CLEAR / Study 307 / KEYNOTE-581 Trial

[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)

[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

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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

[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