probability) 0.6 0.5 46.4% 0.4 0.4 35.4% 33.1% LEN + PEMBRO 0.3 0.3 LEN+ PEMBRO 19.2% +++ 18.0% 0.2 17.1% +++++++++++++++ 0.2 SUN SUN 0.1 0.1 0 + Censored 0 + Censored 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 Time (months) Time (months) No. at risk: No. at risk: 110 91 77 54 48 38 29 16 11 3 0 243 184 136 107 80 61 52 33 14 1 0 124 68 48 30 22 12 9 6 4 1 0 229 75 37 29 19 18 14 6 3 0 0 --- [Slide 4] C 1.0 Median DOR, Months (95% CI) 0.9 LEN + PEMBRO 26.7 (22.8 to 34.6) SUN 14.7 (9.4 to 18.2) Continued Response (probability) 0.8 HR (95% CI) 0.57 (0.43 to 0.76) 0.7 0.6 55.6% 0.5 41.0% 0.4 32.3% 0.3 LEN PEMBRO 24.1% 0.2 SUN 0.1 0 + Censored 0 6 12 18 24 30 36 42 48 54 Time (months) No. at risk: 253 219 167 135 107 79 55 31 8 1 131 87 54 40 27 19 15 8 5 1 FIG 1. Kaplan-Meier plots of final analysis of (A) OS (unadjusted), (B) PFS by IIR per RECIST v1.1, and (C) duration of response by IIR per RECIST v1.1. The 95% Cls are estimated using a generalized Brookmeyer and Crowley method. HR is based on a Cox proportional hazards model including the treatment group as a factor; the Efron method (continued on following page)
Sumanta K. Pal, MD, FASCO
Sumanta K. Pal, MD, FASCO @montypal
CLEAR / Study 307 / KEYNOTE-581 Data
4.1K impressions · 29 likes · Jan 27, 2024
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CLEAR / Study 307 / KEYNOTE-581 conference slide — trial design schema and Kaplan-Meier survival data: not exceed a
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CLEAR / Study 307 / KEYNOTE-581 conference slide — trial design schema and Kaplan-Meier survival data: CheckMate YES
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CLEAR / Study 307 / KEYNOTE-581 conference slide — trial design schema and Kaplan-Meier survival data
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CLEAR / Study 307 / KEYNOTE-581 conference slide — trial design schema and Kaplan-Meier survival data: Best Overall
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[Slide 1] ty° safety not exceed a gression. 20 ASCO Genitourinary 24 Cancers Symposium #GU24 --- [Slide 2] CheckMate YES Efficacy by baseline organ sites of metastases PFS, os, and ORR favored NIVO+CABO versus SUN in subgroups by baseline organ sites of metastases shown here Livers.b Bonea,b Lung** Outcome NIVO+CABO SUN NIVO+CABO SUN NIVO+CABO SUN (n = 73) (n = 55) (n = 79) (n = 73) (n = 241) (n = 251) Median PFS (95% CI), mo 10.9 (7.0-15.2) 6.2 (2.9-8.3) 13.8 (8.3-20.1) 4.4 (3.8-8.2) 16.4 (12.3-21.4) 8.3 (6.9-9.7) HR (95% CI)c 0.54 (0.36-0.81) 0.45 (0.30-0.66) 0.56 (0.46-0.69) Median OS (95% CI), mo 37.6 (23.5-49.9) 22.1 (9.8-29.3) 34.8 (21.4-NE) 20.7 (12.5-25.7) 47.5 (40.6-56.1) 32.6 (24.9-39.7) HR (95% CI)c 0.62 (0.41-0.95) 0.57 (0.38-0.84) 0.73 (0.58-0.92) ORR (95% CI), % 52.1 (40.0-63.9) 21.8 (11.8-35.0) 49.4 (37.9-60.9) 9.6 (3.9-18.8) 57.3 (50.8-63.6) 28.3 (22.8-34.3) "An exploratory analysis of efficacy outcomes by baseline organ sites of metastases was conducted in the ITT population (prespecified for bone; post hoc for liver and lung). "Within each subgroup, all patients had metastasis within the specified site but may have had lesions in more than 1 site. Unstratified Cox proportional hazards model used for HR. --- [Slide 3] - - Safety Treatment-related AEs over time 100 " 12 MYOYES SUM 90 Any - 40 Grade 12 patients at risk (%)$*** 76 54 New events/ 8 50 55 42 " 2 on 11 30 71 17 20 12 13 12 17 7 $ / 3 10 10 DEAD I 1 I 1 1 10 LR 1 M.B. 0 . 126524 2410 626 4 $ . % : Time interval (months) No. - 547 135 (7) 471 445 406 173 112 117 161 17% 776 247 no 214 115 142 117 THE " NEVO-IP us Comparable overall rates of treatment-related AEs of any grade occurred with NIVO+IPI (94%) versus SUN (98%); however, fewer grade 2 3 treatment-related AEs were reported with NIVO+IPI (48%) compared with SUN (64%) - Treatment related AES leading to discontinuation of therapy occurred in 24% of patients with NIVO-IPI and 11% with SUMP - Deaths due to study drug toxicity occurred in 8 patients in the NIVO+IPI arm and 5 patients in the SUN arml or enset of new treatment related AD - time. Rates were calculated is - event) out of of all each patients interval. at na * at the may beginning - country of with - enternal, than - The acrive - preferred Bar chart AZ shows term the may occurrence be included at different related tetervals AEX if all collected intervals at after different 60 months that dates. was 12.76 - . patients includes at events the beginning reported in all treated patients - first door and $ - SUN, 30 intervals. days after incidence the last of dose grade of I study 3 treatment drug. *Among all treated " patients with $ years of follow RIVO-IPL - 209 patients had 1 grade $ event with ANO-PI and 1 patients had . grade - One death assigned to the SUN am occurred in a patient after pressever from SUN to --- [Slide 4] Best Overall Response by Tumor Size (Independent Imaging Review per RECIST v1.1) 100 25 90 11.1 8.0 22.5 29.6 80 Best overall response, % 24.7 70 CR 20.0 75.3 60 19.8 80.0 72.8 71.3 Overall ORR, % (65.9-84.7) (63.2-82.5) Near-CR (71.2-88.8) (61.3-81.2) (95% CI) 60.0 50 Other PR 40 37.0 so 25.9 37.5 30 PD 20 11.1 16.0 18.8 10 16.3 9.9 7.4 3.8 13 0 Q2 Q3 Q4 Q1 (≤ 34.72 mm) (> 34.72 to S 60.06 mm) (> 60.06 to ≤ 108.56 mm) A 108.56 mm) n 80 n = 81 n 80 with n baseline 81 target lesion assessments. 95% CI were calculated using asymptotic normal distribution."Near-CR" of refers to with partial unknown/not response with Includes maximum patients tumor shrinkage 2 75% "Other PR" refers to all other PRs (with maximum turnor shrinkage <75%). The number patients evaluable responses were: Q1, 1.2%; Q2, 2.5%; Q3, 6.2%; Q4, 6.3% Viktor Grünwald, MD, PhD ASCO - OMEN ASCO Genitourinary #GU24 PRESENTED or KNOWLEDGE CONGUERS CA enitourinary Symposium Cancers Symposium Presentation property ha author and ASCO Permission request M - unted
The ASCO Post
The ASCO Post @ASCOPost
CLEAR / Study 307 / KEYNOTE-581 Data
1.4K impressions · 10 likes · Mar 4, 2026
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CLEAR / Study 307 / KEYNOTE-581 conference slide — CLEAR / Study 307 / KEYNOTE-581 Data
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[Slide 1] a 0
Barts Experimental Cancer Medicine Centre
Barts Experimental Cancer Medicine Centre @BartsECMC
CLEAR / Study 307 / KEYNOTE-581 Data
1.2K impressions · 11 likes · Mar 3, 2026
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CLEAR / Study 307 / KEYNOTE-581 conference slide — Kaplan-Meier survival data and response data: POSTER BOARD
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[Slide 1] POSTER BOARD CONQUER CANCER THE F15 Merit Award Recipient KIM-1 in Papillary Renal Cell Carcinoma S. Coca Membribes, F. Jackson-Spence, W. Xu, C. Suárez, P. Patel, J. Larkin, B. Perez Valderrama, A. Rodriguez-Vida, MJ. Mendez Vidal, B. Szabados, E. Nally, C. Graham, G. Priyadarshini, F. Jamal, C. Ackerman, T. Powles Background In papillary RCC, median KIM-1 levels at baseline were higher compared to Kidney Injury Molecule-1 (KIM-1) has emerged as a clear cell RCC (p=0.05) and lower baseline levels correlated with promising biomarker in clear cell renal cell radiological response (p=0.025), suggesting KIM-1 as a potential carcinoma (RCC), but its role in papillary RCC remains unknown biomarker for monitoring treatment response in both subtypes. Methods Results KIM-1 reduction and negative ctDNA 25000 pgimL Dynamic changes in KIM-1 levels correlated with Papillary Durvalumab + Savolitinib Clear Cell 20000 were seen with treatment: A-32% response (p=0.016) in responders vs A-7% in non- 15000 responders and the greatest reduction was seen in MET-driven 10000 tumors (A-43%). 8 weeks (median) 5000 I 5226 KIM-1High at baseline showed 0 Baseline plasma On-treatment plasma Median IMDC IMDC IMDC Liver No liver shorter PFS and OS compared to KIM-1 available (n=31) KIM-1 available (n=19) Good Int Poor mets mets KIM-1Low ctDNA ctDN) negative positive Non-radiological responders Radiological responders 1. Primary objective: To determine whether KIM-1 levels in papillary RCC are raised. as observed in clear cell RCC 2. Secondary objectives: I : Progression Free Survival Overall Survival To assess associations between baseline $229 levels and clinical outcomes 3433 To explore on-treatment KIM-1 changes and ASCO correlate with radiological response Barts Health NHS Barts Baseline On-treatment Cancer Institute Queen Mary X @scocmem I University # I ASCO O
Cristiane D Bergerot
Cristiane D Bergerot @crisbergerot
CLEAR / Study 307 / KEYNOTE-581 Data
562 impressions · 6 likes · Feb 15, 2025
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CLEAR / Study 307 / KEYNOTE-581 conference slide — mechanism of action: Abstract No.
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[Slide 1] Abstract No. Analyses on Impact of Tumor Burden at Progression and Changes in IMDC From Baseline in Patients With 531 Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab in the Phase 3 CLEAR Trial Viktor Grünwald, Daniel Keizman, Jens Bedke,3 Michael D. Staehler," Vsevolod B. Matveev, Saby George, Thomas E. Hutson, Ulka N. Vaishampayan,® Jaime R. Merchan, Masatoshi Eto, Sun Young Rha," Tom Waddell, Roberto Sabbatini,¹ Philippe Barthelemy,* Joseph E. Burgents, Min Ren,16 lan Brown," Hakim Saal," Toni K. Choueiri," Robert J. Motzer University Hospital Essen Essen Germany: Sourasky Medical Center, Avic brant May SAN Center Kinkum Stuffgert Stuffgirt Germany: University Hospital Munich Munich, Germany: State Budgetary institution N.N. Biokhin National Medical Research the finistry Health the Мовсож Funk Park Cancer Instruction New York, USA Texas Tech University tealth Lubbock USA Roger Canc are University Ann ML USA University Mami Sylvester Comprehensive Cancer Center Miami, FL USA "Kyush University Fukuoka Japan incer Center, earn System Seoul South Korea VG Tust K Hospital of bay "Strasbourg University Hospital Strasbourg, Strasbourg France "Merck Co. Inc. Rahway, NJ, USA "Esal Nutley, NJ USA Esa Mattleid Cancer institute, Boston MA, Moan Kattering Cancer New YORK, INTRODUCTION RESULTS (continued) ' in the plus Twenty patients as the Most patients the I is fumor shirikage - received subsequent systemic anticancer medication inglut tree follow with time during 12 13 Table survival of 23. Patients with lower disease burden I an 12. 45% 13. 50%) as her first any the line renal - data from the of the The most used therapies I were (T1, 72. T3, auntinio 12% cell (T% 12. 3% T3. and axtint study numer to of 2 - the at progression showed improved prognosis (11, 72.3% 13. With tume during 06. and with lenvatinib with Table Medications During by From Baseire Target Lesion Diameters - Progression among of their at target with in the lenvatinib-plus-pembrolizumab arm by independent Review - RECIST The turnor lower time I or (% Percentage Change - Sum of All target Lesion Diamater's at from from I at the time . overall of CLEAR. At 6 months, IMDC risk 1% to 5 to 34% 34% received by N first unwal as quartle was - report Renal Cell scores/categories were typically constant Patients who received first subsequent systemic anticancer (37, (NE) Carcinoma Consortium basefine 37 (54.6) 42(71.2) during survival by received : first or improved in patients in the therapy 26 (44.8) 35 (59.3) medication uring time to treatment (01, of 13.2 lenvatinib-plus-pembrolizumab arm. 2(3.4) 5 (8.5) 13(22.0) 17 (29.3) 17 (28.8) 0.00 20.4) 000 METHODS 20.4 35.2) 1 (1.7) The study design of CLEAR has reported previously assessed according 1(1.7) 000 0.00 lesion 8 patients % on 7 (11.90 20.4) 12 (20.3) orally once plus 1 plus by I every I plus everolimus checkpoint nhibitor $(8.5) 5 (8.4) 7 (11.9) suntinb not here - I I | Quick 0.00 352) 000 The data cutoff for 31, (median I I - 000 000 10.7) Data here are to the of medications I 4(6.8) 20.4) 4(6.8) by lesion Medians for survival other progression or dameters by I 1(1.7) 000 20.4) were by and 95% per RECIST mTOR inhibitor: Everolimus 1 (1.7) 2 (3.4) 0 (0.0) (Cis) estimated via score 8 category are inhibitor: 3(5.1) 00.0) 0 (0.0) Other 1 (1.7) 1 (1.7) 0 (0.0) RESULTS - - a - - (b) I - - Gov. Identifier: I - I I - I I I I - Patients the am . Similar I I - target esion Figure median surv vival from time with smaler MDC the or from basefine MDC stayed the same improved furnor sue Figure 6. most patients 10% had increases MDC I regardless most patients Figure 4) KM From CONCLUSIONS of score baseline Time by Figure Figure Figure Target Sum-of the CLI EAR at Figure - Before in Figure Canegory to Baseline by imaging VT an by Review of the to Months per и 10 the when Plus - the and - i scores I or 70 anys, and with most, with E the seen months of patients i : # # Total . - the - - ASCO - - Baseline mategory Poster ABCO 2024 ! NJ. - I a name - - - NA than inc. - I 1 - i I 1 ! I I I USA a - - NJ USA - times I I MDC NOC Poster presented at: ASCO Genitourinary Cancers Symposium February 13-15, Francisco, CA, and Online
Community Discussion

CLEAR / Study 307 / KEYNOTE-581 Top Tweets

Top tweets by impressions — click to view on X

Yüksel Ürün
Yüksel Ürün@DrYukselUrun

Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study:
⭕️Final CLEAR trial results: Lenvatinib+pembrolizumab reduces mortality risk by 21% vs sunitinib in advanced RCC.
⭕️While…

👁 10.3K ♡ 79 ↻ 37 Apr 9, 2024
Sumanta K. Pal, MD, FASCO
Sumanta K. Pal, MD, FASCO@montypal

Always so useful to hear updates on pivotal P3 trials in #kidneycancer. Congrats to @BourlonMaite, Tannir &amp; Grunwald on terrific talks updated #CM9ER, #CM214 &amp; #CLEAR datasets. The #CM214…

👁 4.1K ♡ 29 ↻ 9 Jan 27, 2024
The ASCO Post
The ASCO Post@ASCOPost

🧬 Phase III LITESPARK-022: Adjuvant pembrolizumab + belzutifan improved disease-free survival vs pembrolizumab alone in high-risk clear cell #RCC post-nephrectomy.
➡️ 24-mo DFS: 80.7% vs 73.7%
➡️ HR…

👁 1.4K ♡ 10 ↻ 4 Mar 4, 2026
Barts Experimental Cancer Medicine Centre
Barts Experimental Cancer Medicine Centre@BartsECMC

Dr Sara Membribes @BartsECMC presented exploratory data on KIM-1, a promising new biomarker in papillary renal cancer. Baseline KIM-1 levels were higher than we’ve seen in advanced clear cell RCC…

👁 1.2K ♡ 11 ↻ 5 Mar 3, 2026
Cristiane D Bergerot
Cristiane D Bergerot@crisbergerot

Exploring the impact of tumor burden at progression &amp; IMDC changes in advanced RCC patients treated with lenvatinib + pembrolizumab in the phase 3 CLEAR trial. 📊💡 Key findings that could shape…

👁 562 ♡ 6 ↻ 3 Feb 15, 2025
OncUpdates
OncUpdates@OncUpdates

⭐️@ASCO #GU26 Insights: Radiotherapy + Immunotherapy in Metastatic Clear Cell RCC!

@MikeSerzanMD +@KalantriShreyas discuss #CYTOSHRINK!

❌ Did NOT improve PFS (primary endpoint)
🗣️ Biomarker…

👁 505 ♡ 7 ↻ 4 Mar 17, 2026
HemOnc Today
HemOnc Today@HemOncToday

🧑‍🤝‍🧑 Patients with clear cell #RenalCellCarcinoma who worsen after immunotherapy have many options.

Data from #ASCOGU26 @ASCO showed #belzutifan plus #lenvatinib @EisaiUS significantly improved PFS…

👁 279 ♡ 5 ↻ 0 Mar 10, 2026
Martha bel
Martha bel@martharbelie

Urology update(March 11, 2026)

LITESPARK-011: At the ASCO GU Symposium, Dr. Robert Motzer presented phase 3 results showing that a combination of belzutifan (Welireg) and lenvatinib improved…

👁 146 ♡ 2 ↻ 1 Mar 11, 2026
HemOnc Today
HemOnc Today@HemOncToday

👀 Adjuvant #pembrolizumab @KEYTRUDA plus #belzutifan @Merck improved disease-free survival 2️⃣8️⃣% for patients with clear cell #RenalCellCarcinoma, according to data presented at #ASCOGU26 @ASCO.

📈…

👁 136 ♡ 4 ↻ 1 Mar 10, 2026
HemOnc Today
HemOnc Today@HemOncToday

⏫ #Belzutifan @Merck plus #lenvatinib significantly improved PFS and response for patients with clear cell #RenalCellCarcinoma compared with #cabozantinib.

📊 @motzermd @MSKCancerCenter presented the…

👁 118 ♡ 3 ↻ 0 Mar 3, 2026
Trial Background

About the CLEAR / Study 307 / KEYNOTE-581 Trial

One of three IO-TKI combinations established as 1L standard for aRCC. Counterintuitive final OS (mOS 53.7 vs 54.3 mo; HR 0.79, CI 0.63-0.99) reflects high crossover in control arm — PFS benefit (HR 0.47) and ORR (71% vs 36%) remain robust. Selection among CLEAR, CheckMate-9ER (nivo+cabo), KEYNOTE-426 (axi+pembro) is individualized by IMDC risk and toxicity tolerability.

📄 NCT02811861 📄 Pivotal Publication
Regulatory Milestone

FDA Approval

FDA APPROVED Lenvima + Keytruda — Adults with advanced renal cell carcinoma (first-line).

FDA approval date: 2021-08-10.

📄 Source: FDA Press Release →
Study Design

Trial Methodology & Results

Progression-Free Survival (PFS) — Primary Endpoint

Median PFS was 23.9 months with lenvatinib+pembrolizumab vs. 9.2 months with sunitinib (HR 0.47, 95% CI 0.38-0.57). ORR: 71% vs. 36%. Highly significant benefit across all IMDC risk categories.

✓ mPFS 23.9 vs. 9.2 mo (HR 0.47)

📄 Source: KOL commentary on X →

Overall Survival (OS)

Final OS analysis: median OS 53.7 mo (lenva+pembro) vs. 54.3 mo (sunitinib) with HR 0.79 (95% CI 0.63-0.99). 36-month OS: 66.4% vs. 60.2%. The counterintuitive median OS reflects high crossover from the control arm; PFS and ORR benefits remain the most robust efficacy signals.


📄 Source →

Safety & Tolerability

Grade ≥3 treatment-related AEs occurred in 72% with lenva+pembro vs. 62% with sunitinib. Most common AEs: hypertension, diarrhea, fatigue. Lenvatinib dose modifications commonly required. No new safety signals in extended follow-up.

G≥3 TRAE: 72% vs. 62% (lenvatinib management required)

📄 Source →

Clinical Implications

✅ 1L standard of care for advanced RCC (all IMDC risk groups). One of three IO-TKI combinations established as 1L standard for aRCC. Counterintuitive final OS (mOS 53.7 vs 54.3 mo; HR 0.79, CI 0.63-0.99) reflects high crossover in control arm — PFS benefit (HR 0.47) and ORR (71% vs 36%) remain robust. Selection among CLEAR, CheckMate-9ER (nivo+cabo), KEYNOTE-426 (axi+pembro) is individualized by IMDC risk and toxicity tolerability.

Frequently Asked Questions

CLEAR / Study 307 / KEYNOTE-581 FAQ

What is the CLEAR trial?

CLEAR (also called Study 307 or KEYNOTE-581; NCT02811861) is a multicenter, open-label, randomized Phase 3 trial comparing lenvatinib plus pembrolizumab, and lenvatinib plus everolimus, against sunitinib in first-line advanced renal cell carcinoma. It was run by Eisai in partnership with Merck, with primary results at ASCO GU 2021 and a long-term update at ASCO 2024.

What did CLEAR show?

Lenvatinib + pembrolizumab delivered median PFS of 23.9 months vs 9.2 months with sunitinib (HR 0.47, 95% CI 0.38-0.57; final analysis; primary NEJM 2021 HR 0.39) and an ORR of 71% vs 36%, with benefit across all IMDC risk categories. The final OS analysis showed HR 0.79 (95% CI 0.63-0.99) with median OS 53.7 vs 54.3 months - medians confounded by high crossover from the control arm.

Is lenvatinib plus pembrolizumab FDA approved for kidney cancer?

Yes. On August 10, 2021 the FDA approved lenvatinib (Lenvima) in combination with pembrolizumab (Keytruda) for the first-line treatment of adult patients with advanced renal cell carcinoma, based on the CLEAR trial.

What is the safety profile of lenvatinib plus pembrolizumab in CLEAR?

Grade >=3 treatment-related adverse events occurred in 72% of the lenvatinib + pembrolizumab arm vs 62% with sunitinib. The most common AEs were hypertension, diarrhea, and fatigue, and lenvatinib dose modifications were commonly required. No new safety signals emerged in extended follow-up.

Why did median OS look similar between arms in CLEAR?

The final OS medians (53.7 vs 54.3 months) look counterintuitive because a large share of control-arm patients crossed over to subsequent therapy, diluting the between-arm difference; the OS hazard ratio still favored the combination (HR 0.79, 95% CI 0.63-0.99). The PFS benefit (HR 0.47) and ORR advantage (71% vs 36%) remain the most robust efficacy signals, and selection among CLEAR, CheckMate-9ER, and KEYNOTE-426 is individualized by IMDC risk and toxicity tolerability.

Major Media & Publications

CLEAR / Study 307 / KEYNOTE-581 in the News

Publication
Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma
NEJM (Motzer et al.)2021-04-08
 FDA
FDA Approves Lenvatinib plus Pembrolizumab for Advanced RCC
FDA.gov2021-08-10
 Publication
Final OS Analysis of CLEAR/KEYNOTE-581 (Grunwald et al.)
ASCO Post / January 20242024-01
 Publication
CLEAR Patterns of Progression (Grunwald ASCO 2024 poster)
ASCO 20242024
Physician Opinions

Key KOL Sentiments — CLEAR / Study 307 / KEYNOTE-581

DoctorSentimentComment
Sumanta K. Pal, MD, FASCO ● POSITIVE Always so useful to hear updates on pivotal P3 trials in #kidneycancer. Congrats to @BourlonMaite, Tannir &amp; Grunwald on terrific talks updated #CM9ER, #CM214 &amp; #CLEAR datasets. The #CM214 favorable risk data is particularly intriguing, but in general, the data today reinforces… https://t.co/FxE4YvfCin https://t.co/6DkITOjTGh
Yüksel Ürün ● NEUTRAL Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study: ⭕️Final CLEAR trial results: Lenvatinib+pembrolizumab reduces mortality risk by 21% vs sunitinib in advanced RCC. ⭕️While median OS is similar, the combo’s lower HR &amp; tight 95% CI underscore its robust… https://t.co/1QJtgWqtah https://t.co/Ddiao8tRSi
The ASCO Post ● NEUTRAL 🧬 Phase III LITESPARK-022: Adjuvant pembrolizumab + belzutifan improved disease-free survival vs pembrolizumab alone in high-risk clear cell #RCC post-nephrectomy. ➡️ 24-mo DFS: 80.7% vs 73.7% ➡️ HR = 0.72 (P = .0003) 🥼Presented by @DrChoueiri @ #GU26 🔗 https://t.co/FXsAbTL6Wu https://t.co/ujx6rfdGxc
Barts Experimental Cancer Medicine Centre ● NEUTRAL Dr Sara Membribes @BartsECMC presented exploratory data on KIM-1, a promising new biomarker in papillary renal cancer. Baseline KIM-1 levels were higher than we’ve seen in advanced clear cell RCC &amp; lower levels were seen in those who responded to treatment. ASCO #GU26 @scocmem https://t.co/MLxtGtWP6w
Cristiane D Bergerot ● NEUTRAL Exploring the impact of tumor burden at progression &amp; IMDC changes in advanced RCC patients treated with lenvatinib + pembrolizumab in the phase 3 CLEAR trial. 📊💡 Key findings that could shape future treatment strategies @ASCO #GU25! @ViktorGruenwald https://t.co/R5OCq5B0pI
OncUpdates ● NEUTRAL ⭐️@ASCO #GU26 Insights: Radiotherapy + Immunotherapy in Metastatic Clear Cell RCC! @MikeSerzanMD +@KalantriShreyas discuss #CYTOSHRINK! ❌ Did NOT improve PFS (primary endpoint) 🗣️ Biomarker Strategies (KIM-1) #OncTwitter #MedTwitter Full discussion👇 https://t.co/oF8K9BQXzS
HemOnc Today ● NEUTRAL 🧑‍🤝‍🧑 Patients with clear cell #RenalCellCarcinoma who worsen after immunotherapy have many options. Data from #ASCOGU26 @ASCO showed #belzutifan plus #lenvatinib @EisaiUS significantly improved PFS and response vs. #cabozantinib. https://t.co/cFJg6lq3nz
Martha bel ● NEUTRAL Urology update(March 11, 2026) LITESPARK-011: At the ASCO GU Symposium, Dr. Robert Motzer presented phase 3 results showing that a combination of belzutifan (Welireg) and lenvatinib improved outcomes for patients with advanced clear cell renal cell carcinoma (ccRCC) who had https://t.co/o87tVwJsxh
HemOnc Today ● NEUTRAL 👀 Adjuvant #pembrolizumab @KEYTRUDA plus #belzutifan @Merck improved disease-free survival 2️⃣8️⃣% for patients with clear cell #RenalCellCarcinoma, according to data presented at #ASCOGU26 @ASCO. 📈 Early data also favored overall survival. https://t.co/v7jEmb9Kcs
HemOnc Today ● NEUTRAL ⏫ #Belzutifan @Merck plus #lenvatinib significantly improved PFS and response for patients with clear cell #RenalCellCarcinoma compared with #cabozantinib. 📊 @motzermd @MSKCancerCenter presented the “remarkable” data at #ASCOGU26. https://t.co/iC3uRp0Du1
HemOnc Today ● NEUTRAL ➕ Adding #belzutifan @Merck to adjuvant #pembrolizumab significantly improved disease-free survival for clear cell #RenalCellCarcinoma. 📊 @DrChoueiri @DanaFarber @harvardmed presented the “clinically meaningful” data at #ASCOGU26. https://t.co/1YhpGyaR0f
MedJ ● NEUTRAL Updated phase 2 data presented at #ASCOGU26 suggest that first-line fruquintinib plus serplulimab may provide durable disease control with manageable toxicity in metastatic or unresectable non-clear cell renal cell carcinoma. Read Full Article: https://t.co/2gRDAGTJD5 #MedJ https://t.co/wRQQ9sdBFo
Alessandro Samuelly ● NEUTRAL Grouped updates for first line RCC for favorable risk diseases - more might not be better in some patients. https://t.co/2z5PuEvPO3
Alessandro Samuelly ● NEUTRAL The results, in addition to those from the CLEAR trial, show a need to improved selection of pts in the favourable risk, likely selecting for the combination tx only those within the group at a worse prognosis (e.g. brain mts , high mts burden beyond lung, symptomatic pts).
Julia Mitchell ● NEUTRAL @OncoAlert @GuardConsortium @mjuanfi81 LOOK! ctDNA clearance predicting survival! Precision oncology at its best. Clear parallels with how we use advanced imaging to guide treatment. Great work from our Spanish colleagues at #GU26 👍
Mirrors of Medicine ● NEUTRAL Phase 3 LITESPARK-022 trial Presented at #GU26 https://t.co/VgY98oyuIv The addition of belzutifan to one year of pembrolizumab after nephrectomy in patients with high-risk clear cell RCC significantly improved disease-free survival compared with pembrolizumab alone, https://t.co/jyVu2T1v5l
Martha bel ● NEUTRAL LITESPARK-011 (March 11): At the ASCO GU Symposium, Dr. Robert Motzer presented phase 3 results showing that a combination of belzutifan (Welireg) and lenvatinib improved outcomes for patients with advanced clear cell renal cell carcinoma (ccRCC) who had progressed on prior https://t.co/1bKjPHiEAg
MedJ ● NEUTRAL Two late-breaking trials presented at the #ASCOGU26 evaluated the HIF-2α inhibitor Belzutifan across the treatment continuum of clear cell renal cell carcinoma. In the phase 3 LITESPARK-011 and LITESPARK-022 studies, belzutifan-based combinations improved key time-to-event https://t.co/pHjD9SAWZz