CCO Conference Highlights of ASCO GU 2021 CCO

CCO Conference Highlights of ASCO GU 2021 CCO Independent Conference Coverage* of the Virtual 2021 Genitourinary (GU) Cancers Symposium, February 11 -13, 2021 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from Astellas, Eisai, Merck Sharp & Dohme Corp. , and Seagen Inc.

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Faculty Robert Motzer, MD Attending Physician Memorial Sloan Kettering Cancer Center New York, New York Daniel P. Petrylak, MD Professor of Medicine, Medical Oncology Director, Prostate and GU Medical Oncology Director, Prostate Cancer Translational Research Group Yale Cancer Center New Haven, Connecticut

Faculty Disclosures The faculty reported the following financial relationships or relationships to products or devices they have with commercial interests related to the content of this CME/CE activity: Robert Motzer, MD, has disclosed that he has received consulting fees from Eisai, Exelixis, Genentech/Roche, Merck, and Pfizer and funds for research support from Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, Lilly Oncology, and Pfizer. Daniel P. Petrylak, MD, has disclosed that he has received consulting fees from Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, Astra. Zeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Exelixis, Incyte, Janssen, Lilly, Pfizer, Pharmacyclics, Roche, Seagen, and Urogen; has received funds for research support from Ada Cap (Advanced Accelerator Applications), Astellas, Astra. Zeneca, Bayer, Bristol-Myers Squibb, Clovis, Incyte, Genentech, Innocrin, Lilly, Med. Immune, Merck, Novartis, Pfizer, Progenics, Roche, Sanofi, Seagen; and has ownership interests in Bellicum and Tyme.

Urothelial Cancers

Check. Mate 274: Adjuvant Nivolumab vs Placebo After Radical Surgery ± Neoadjuvant CT in High-Risk MIUC § First analysis of international, randomized, double-blind phase III trial Stratified by PD-L 1 status (< vs ≥ 1%*), previous neoadjuvant cisplatin-based CT, nodal status Patients with high-risk MIUC; if yp. T 2 -yp. T 4 a or yp. N+, received neoadjuvant cisplatin CT; if p. T 3 -p. T 4 a or p. N+, did not receive neoadjuvant cisplatin CT and ineligible for/refused adjuvant cisplatin CT; underwent radical surgery ≤ 120 days; disease free within 4 wks of study dosing (N = 709) Nivolumab 240 mg IV Q 2 W (n = 351) § Primary endpoints: DFS is ITT population, DFS in all randomized patients with PD-L 1 ≥ 1% *Per PD-L 1 IHC 28 -8 Pharm. Dx assay. †OS data immature at time of analysis. Bajorin. ASCO GU 2021. Abstr 391. NCT 02632409. Placebo IV Q 2 W (n = 348) Treatment for up to 1 yr of adjuvant therapy § Secondary endpoints: nonurothelial tract recurrence-free survival, disease-specific survival, OS† § Exploratory endpoints: distant metastasis– free survival, safety, HRQo. L Slide credit: clinicaloptions. com

Check. Mate 274: Baseline Characteristics, Patient Disposition Parameter Nivolumab Placebo Parameter, % Nivolumab Placebo n = 353 n = 356 Characteristic n = 353 n = 356 65. 3 (30 -92) 65. 9 (42 -88) 75. 1 77. 2 13. 9 48. 2 22. 7 15. 3 14. 9 48. 0 20. 8 16. 3 22. 7 58. 4 16. 1 2. 5 24. 2 57. 3 17. 4 0. 8 47. 3 47. 2 63. 5 34. 6 2. 0 62. 1 35. 1 2. 5 27. 8 ECOG PS, % § 0 § 1 § 2* 26. 6 25. 8 24. 7 Tumor origin § Urinary bladder § Upper tract 79. 0 21. 0 78. 9 21. 1 Disposition n = 351 n = 348 Ongoing tx 6. 0 5. 7 Minor histological variants 41. 1 39. 6 Completed tx 40. 7 37. 9 PD-L 1 ≥ 1% 39. 7 39. 9 D/c tx 53. 3 56. 3 Previous neoadjuvant cisplatin 43. 3 43. 5 Characteristic Mean age, yrs (range) Male, % Region, % § § US Europe Asia Rest of world *ECOG PS of 2 only permitted in those without previous neoadjuvant cisplatin-based CT and ineligible for adjuvant cisplatin-based CT. Bajorin. ASCO GU 2021. Abstr 391. § p. T 0 -2 p. T 3 p. T 4 a Other Pathologic T stage at resection § § Nodal status at resection § N+ § N 0/x with < 10 nodes removed § N 0 with ≥ 10 nodes removed With nivolumab vs placebo, fewer d/c due to disease recurrence (25. 6% vs 42. 2%), more d/c due to study drug toxicity (14. 0% vs 2. 3%) Slide credit: clinicaloptions. com

Check. Mate 274: Efficacy Outcomes ITT Median, Mos DFS (primary endpoints) § HR for DFS NUTRFS § HR for NUTRFS DMFS § HR for DMFS PD-L 1 ≥ 1% Nivolumab (n = 353) Placebo (n = 356) Nivolumab (n = 140) Placebo (n = 142) 21. 0 10. 9 NR 10. 8 0. 70 (98. 31% CI: 0. 54 -0. 89); P <. 001 24. 6 13. 7 0. 72 (95% CI: 0. 58 -0. 89) 35. 0 29. 0 0. 74 (95% CI: 0. 58 -0. 93) 0. 53 (98. 87% CI: 0. 34 -0. 84); P <. 001 NR 10. 9 0. 54 (95% CI: 0. 38 -0. 77) NR 21. 2 0. 60 (95% CI: 0. 41 -0. 88) § Study met its primary endpoints: nivolumab significantly prolonged DFS vs placebo in the ITT population and patients with PD-L 1 ≥ 1% (both P <. 001) § Nivolumab prolonged DFS vs placebo in most subgroups of ITT population except for patients with initial tumor origin in renal pelvis (HR: 1. 16; 95% CI: 0. 63 -2. 13) and ureter (HR: 1. 55; 95% CI: 0. 70 -3. 45) Bajorin. ASCO GU 2021. Abstr 391. Slide credit: clinicaloptions. com

Check. Mate 274: Safety and HRQo. L Safety Outcome, % Nivolumab Any Gr Outcome Gr ≥ 3 Placebo Any Gr n = 351 Gr ≥ 3 n = 348 Select TRAE With Potential Inflammatory Mechanism Nivolumab (n = 351) Placebo (n = 348) Any Gr Gr ≥ 3 Any-cause AE 98. 9 42. 7 95. 4 36. 8 Skin 40. 7 17. 8 0 TRAE 77. 5 17. 9 55. 5 7. 2 Endocrine 19. 1 0. 3 3. 7 0 TRAE leading to d/c 12. 8 7. 1 2. 0 1. 4 Gastrointestinal 18. 5 1. 7 11. 2 0. 9 Hepatic 8. 3 1. 7 4. 9 0. 3 TRAE in ≥ 5% of Patients* Pruritus 23. 1 0 11. 5 0 Renal 7. 1 1. 1 3. 4 0 Fatigue 17. 4 0. 3 12. 1 0 Pulmonary 5. 4 1. 4† 1. 4 0 Diarrhea 16. 8 0. 9 10. 9 0. 3 Rash 15. 1 0. 6 5. 5 0 Lipase increase 9. 7 5. 1 5. 7 2. 6 Hypothyroidism 9. 7 0 1. 4 0 Amylase increase 9. 4 3. 7 5. 7 1. 4 Hyperthyroidism 9. 4 0 0. 9 0 Bajorin. ASCO GU 2021. Abstr 391. § Most common Gr ≥ 3 select TRAEs with nivolumab: 0. 9% each for diarrhea, colitis, pneumonitis; with placebo, colitis (0. 6%); 0. 3% each for diarrhea, GGT increase, hepatitis § No HRQo. L deterioration with nivolumab vs placebo *Also included asthenia, nausea, decreased appetite, blood creatinine increase, and maculopapular rash. † 1 patient with grade 4 pneumonitis; 1 grade 3 immune mediated with fatal outcome. Slide credit: clinicaloptions. com

EV-301: Enfortumab Vedotin vs Chemotherapy in LA or Metastatic UC After Platinum and Anti–PD-(L)1 Therapy § Interim analysis of international, randomized, open-label phase III trial of enfortumab vedotin, a Nectin-4–directed antibody–drug conjugate (data cutoff: July 15, 2020) Stratified by liver mets (yes vs no), ECOG PS (0 vs 1), region (US/Western Europe vs ROW) Patients with locally advanced or metastatic histology/cytology confirmed UC; previously treated with platinumcontaining CT*; radiographic progression or relapse on/after PD-(L)1 tx; ECOG PS ≤ 1 (N = 608) Enfortumab Vedotin 1. 25 mg/kg IV on Days 1, 8, 15 of 28 -day cycles (n = 301) Investigator’s choice of chemotherapy† (n = 307) *If used in the adjuvant/neoadjuvant setting, PD must be ≤ 12 of completion. †Standard docetaxel (75 mg/m 2), paclitaxel (175 mg/m 2), or vinflunine (320 mg/m 2) on Day 1 of each 21 -day cycle. § Primary endpoint: OS ‒ Interim analysis planned after 285 (65%) deaths, final analysis after 439 deaths Powles. ASCO GU 2021. Abstr 393. NCT 03474107. § Secondary endpoints: investigator-assessed PFS, DCR, and ORR (all per RECIST v 1. 1); safety Slide credit: clinicaloptions. com

EV-301: Baseline Characteristics, Patient Disposition Enfortumab Vedotin (n = 301) Chemotherapy (n = 307) Median age, yrs 68 68 Male, % 79 76 42 42 14 44 60 60 67 30 68 31 31 31 87 13 88 12 20 16 Characteristic Region, % § Western Europe § US § Rest of world ECOG PS 1, % Bellmunt risk score, % § 0 -1 § ≤ 2 Liver mets, % No. of previous lines of systemic tx, % § 1 -2 § ≥ 3 Response to prior ICI, % Powles. ASCO GU 2021. Abstr 393. Enfortumab Vedotin (n = 301) Chemotherapy (n = 307) Deaths, n 134 167 Received study tx, % 98 95 Median tx exposure, mos (range) 5. 0 (0. 5 -19. 4) 3. 5 (0. 2 -15. 0) Median follow-up, mos (95% CI) 11. 1 (10. 4 -11. 9) 11. 1 (10. 0 -12. 1) 81 59 14 5 2 93 59 15 9 7 Disposition Treatment discontinuation, % § PD § TEAE § Patient withdrawal § Physician decision Slide credit: clinicaloptions. com

EV-301: Efficacy Outcomes Outcome Median, mos OS (primary endpoint) § HR for OS PFS § HR for PFS Response, % Enfortumab Vedotin Chemotherapy n = 301 n = 307 12. 88 8. 97 0. 70 (95% CI: 0. 56 -0. 89; P =. 00142) 5. 55 3. 71 0. 62 (95% CI: 0. 51 -0. 75; P <. 00001) n = 288 n = 296 Confirmed ORR § CR § PR 40. 6* 4. 9 35. 8 17. 9* 2. 7 15. 2 DCR 71. 9* 53. 4* *P <. 001 Powles. ASCO GU 2021. Abstr 393. § Interim analysis met its primary endpoint of significantly improved OS with enfortumab vedotin vs chemotherapy (P =. 00142) ‒ OS favored enfortumab vedotin across all subgroups except women (HR: 1. 17; 95% CI: 0. 721. 89) § Investigator-assessed PFS, ORR, and DCR all significantly improved with enfortumab vedotin vs chemotherapy Slide credit: clinicaloptions. com

EV-301: TRAEs Any-Grade TRAE in ≥ 20% or Grade ≥ 3 TRAE in ≥ 5% of Patients, % Enfortumab Vedotin (n = 296) Chemotherapy (n = 291) All Gr Gr ≥ 3 Nausea 23 1 22 1 Rash maculopapular 16 7 2 0 Anemia 12 3 20 8 0 Neutrophil count decreased 10 6 17 13 23 5 Neutropenia 7 5 8 6 3 23 2 24 3 17 2 White blood cell decreased 5 1 11 7 24 0 7 0 Febrile neutropenia 1 1 6 6 All Gr Gr ≥ 3 Any 94 51 92 50 Alopecia 45 0 36 0 Peripheral sensory neuropathy 34 3 21 2 Pruritus 32 1 5 Fatigue 31 6 Decreased appetite 31 Diarrhea Dysgeusia § Comparable rates with enfortumab vedotin vs chemotherapy for any-grade serious AEs (23% vs 23%) and any-grade TRAEs leading to treatment withdrawal (14% vs 11%) Powles. ASCO GU 2021. Abstr 393. Slide credit: clinicaloptions. com

EV-301: AEs of Special Interest TRAE, % Enfortumab Vedotin (n = 296) Chemotherapy (n = 291) All Grades Grade ≥ 3 Skin reactions § Rash § Severe cutaneous adverse reactions 47 44 20 15 15 5 16 10 8 1 0* 1 Peripheral neuropathy § Sensory § Motor 46 44 7 5 4 2 31 30 2 2 2 0 Hyperglycemia 6 4 0* 0 *Occurred in 1 patient. § Most TRAEs of special interest were mild to moderate in severity Powles. ASCO GU 2021. Abstr 393. Slide credit: clinicaloptions. com

EV-201 Cohort 2: Enfortumab Vedotin in Cisplatin. Ineligible Patients With UC and Prior PD-(L)1 Inhibitor § International, open-label, single-arm, multicohort phase II trial Patients with previously treated locally advanced or metastatic UC who had previous PD-(L)1 tx; no ongoing grade ≥ 2 sensory or motor neuropathy, active CNS metastases, or uncontrolled DM (N = 219) Cohort 1 Prior PD-(L)1 inhibitor and platinum-based tx (n = 125)* Enfortumab vedotin 1. 25 mg/kg IV on Days 1, 8, 15 of each 28 -day cycles Cohort 2 Prior PD-(L)1 inhibitor, cisplatin ineligible, no prior platinum (n = 89)† Enfortumab vedotin 1. 25 mg/kg IV on Days 1, 8, 15 of each 28 -day cycles Current analysis *3 additional patients enrolled who did not receive enfortumab vedotin; 1 patient decision to d/c, 1 clinical deterioration, and 1 with low hemoglobin. † 2 additional patients enrolled who did not receive enfortumab vedotin due to hospital admission for progressive disease and to enter hospice care, respectively. § Primary endpoint: confirmed ORR per BICR (RECIST v 1. 1) Balar. ASCO GU 2021. Abstr 394. NCT 03219333. § Secondary endpoints: Do. R, PFS, OS, safety Slide credit: clinicaloptions. com

EV-201 Cohort 2: Patient Disposition Characteristic, n (%) Cohort 2 (N = 89*) § Data cutoff for primary analysis September 8, 2020 Patients treated with enfortumab vedotin § Discontinued treatment § On treatment 89 (100) 73 (82) 16 (18) § Median follow-up: 13. 4 mos Reasons for discontinuation § PD § AE § Patient decision § Physician decision 45 (51) 21 (24) 6 (7) 1 (1) Study discontinuation § Death § Withdrawal by patient 44 (49) 3 (3) In follow-up for progression or survival 26 (29) § Maximum time on treatment: 24. 6 mos § Median time on treatment: 6 mos (range: 0. 3 -24. 6) *Analysis based on 89 patients enrolled and 89 treated: 2 patients did not receive enfortumab vedotin due to hospital admission for PD and to enter hospice care, respectively. Balar. ASCO GU 2021. Abstr 394. Slide credit: clinicaloptions. com

EV-201 Cohort 2: Baseline Characteristics Characteristic Median age, yrs (range) Cohort 2 (N = 89) 75 (49 -90) Male, n (%) 66 (74) ECOG PS, n (%) § 0/1 § 2 78 (88) 11 (12) BMI ≥ 30 kg/m 2, n (%) 13 (15) Renal function, n (%) § Normal/mild decrease (Cr. Cl ≥ 60 m. L/min) § Moderate decrease (Cr. Cl ≥ 30 to < 60 m. L/min) § Severe decrease (Cr. Cl ≥ 15 to < 30 m. L/min) Balar. ASCO GU 2021. Abstr 394. 27 (30) 60 (67) 2 (2) Characteristic, n (%) Cohort 2 (N = 89) Primary tumor location § Upper tract* § Bladder/other 38 (43) 51 (57) Metastasis sites § LN only § Visceral disease† • Liver 18 (20) 70 (79) 21 (24) Received PD-(L)1 tx in first line 88 (99) Responded‡ to PD-(L)1 tx 22 (25) *Includes renal pelvis and ureter. †Sites of visceral disease included liver, lung, intrathoracic, or intra-abdominal soft tissue, kidney, spleen, ovary, adrenal glands, and bone. ‡Responses were reported by investigator. Slide credit: clinicaloptions. com

H-Score of Nectin-4 Expression at BL EV-201 Cohort 2: Nectin-4 Expression 300 275 250 225 § Median H-score for Nectin-4 levels by IHC of biopsies: 275 (range: 0 -300)* 200 175 150 125 100 75 50 25 0 Individual Patients (n = 80) *H-score = [% of strongly positive tumor cells x 3] + [% of moderately positive tumor cells x 2] + [% of weakly positive tumor cells x 1], where 0 = no expression and 300 = maximum possible expression. Balar. ASCO GU 2021. Abstr 394. Reproduced with permission. Slide credit: clinicaloptions. com

EV-201 Cohort 2: Response per BICR, % Confirmed ORR (primary endpoint) Cohort 2 (N = 89) 52 Best overall response* § CR § PR § SD § PD § NE† 20 31 30 9 9 Median TTR, mos (IQR) 1. 81 (1. 68 -1. 87) *According to RECIST v 1. 1. , with CR and PR confirmed by repeat scans ≥ 28 days after initial response. †Includes 5 patients who did not have response assessment post-BL, 2 whose BL assessment did not meet the minimum interval requirement for SD, and 1 patient whose response cannot be assessed due to incomplete anatomy. Balar. ASCO GU 2021. Abstr 394. § Responses observed in all subgroups ‒ Included those with primary tumor site in upper tract (ORR: 61%), with liver metastasis (48%), and who did not respond to prior PD-(L)1 tx (48%) § Higher ORR (64%) observed in those who responded to prior PD-(L)1 tx Slide credit: clinicaloptions. com

EV-201 Cohort 2: Change in Tumor Measurements (BICR) 100 Change From BL in Sum of Target Lesion Diameter (%) 80 60 40 § 88% of assessable patients had a decrease in tumor measurements from baseline 20 0 -20 -40 -60 -80 -100 Individual Patients (n = 77)* *Data not available for 12 patients due to lack of response assessment after BL (n =5), incomplete assessment of target lesion after BL (n = 1), or no measurable disease at BL per BICR (n = 6). Balar. ASCO GU 2021. Abstr 394. Reproduced with permission. Slide credit: clinicaloptions. com

EV-201 Cohort 2: Duration of Response* 100 Do. R Probability (%) 90 80 Events Median Do. R, Mos 20 10. 9 (95% CI: 5. 78 -NR) Responders without PD or death (n = 46) 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Mos Patients at Risk, n 46 45 *Per BICR. 41 36 30 29 23 19 16 14 12 Balar. ASCO GU 2021. Abstr 394. Reproduced with permission. 8 6 6 3 1 1 1 Slide credit: clinicaloptions. com

EV-201 Cohort 2: PFS and OS PFS* 90 Patients (N = 89) PFS Probability (%) 80 70 60 56 Median PFS, Mos 100 5. 8 (95% CI: 5. 03 -8. 28) 80 5. 8 mos 50 40 30 60 *Per BICR. Balar. ASCO GU 2021. Abstr 394. Reproduced with permission. 14. 7 (95% CI: 10. 51 -18. 20) 30 10 Mos 44 40 10 Patients at Risk, n 89 84 73 69 52 47 35 44 26 22 16 14 13 7 6 6 3 2 2 1 1 Median OS, Mos 14. 7 mos 50 20 0 1 2 3 4 5 6 7 8 9 10 111213 14151617 18 192021 2223 24 Patients (N = 89) 70 20 0 OS Events 90 OS Probability (%) PFS Events 100 OS 0 0 Patients at Risk, n 89 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Mos 82 75 73 58 45 37 21 13 9 7 6 3 1 1 Slide credit: clinicaloptions. com

EV-201 Cohort 2: TRAEs Common Any-Grade and/or High-Grade TRAE, * n (%) Cohort 2 (N = 89) Any Grade ≥ 3 Alopecia 45 (51) -- Peripheral sensory neuropathy 42 (47) 3 (3) Fatigue 30 (34) 6 (7) Decreased appetite 29 (33) 5 (6) Pruritus 27 (30) 3 (3) Rash maculopapular 27 (30) 7 (8) Dysgeusia 24 (27) -- Weight decreased 23 (26) 1 (1) Anemia 22 (25) 5 (6) Diarrhea 20 (22) 5 (6) Nausea 20 (22) 1 (1) Neutropenia 11 (12) 8 (9) Hyperglycemia 8 (9) 5 (6) Lipase increased 7 (8) 5 (6) Balar. ASCO GU 2021. Abstr 394. § TRAEs in 97% of patients (grade ≥ 3 in 55%) § 4 deaths considered treatment-related ‒ n = 1 each of acute kidney injury, metabolic acidosis, multiple organ dysfunction syndrome, pneumonitis ‒ 3/4 deaths within 30 days of first dose; all 3 patients had BMI ≥ 30 kg/m 2 ‒ All 4 deaths occurred in patients aged ≥ 75 yrs, with comorbidities § TRAEs led to d/c in 16% of patients ‒ Most commonly peripheral sensory neuropathy (4%) *Any grade in ≥ 20% or grade ≥ 3 in ≥ 5% of patients. Slide credit: clinicaloptions. com

EV-201 Cohort 2: TRAEs of Special Interest Skin reactions PN Hyperglycemia Cohort 2 § Any grade, % 61 § Grade ≥ 3, % 17 § Median onset, mos 0. 5 § Resolution/improvement, % 80 § Any grade, % 54 § Grade ≥ 3, % 8 § Median onset, mos 2. 4 § Resolution/improvement, % 56 § Any grade, % 10 § Grade ≥ 3, % 6 § Median onset, mos 0. 5 § Resolution/improvement, % 89 Balar. ASCO GU 2021. Abstr 394. § No grade 5 skin reactions, 1 grade 4 event § 13 patients had severe cutaneous adverse reactions; mostly low grade (no grade 4/5 events) ‒ Grade 3 events: 1 each of stomatitis, skin exfoliation, dermatitis bullous, dermatitis exfoliative generalized ‒ Led to 1 discontinuation § PN rates comparable in those with vs without preexisting PN (53% vs 54%) § Hyperglycemia more common in those with vs without preexisting hyperglycemia (20% vs 7%), with BMI ≥ vs < 30 kg/m 2 (23% vs 8%) Slide credit: clinicaloptions. com

Urothelial Cancer Studies: Summary § Check. Mate 274: compared with placebo, adjuvant nivolumab significantly prolonged DFS in high-risk MIUC, both in ITT and patients with PD-L 1 ≥ 1%, with no HRQo. L deterioration observed[1] § EV-301: enfortumab vedotin significantly improved OS, PFS, and ORR vs chemotherapy in previously treated (platinum CT) patients with advanced UC [2] ‒ OS favored enfortumab vedotin across all patient subgroups with a 30% reduction in risk of death in the overall patient population § EV-201 Cohort 2: in cisplatin-ineligible patients with LA/metastatic UC previously treated with a PD-(L)1 inhibitor, enfortumab vedotin yields an ORR between 48% and 61%, including in patients with upper tract tumors, with liver metastases, and no previous response to PD-(L)1 treatment[3] 1. Bajorin. ASCO GU 2021. Abstr 391. 2. Powles. ASCO GU 2021. Abstr 393. 3. Balar. ASCO GU 2021. Abstr 394. Slide credit: clinicaloptions. com

Prostate Cancer

KEYNOTE-365 Cohort B: Pembrolizumab + Docetaxel in Pretreated Patients With m. CRPC § Multicohort, nonrandomized, open-label phase Ib/II study[1 -3]*† ‒ After a median of 13 mo follow-up, pembro + docetaxel and prednisone showed activity (ORR: 18%; DCR: 51%) in patients with m. CRPC who failed previous antihormonal therapy [1] ‒ This analysis reports 1 additional yr of follow-up for KEYNOTE-365 Cohort B [3] Patients with m. CRPC and PD ≤ 6 mos before screening; failed or intolerant of ≥ 4 wks treatment with either abiraterone or enzalutamide (not both); no previous chemotherapy (N = 104) Pembrolizumab 200 mg + Docetaxel 75 mg/m 2 Q 3 W + Prednisone 5 mg BID Imaging assessments every 9 wks through Wk 54 and every 12 wks thereafter until PD; PSA assessed every 3 wks until PD § Coprimary endpoints: Safety, PSA response rate, ORR by RECIST v 1. 1 (BICR) § Key secondary endpoints: DCR, radiographic PFS by PCWG-modified RECIST v 1. 1, OS *Other cohorts include: Cohort A, with pembrolizumab plus Olaparib; Cohort C, of pembrolizumab plus enzalutamide; and Cohort D, of pembrolizumab plus prednisone. †Median time from enrollment to data cutoff: 32. 4 mos. 1. Kolinsky. ASCO GU 2020. Abstr 103. 2. NCT 02861573. 3. Appleman. ASCO GU 2021. Abstr 10. Slide credit: clinicaloptions. com

KEYNOTE-365 Cohort B: Baseline Characteristics Characteristic Median age, yrs (range) § < 65 yrs § ≥ 65 yrs Patients (n = 104) 68 (50 -86) 26. 0 74. 0 ECOG PS 0, % 53. 8 RECIST 1. 1 measurable by BICR, % § Yes § No 50. 0 Visceral disease in soft tissue, % § Yes § No 25. 0 75. 0 PD-L 1 status by IHC 22 C 3 assay, % § Positive § Negative § Unknown 23. 1 73. 1 3. 8 Appleman. ASCO GU 2021. Abstr 10. Slide credit: clinicaloptions. com

KEYNOTE-365 Cohort B: ORR and PSA Response Best Response Measurable Disease (n = 52) Nonmeasurable Disease (n = 52) All Patients (n = 104) ORR, % (95% CI) 23. 1 (12. 5 -36. 8) NA NA DCR, % (95% CI) 73. 1 (59. 0 -84. 4) 78. 8 (65. 3 -88. 9) 76. 0 (66. 6 -83. 8) 0 23. 1 50. 0 0 28. 8 26. 9 NA NA 0 78. 8 55. 8 21. 2 NA NA 25. 0 39. 4 42. 3 24. 0 Measurable Disease* (n = 51) Nonmeasurable Disease* (n = 52) All Patients (n = 103) 27. 5 40. 4 34. 0 Confirmed best response, % § CR § PR § SD of any duration § Non-CR/non-PD § SD or non-CR/non-PD ≥ 6 mos § PD PSA Response Confirmed PSA response rate (≥ 50% reduction), % *Per RECIST. Appleman. ASCO GU 2021. Abstr 10. Slide credit: clinicaloptions. com

KEYNOTE-365 Cohort B: r. PFS and OS Outcome Patients (n = 104) r. PFS § Median r. PFS, mos (95% CI) 8. 5 (8. 3 -10. 1) § 6 -mo r. PFS, % 76. 9 § 12 -mo r. PFS, % 26. 2 OS § Median OS, mos (95% CI) 20. 2 (16. 9 -24. 2) § 6 -mo OS, % 96. 2 § 12 -mo OS, % 75. 9 Appleman. ASCO GU 2021. Abstr 10. Slide credit: clinicaloptions. com

KEYNOTE-365 Cohort B: Safety Patients (n = 104) TRAE in ≥ 10% of Patients, % Any Grade 3 -5 Diarrhea 41. 3 2. 9 Fatigue 41. 3 Alopecia Immune-Mediated AEs and Infusion Reactions, % Patients (n = 104) Any Grade 3 -5 Any 32. 7 8. 7 2. 9 Infusion reaction 9. 6 0. 0 40. 4 0. 0 Hyperthyroidism 8. 7 0. 0 Dysgeusia 26. 9 0. 0 Pneumonitis 7. 7 3. 8 Nausea 26. 0 0. 0 Colitis 5. 8 3. 8 Peripheral neuropathy 22. 1 0. 0 Hypothyroidism 5. 8 0. 0 Asthenia 21. 2 1. 9 Adrenal insufficiency 1. 0 0. 0 Anemia 18. 3 4. 8 Severe skin reaction 1. 0 Decreased appetite 15. 4 0. 0 Peripheral edema 14. 4 1. 0 Mucosal inflammation 12. 5 0. 0 Febrile neutropenia 11. 5 Dyspepsia 10. 6 0. 0 Paresthesia 10. 6 0. 0 Appleman. ASCO GU 2021. Abstr 10. § There were 2 treatment-related deaths due to pneumonitis § Mean treatment duration was 7. 7 mos (range: 0. 9 -23. 5 mos) Slide credit: clinicaloptions. com

Check. Mate 9 KD Arm B: Nivolumab + Docetaxel in Chemotherapy-Naive m. CRPC § Multiarm, open-label, phase II study[1 -3] Patients with chemotherapy-naive m. CRPC; eligible for docetaxel; ongoing ADT or bilateral orchiectomy; mandatory tumor tissue (< 5 yrs old); ≤ 2 previous novel anti-androgen therapies; ECOG PS 0/1; (N = 84) Nivolumab 360 mg + Docetaxel 75 mg/m 2 Q 3 W + Prednisone 5 mg BID For ≤ 10 cycles Nivolumab 480 mg Q 4 W Up to 2 yrs, or until PD, or unacceptable toxicity § Coprimary endpoints: ORR per investigator, * PSA response rate (≥ 50% decrease from baseline PSA) ‒ Previous interim report showed encouraging efficacy for nivolumab in combination with docetaxel with no new safety signals[2] ‒ The current analysis reports results for nivolumab plus docetaxel with a larger patient sample and longer follow-up[3] § Key secondary endpoints: radiographic PFS, OS, TTR, Do. R, time to PSA progression, safety *By PCWG 3 criteria in treated patients with measurable disease. 1. NCT 03338790. 2. Fizazi. ESMO 2019. Abstr LBA 52. 3. Fizazi. ASCO GU 2021. Abstr 12. Slide credit: clinicaloptions. com

Check. Mate 9 KD Arm B: Baseline Characteristics and Patient Disposition Characteristic Median age, yrs (range) ECOG PS 1, n (%) Gleason score, n (%) § ≤ 7 § >7 § Missing Patients (N = 84) Characteristic, n (%) Patients (N = 84) 71 (53─88) Measurable disease 45 (53. 6) Previous cancer surgery 40 (47. 6) Prior radiotherapy 54 (64. 3) Previous novel antiandrogen therapy § Abiraterone only § Enzalutamide only § Abiraterone and enzalutamide § Apalutamide only 54 (64. 3) 17 (20. 2) 24 (28. 6) 12 (14. 3) 1 (1. 2) 48 (57. 1) 33 (39. 3) 49 (58. 3) 2 (2. 4) Median time since diagnosis, yrs (range) 4. 6 (0. 3 -47. 7) Median PSA, ng/m. L (range) 49. 5 (1. 2 -1085. 0) Presence of visceral metastases, n (%) § Yes § Not reported Fizazi. ASCO GU 2021. Abstr 12. 23 (27. 4) 59 (70. 2) 2 (2. 4) § Median follow-up: 15. 2 mos § Median number of nivolumab and docetaxel doses were 11 and 8, respectively § 76 patients had d/c treatment by July 2020 ─ 50 (59. 5%) due to PD; 15 (17. 9%) due to toxicity ─ 8 (9. 5%) remained on treatment at the time of analysis Slide credit: clinicaloptions. com

Check. Mate 9 KD Arm B: ORR and PSA Response Objective Response* ORR, % (95% CI) Best overall response, n (%) § CR § PR § SD § PD PSA Response† Confirmed PSA response rate, % (95% CI) All Patients (n = 45) No Prior NAT (n = 14) Prior NAT (n = 31) 40. 0 (25. 7 -55. 7) 42. 9 (17. 7 -71. 1) 38. 7 (21. 8 -57. 8) 1 (2. 2) 17 (37. 8) 24 (53. 3) 3 (6. 7) 0 6 (42. 9) 7 (50. 0) 1 (7. 1) 1 (3. 2) 11 (35. 5) 17 (54. 8) 2 (6. 5) All Patients (n = 81) No Prior NAT (n = 28) Prior NAT (n = 53) 46. 9 (35. 7 -58. 3) 60. 7 (40. 6 -78. 5) 39. 6 (26. 5 -54. 0) *Confirmed CR or PR per PCWG 3 in patients with measurable disease at BL. †Represents patient with PSA response ≥ 50% decrease from BL to lowest post-BL PSA result, with a second consecutive value obtained after ≥ 3 wks for confirmation of PSA response. § Among the 18 objective responders, median TTR was 2. 0 mos and median Do. R was 7. 0 mos § Among the 81 PSA-evaluable patients, median time to PSA progression was 8. 7 mos (95% CI: 7. 3 -10. 4) Fizazi. ASCO GU 2021. Abstr 12. Slide credit: clinicaloptions. com

Change From BL in Sum of Target Lesion Diameter (%) Check. Mate 9 KD Arm B: Maximum Tumor Size Change From BL 60 n = 44† 40 Prior NAT status No prior NAT Prior NAT 20 0 -20 * -40 -60 * * * †Patients * * *Confirmed objective responders (CR or PR). -80 -100 * * * * * with measurable target lesion at BL and ≥ 1 on-treatment tumor assessment; 1 patients lacked tumor change data. § A reduction from BL in the sum of diameters of target lesions was observed in 35/44 evaluable patients (79. 5%) § Median tumor size change from BL for all patients was -32. 1% § Tumor shrinkage and PCWG 3 response observed in patients with or without previous NAT treatment Fizazi. ASCO GU 2021. Abstr 12. Reproduced with permission. Slide credit: clinicaloptions. com

Maximum Change in PSA From BL (%) Check. Mate 9 KD Arm B: Maximum PSA Change From BL -100 80 60 40 20 0 -20 -40 -60 -80 -100 n = 81† * ** *** †Patients Prior NAT status No prior NAT Prior NAT ** *Confirmed PSA responders ***** with BL PSA and ≥ 1 post-BL assessment. ** * *** ** ***** § A reduction from baseline in PSA was observed in 68/81 evaluable patients (84. 0%) § Median PSA change from baseline for all patients was -54. 6% § PSA reduction/response observed in patients with or without previous NAT treatment Fizazi. ASCO GU 2021. Abstr 12. Reproduced with permission. Slide credit: clinicaloptions. com

Check. Mate 9 KD Arm B: Radiographic PFS and OS No Prior NAT (n = 30) Prior NAT (n = 54) Events, n 61 19 42 Events, n Median r. PFS, mos 9. 0 12. 0 8. 5 Median OS, mos Radiographic PFS 1. 0 All patients No prior NAT Prior NAT 0. 8 0. 6 51% 0. 4 36% 0. 2 26% 0 Patients at Risk, n All patients No prior NAT Prior NAT OS Probability (%) Radiographic PFS Probability (%) All Patients (N = 84) 0 84 30 54 3 73 27 46 6 54 21 33 9 37 18 19 12 Mos 22 13 9 Fizazi. ASCO GU 2021. Abstr 12. Reproduced with permission. 15 15 9 6 18 7 5 2 No Prior NAT (n = 30) Prior NAT (n = 54) 44 11 33 18. 2 NR 16. 2 OS 1. 0 All patients No prior NAT Prior NAT 70% 69% 0. 8 69% 0. 6 0. 4 0. 2 0 21 0 0 0 All Patients (N = 84) Patients at Risk, n All patients No prior NAT Prior NAT 0 3 6 9 84 30 54 83 29 54 73 24 49 64 21 43 12 15 18 21 24 27 Mos 55 19 36 44 19 25 26 15 11 7 5 2 2 1 1 0 0 0 Slide credit: clinicaloptions. com

Check. Mate 9 KD Arm B: Safety TRAE in ≥ 10% of Patients, n (%) Patients (N = 84) Any Grade 3/4 Rash 15 (17. 9) 2 (2. 4) 4 (4. 8) Peripheral edema 15 (17. 9) 0. 0 30 (35. 7) 4 (4. 8) Asthenia 12 (14. 3) 3 (3. 6) Alopecia 29 (34. 5) 0. 0 Dysgeusia 12 (14. 3) 0. 0 Nausea 25 (29. 8) 1 (1. 2) Pneumonitis 11 (13. 1) 4 (4. 8) Anemia 20 (23. 8) 3 (3. 6) Dyspnea 11 (13. 1) 2 (2. 4) Peripheral neuropathy 20 (23. 8) 0. 0 Constipation 10 (11. 9) 1 (1. 2) Decreased appetite 16 (19. 0) 0. 0 Cough 9 (10. 7) 1 (1. 2) Neutropenia 15 (17. 9) 14 (16. 7) Any Grade 3/4 Any 80 (95. 2) 40 (47. 6) Fatigue 33 (39. 3) Diarrhea § Grade 3/4 TRAEs of interest reported: GI, 7. 1%; pulmonary, 4. 8%; skin related, 3. 6%; hepatic, 1. 2%; endocrine, 0%; and renal 0% Fizazi. ASCO GU 2021. Abstr 12. § Discontinuation due to TRAEs (any grade) with 1 or both drugs occurred in 29. 8% of patients and grade 3/4 TRAEs led to discontinuation in 14. 3% of patients § There were 3 treatment-related deaths: 1 case of pneumonitis related to nivolumab and 2 cases of pneumonia related to docetaxel Slide credit: clinicaloptions. com

ACIS: Apalutamide + Abiraterone vs Placebo + Abiraterone in Chemotherapy-Naive m. CRPC § Randomized, double-blind, placebo-controlled phase III trial Stratified by visceral metastases (presence vs absence), ECOG PS (0 vs 1), region (North America/Europe vs rest of world) Patients with m. CRPC progressed on ADT; ECOG PS 0/1; pain score (BPI-SF) ≤ 3; no previous 1: 1 systemic therapy for CRPC (N = 982) § Primary endpoint: radiographic PFS (by investigators) Rathkopf. ASCO GU 2021. Abstr 9. NCT 02257736 Apalutamide 240 mg QD + Abiraterone 1000 mg QD + Prednisone 5 mg BID (n = 492) Placebo + Abiraterone 1000 mg QD + Prednisone 5 mg BID (n = 490) 28 -day cycles until PD, withdrawal of consent, or unacceptable toxicity; patients received ongoing ADT § Secondary endpoints: OS, time to chemotherapy, time to pain progression, time to chronic opioid use § Exploratory endpoints: time to clinical progression, time to first subsequent anticancer therapy, time to second PFS, decline in PSA level, time to PSA progression, subgroup analysis, PRO, safety Slide credit: clinicaloptions. com

ACIS: Baseline Characteristics Characteristic Median age, yrs (range) ECOG PS 0, % Gleason score at diagnosis, % § ≤ 7 § >7 § Unknown Median PSA, ng/m. L (range) Site of disease, % § Bone § Lymph node § Soft tissue § Visceral § Liver § Lung Metastasis stage at diagnosis, % Rathkopf. ASCO GU 2021. Abstr 9. § M 0 § M 1 § Unknown Apalutamide + Abiraterone (n = 492) Placebo + Abiraterone (n = 490) 71 (46 -91) 71 (48 -92) 68. 3 68. 0 42. 6 53. 0 4. 5 41. 5 52. 8 5. 7 32. 3 (1 -6051) 31. 2 (1 -8246) 83. 2 48. 2 12. 3 15. 2 4. 3 10. 9 86. 9 47. 2 13. 6 14. 2 4. 1 10. 3 46. 7 33. 5 19. 8 41. 9 35. 1 23. 0 Slide credit: clinicaloptions. com

ACIS: r. PFS (Primary Endpoint) Outcome Apalutamide + Abiraterone (n = 492) Placebo + Abiraterone (n = 490) 22. 6 16. 6 r. PFS* with median follow-up of 25. 7 mos § Median r. PFS, mos § HR (95% CI) 0. 69 (0. 58 -0. 83); P <. 0001 r. PFS with median follow-up of 54. 8 mos § Median r. PFS, mos § HR (95% CI) 24. 0 16. 6 0. 70 (0. 60 -0. 83) *r. PFS benefit was observed across prespecified subgroups including patients with visceral metastases and who were ≥ 75 yrs of age. Rathkopf. ASCO GU 2021. Abstr 9. Slide credit: clinicaloptions. com

ACIS: Other Endpoints Apalutamide + Abiraterone (n = 492) Placebo + Abiraterone (n = 490) HR (95% CI) P Value Secondary endpoint § OS § Initiation of chemotherapy § Chronic opioid use § Pain progression 36. 2 36. 1 47. 0 21. 8 33. 7 34. 2 53. 3 26. 5 0. 95 (0. 81 -1. 11) 0. 94 (0. 78 -1. 13) 1. 07 (0. 87 -1. 32) 1. 12 (0. 95 -1. 33) . 498. 509. 500. 188 Exploratory endpoint § Clinical progression § First subsequent therapy § Second PFS 16. 0 25. 6 31. 8 18. 1 23. 5 30. 2 1. 10 (0. 96 -1. 27) 0. 96 (0. 82 -1. 13) 0. 92 (0. 78 -1. 08) . 185. 630. 309 Median Time to Endpoint, Mos Rathkopf. ASCO GU 2021. Abstr 9. Slide credit: clinicaloptions. com

ACIS: PSA Outcomes Apalutamide + Abiraterone (n = 492) Placebo + Abiraterone (n = 490) RR or HR (95% CI) P Value Confirmed decline of ≥ 50% in PSA level 391 (79. 5) 357 (72. 9) RR: 1. 09 (1. 02 -1. 17) . 015 Undetectable PSA (< 0. 2 ng/m. L) at any time during treatment 121 (24. 6) 94 (19. 2) RR: 1. 28 (1. 01 -1. 62) . 040 13. 8 12. 0 HR: 0. 87 (0. 74 -1. 02) . 076 Outcome, n (%) Median time to PSA progression, mos Rathkopf. ASCO GU 2021. Abstr 9. Slide credit: clinicaloptions. com

ACIS: Safety TEAE, % Any TEAE* § SAE § TEAE leading to discontinuation Apalutamide + Abiraterone (n = 490) Placebo + Abiraterone (n = 489) Any Grade 3/4 98. 8 39. 2 16. 9 63. 3 37. 3 9. 4 96. 7 33. 7 12. 5 56. 2 31. 1 6. 3 TEAE of special interest § Fatigue 43. 5 4. 7 37. 4 3. 9 § Hypertension 32. 2 20. 6 26. 6 12. 5 § Fall 21. 8 3. 3 19. 0 0. 6 § Skin rash 20. 6 4. 5 10. 0 0. 4 § Cardiac disorders 19. 0 19. 2 5. 7 § Hypokalemia 16. 1 3. 5 15. 1 4. 1 § Peripheral edema 18. 8 0. 2 19. 0 0. 8 § Fracture and osteoporosis 15. 1 4. 1 12. 1 1. 4 § Ischemic cerebrovascular disorders 1. 8 0. 6 2. 9 1. 2 § Seizures 0. 6 0. 2 0 *Grade 5 TEAEs occurred in 3. 5% of patients receiving apalutamide + abiraterone and in 7. 6% of patients receiving placebo + abiraterone. Rathkopf. ASCO GU 2021. Abstr 9. Slide credit: clinicaloptions. com

SPARTAN: Apalutamide vs Placebo in nm. CRPC § Multicenter, randomized, double-blind, placebo-controlled phase III trial [1 -3] ‒ Current analysis aims to identify molecular signatures in patients with long-term response vs early progression[3] Stratified by PSADT (≤ 6 vs > 6 mos), bonesparing agent use (yes or no), N 0 vs N 1 Patients with nm. CRPC (pelvic nodes < 2 cm below iliac bifurcation allowed) and PSADT ≤ 10 mos (N = 1207) Apalutamide 240 mg QD + ADT (n = 806) 2: 1 Placebo + ADT (n = 401) § Primary endpoint: MFS ‒ After a median follow-up of 20. 3 mos, median MFS was 40. 5 mos for apalutamide + ADT and 16. 2 with placebo + ADT (HR: 0. 28; P <. 001)[1] 1. Smith. NEJM. 2018; 378: 1408. 2. NCT 01946204. 3. Feng. ASCO GU 2021. Abstr 8. Upon distant metastasis, treatment for m. CRPC at discretion of treating physician Crossover allowed after unblinding if no PD § Key secondary endpoints: time to metastasis, PFS, time to symptomatic progression, OS, time to chemotherapy, PFS 2, TTPP Slide credit: clinicaloptions. com

SPARTAN Biomarker Analysis: Methods § Patients in both arms were divided into quartiles based on number and timing of metastatic events ‒ LTR: patients without progression or who reached metastatic event later (fourth quartile) ‒ EP: patients who had a metastatic event in the first quartile § Tumor samples from 233 patients went through transcriptome analysis and were characterized based on expression of predefined molecular signatures § Signatures associated with response and resistance to each treatment were identified by parallel methods of analysis Feng. ASCO GU 2021. Abstr 8. Slide credit: clinicaloptions. com

SPARTAN Biomarker Analysis: Baseline Characteristics Characteristic Apalutamide (n = 60) Placebo (n = 37) EP (n = 21) LTR (n = 39) P Value EP (n = 17) LTR (n = 20) P Value Median age, yrs (range) 73 (67 -79) 72 (64 -76) . 352 74 (67 -77) 76 (71 -81) . 205 Median ALP, U/L (range) 75 (70 -93) 79 (64 -98) . 969 82 (80 -89) 80 (71 -90) . 572 Median testosterone, nmol/L (range) 0. 50 (0. 40 -1. 30) 1. 00 (0. 55 -1. 25) . 167 0. 80 (0. 50 -1. 20) 0. 80 (0. 48 -1. 00) . 736 8 (3 -13) 10 (5 -24) . 423 15 (7 -28) 12 (3 -18) . 656 Media PSA, ng/m. L (range) Median PSADT, n (%) § ≤ 6 mos § > 6 mos 15 (71) 6 (29) 28 (72) 11 (28) ECOG PS 0, n (%) 20 (95) 34 (87) >. 999 . 412 13 (76) 4 (24) 12 (60) 8 (40) 13 (76) 15 (75) . 475 >. 999 § No significant differences between the biomarker cohort and the overall ITT population Feng. ASCO GU 2021. Abstr 8. Slide credit: clinicaloptions. com

SPARTAN Biomarker Analysis: Results § In the apalutamide arm, increased immune activity, decreased vascularization or proliferative capacity were associated with LTR ‒ None of these signatures was associated with LTR in the placebo arm § Increased expression of signatures suggestive of T-cell proliferation was associated with longer MFS in the apalutamide arm (HR: 0. 43; 95% CI: 0. 21 -0. 86; P =. 0180) but not in the placebo arm (HR: 1. 10; 95% CI: 0. 57 -2. 11; P =. 7825) § Luminal tumors have longer MFS than basal tumors treated with apalutamide (HR: 0. 40; 95% CI: 0. 18 -0. 91; P =. 0295) ‒ Basal tumors with high T-cell proliferation have similar MFS to luminal tumors treated with apalutamide ‒ Basal tumors with low T-cell proliferation have significantly lower MFS compared with luminal or T-cell high tumors (P =. 0013) Feng. ASCO GU 2021. Abstr 8. Slide credit: clinicaloptions. com

Prostate Cancer Studies: Summary § KEYNOTE-365 Cohort B: after one additional yr of follow-up, the combination of pembrolizumab with docetaxel and prednisone continues to show promising antitumor activity in previously treated m. CRPC[1] ‒ ORR: 23. 1%; DCR: 73. 1%; median radiographic PFS: 8. 5 mos; median OS: 20. 2 mos § Check. Mate 9 KD Arm B: nivolumab with docetaxel and prednisone showed promising antitumor activity in a larger number of patients with chemotherapy-naive m. CRPC; authors suggest immunerelated AEs should be carefully monitored for this combination[2] ‒ ORR: 40. 0%; median radiographic PFS: 9. 0 mos; median OS: 18. 2 mos; 3 grade 5 AEs: 1 related to nivolumab (pneumonitis) and 2 related to docetaxel (pneumonia) § ACIS: treatment with apalutamide plus abiraterone and prednisone yielded a 31% reduction in risk of radiographic PFS compared with abiraterone plus placebo[3] § SPARTAN Biomarker Analysis: authors suggested patients may experience long-term benefit from APA + ADT if their tumors are associated with features of immune activity, hormone dependence, or lower proliferation at baseline[4] 1. Appleman. ASCO GU 2021. Abstr 10. 2. Fizazi. ASCO GU 2021. Abstr 12. 3. Rathkopf. ASCO GU 2021. Abstr 9. 4. Feng. ASCO GU 2021. Abstr 8. Slide credit: clinicaloptions. com

Kidney Cancer

CLEAR: First-line Lenvatinib + Pembrolizumab or Everolimus vs Sunitinib in Advanced RCC § Multicenter, randomized, open-label phase III trial Stratified by region (Western Europe and North America vs rest of the world), MSKCC risk category (favorable vs intermediate vs poor) Patients with treatmentnaive advanced clear-cell RCC; Karnofsky PS ≥ 70; with measurable disease, adequate organ function, and no CNS mets (N = 1069) Lenvatinib 20 mg PO QD + Pembrolizumab* 200 mg IV Q 3 W (n = 355) Lenvatinib 18 mg PO QD + Everolimus 5 mg PO QD (n = 357) Sunitinib 50 mg PO QD 4 wks on/2 wks off (n = 357) Cutoff for this final PFS and interim OS analyses: August 28, 2020 § Median follow-up: 27 mos § Analysis at ~ 338 PFS events for 90% power and a 2 -sided α =. 045 *Patients could receive a maximum of 35 pembrolizumab doses. § Primary endpoint: PFS by IRC (per RECIST v 1. 1) Motzer. ASCO GU 2021. Abstr 269. NCT 02811861. § Secondary endpoints: OS, ORR by IRC (per RECIST v 1. 1), safety, HRQo. L § Key exploratory endpoints: Do. R, biomarkers Slide credit: clinicaloptions. com

CLEAR: Baseline Characteristics Lenvatinib + Pembrolizumab (n = 355) Lenvatinib + Everolimus (n = 357) Sunitinib (n = 357) Median age, yrs (range) 64 (34 -88) 62 (32 -86) 61 (29 -82) Region, % § Western Europe and North America 55. 8 56. 0 55. 7 MSKCC prognostic risk group, % § Favorable/intermediate/poor 27. 0/63. 9/9. 0 27. 5/63. 6/9. 0 27. 2/63. 9/9. 0 IMDC risk group, % § Favorable/intermediate/poor 31. 0/59. 2/9. 3 31. 9/54. 6/11. 8 34. 7/53. 8/10. 4 7. 9 6. 7 5. 9 30. 1/31. 5/38. 3 32. 5/33. 1/34. 5 33. 3/28. 9/37. 8 73. 8 72. 8 77. 0 Characteristic Sarcomatoid features, % PD-L 1 expression level, % § ≥ 1%/< 1%/not available Previous nephrectomy, % Motzer. ASCO GU 2021. Abstr 269. Slide credit: clinicaloptions. com

CLEAR: PFS Probability (%) 100 LEN + PEMBRO vs SUN: HR: 0. 39 (95% CI: 0. 32 -0. 49; P <. 001) LEN + EVE vs SUN: HR: 0. 65 (95% CI: 0. 53 -0. 80; P <. 001) 80 60 LEN + PEMBRO 40 20 Median PFS, Mos (95% Cl) LEN + PEMBRO 23. 9 (20. 8 -27. 7) LEN + EVE 14. 7 (11. 1 -6. 7) SUN 9. 2 (6. 0 -11. 0) 0 0 4 Patients at Risk, n 355 357 300 259 218 LEN + EVE SUN 8 12 16 259 185 124 213 149 85 160 105 62 20 24 28 32 36 40 126 70 42 80 37 25 30 13 9 6 3 2 1 0 0 0 Mos § The PFS benefits of LEN + PEMBRO or LEN + EVE vs SUN were observed across all patient subgroups Motzer. ASCO GU 2021. Abstr 269. Reproduced with permission. *By Independent Review Committee per RECISTv 1. 1. Slide credit: clinicaloptions. com

CLEAR: OS OS Probability (%) 100 80 60 LEN + EVE 40 LEN + PEMBRO vs SUN: HR: 0. 66 (95% CI: 0. 49 -0. 88; P =. 005) Median OS, Mos (95% Cl) LEN + PEMBRO NR (33. 6 -NE) LEN + EVE NR (NE) SUN NR (NE) 20 0 SUN LEN + PEMBRO 0 3 6 Patients at Risk, n 355 357 342 346 332 338 321 307 9 12 LEN + EVE vs SUN: HR: 1. 15 (95% CI: 0. 88 -1. 50; P =. 3) 15 18 21 24 27 30 33 36 39 42 45 48 10 8 7 2 2 2 0 0 2 1 0 51 Mos 327 299 289 313 277 264 280 246 236 Motzer. ASCO GU 2021. Abstr 269. Reproduced with permission. 253 205 207 222 183 186 188 154 160 129 109 112 66 46 60 26 22 25 Slide credit: clinicaloptions. com

CLEAR: OS in Patient Subgroups Subgroup Overall Age < 65 yrs ≥ 65 yrs Sex Male Female Geographic region Western Europe and NA Rest of the World PD-L 1 expression ≥ 1 <1 IMDC risk group Favorable Intermediate Poor Prior nephrectomy Yes No Sarcomatoid features Yes No LEN + PEMBRO SUN Events/no. of patients HR (95% Cl) 80/355 101/357 0. 66 (0. 49 -0. 88) 41/194 39/161 57/225 44/132 0. 63 (0. 41 -0. 95) 0. 61 (0. 40 -0. 95) 59/255 21/100 71/275 30/82 0. 70 (0. 49 -0. 99) 0. 54 (0. 30 -0. 94) 46/198 34/157 57/199 44/158 0. 68 (0. 46 -1. 00) 0. 63 (0. 40 -0. 99) 28/107 21/112 36/119 31/103 0. 76 (0. 46 -1. 27) 0. 50 (0. 28 -0. 89) 14/110 56/210 10/33 15/124 60/192 25/37 1. 15 (0. 55 -2. 40) 0. 72 (0. 50 -1. 05) 0. 30 (0. 14 -0. 64) 50/262 30/93 66/275 35/82 0. 71 (0. 49 -1. 03) 0. 52 (0. 31 -0. 86) 9/28 71/327 7/21 94/336 0. 91 (0. 32 -2. 58) 0. 64 (0. 47 -0. 87) 0. 1 Favors LEN + PEMBRO 1 2 Favors SUN § The OS benefit favored LEN + PEMBRO vs SUN across key subgroups except for IMDC favorable risk (HR: 1. 15; 95% CI: 0. 55 -2. 40) Motzer. ASCO GU 2021. Abstr 269. Reproduced with permission. Slide credit: clinicaloptions. com

CLEAR: ORR Outcome, % Lenvatinib + Pembrolizumab (n = 355) Lenvatinib + Everolimus (n = 357) Sunitinib (n = 357) ORR* (95% CI) 71. 0 (66. 3 -75. 7) 53. 5 (48. 3 -58. 7) 36. 1 (31. 2 -41. 1) 16. 1 54. 9 19. 2 5. 4 4. 5 9. 8 43. 7 33. 6 7. 3 5. 6 4. 2 31. 9 38. 1 14. 0 11. 8 1. 97 (1. 69 -2. 29) <. 001 1. 48 (1. 26 -1. 74) <. 001 --- Best overall response § CR § PR § SD § PD § Unknown/not evaluable Relative risk vs sunitinib (95% CI) § P value *By IRC per RECIST. Motzer. ASCO GU 2021. Abstr 269. Slide credit: clinicaloptions. com

CLEAR: Do. R Probability (%) 100 80 60 40 Median DOR, Mos (95% Cl) LEN + PEMBRO 25. 8 (22. 1 -27. 9) LEN + EVE 16. 6 (14. 6 -20. 6) SUN 14. 6 (9. 4 -16. 7) 20 0 LEN + PEMBRO 0 4 LEN + EVE SUN 8 12 16 20 Mos 24 28 32 36 197 125 73 153 93 47 112 65 33 83 39 20 45 18 13 9 6 2 3 0 1 1 Patients at Risk, n 252 191 129 234 159 91 Motzer. ASCO GU 2021. Abstr 269. Reproduced with permission. 40 Slide credit: clinicaloptions. com

CLEAR: Treatment Exposure and Safety Lenvatinib + Pembrolizumab (n = 352) Lenvatinib + Everolimus (n = 355) Sunitinib (n = 340) 17. 0 (0. 1 -39. 1) 11. 0 (0. 1 -40. 0) 7. 8 (0. 1 -37. 0) Patients with any TRAEs, % § Grade ≥ 3* 96. 9 71. 6 97. 7 73. 0 92. 1 58. 8 Any TRAEs leading to dose reductions (LEN or SUN), % 67. 3 69. 3 49. 7 18. 5 25. 0 9. 7 16. 1 19. 2 13. 5 10. 0 --- Outcome Median duration of treatment, mos (range) Any TRAEs leading to discontinuation, % § LEN or SUN § PEMBRO or EVE § LEN + PEMBRO or LEN + EVE *Grade 5 TRAEs were observed in 1. 1% of patients in the LEN + PEMBRO arm, 0. 8% in the LEN + EVE arm, and 0. 3% in the SUN arm. Motzer. ASCO GU 2021. Abstr 269. Slide credit: clinicaloptions. com

CLEAR: TRAEs in ≥ 20% of Patients (LEN + PEMBRO vs SUN) LEN + PEMBRO Diarrhea 54. 5 8. 2 Hypertension 52. 3 Fatigue Hand–foot syndrome Decreased appetite 4. 4 17. 9 32. 1 1. 7 32. 1 28. 1 37. 4 26. 7 Proteinuria 27. 6 Dysgeusia 23. 2 3. 1 3. 8 4. 0 3. 2 3. 4 34. 9 32. 1 35. 9 1. 5 24. 7 27. 6 1. 7 0. 6 2. 9 12. 1 7. 4 10. 8 0. 3 Asthenia 20. 2 4. 5 Rash 21. 9 3. 4 24. 7 39. 1 2. 1 1. 1 0 42. 6 Nausea Dysphonia 44. 4 25. 3 Stomatitis Hypothyroidism* SUN 25. 9 3. 2 Grade ≥ 3 ‒ Grade 3 in 3. 1% of patients in LEN + PEMBRO arm vs 1. 8% in SUN arm § AST elevation observed in 9. 4% of patients with LEN + PEMBRO arm and in 8. 8% of patients in SUN arm ‒ Grade 3 in 2. 6% of patients in LEN + PEMBRO arm vs 0. 6% in SUN arm 15. 9 0. 6 10. 9 0 0 70 60 50 40 30 20 10 0 Any Grade § ALT elevation observed in 9. 7% of patients with LEN + PEMBRO arm and in 8. 8% of patients in SUN arm 2. 6 10 20 30 40 50 60 70 *Adverse event of interest for pembrolizumab Motzer. ASCO GU 2021. Abstr 269. Reproduced with permission. Slide credit: clinicaloptions. com

CLEAR: TRAEs in ≥ 20% of Patients (LEN + EVE vs SUN) LEN+EVE Diarrhea 59. 7 45. 6 Stomatitis Hypertension SUN 9. 6 4. 4 20. 8 17. 9 Fatigue 36. 6 5. 9 3. 8 Decreased appetite 34. 9 5. 1 1. 5 Nausea 30. 7 Hand–foot syndrome Hypothyroidism Proteinuria Dysgeusia 2. 3 22. 0 8. 2 Vomiting Rash 22. 0 Weight decreased Hypertriglyceridemia 22. 0 Dysphonia 22. 3 24. 7 35. 9 23. 2 2. 9 12. 1 0 0. 3 25. 9 0. 9 13. 2 2. 3 0. 6 10. 9 20. 6 32. 1 3. 2 0. 3 0 16. 6 39. 1 27. 6 0. 6 2. 8 24. 5 31. 8 37. 4 2. 1 6. 2 43. 1 44. 4 5. 9 0 20. 0 10. 1 Any Grade § ALT elevation observed in 10. 4% of patients with LEN + EVE arm and in 8. 8% of patients in SUN arm ‒ Grade 3 in 2. 1% of patients in LEN + PEMBRO arm vs 1. 8% in SUN arm § AST elevation observed in 11. 5% of patients with LEN + EVE arm and in 8. 8% of patients in SUN arm ‒ Grade 3 in 1. 4% of patients in LEN + PEMBRO arm vs 0. 6% in SUN arm Grade ≥ 3 5. 6 4. 1 6. 8 0. 6 0 2. 6 70 60 50 40 30 20 10 20 30 40 50 60 70 Motzer. ASCO GU 2021. Abstr 269. Reproduced with permission. Slide credit: clinicaloptions. com

KEYNOTE-426: Outcomes in Patients With RCC Completing 2 Yrs of Pembrolizumab + Axitinib § Randomized, open-label phase III trial[1 -3] Stratified by IMDC risk group (favorable vs intermediate vs poor), region (N. America vs W. Europe vs ROW) Patients with newly diagnosed/ recurrent stage IV clear-cell RCC with measurable disease; no prior systemic therapy for advanced disease (N = 861)[1 -3] Pembrolizumab 200 mg Q 3 W for up to 35 cycles + Axitinib 5 mg PO BID* (n = 432) Sunitinib 50 mg PO QD for first 4 wks of each 6 -wk cycle* (n = 429) § Dual primary endpoints: OS, PFS† ‒ Pembrolizumab + axitinib previously showed significant efficacy improvements vs sunitinib: OS, HR: 0. 68 (P <. 0003); PFS, HR: 0. 71 (P <. 0001); ORR: 60% vs 40% (P <. 0001); CR rate: 9% vs 3%[1] § Secondary endpoints: ORR, † DCR, Do. R, safety ‒ Current exploratory analyses describes outcomes in 103 patients who completed 2 yrs of pembrolizumab + axitinib but did not discontinue because of PD (completers)‡[2] *Dose could be increased to 7 mg then 10 mg BID or decreased to 3 mg, then 2 mg to manage toxicity. †Blinded independent central review per RECIST v 1. 1. ‡Data cutoff: January 6, 2020. 1. Powles. Lancet. 2020; 12: 1563. 2. Plimack. ASCO GU 2021. Abstr 327. 3. NCT 02853331. Slide credit: clinicaloptions. com

KEYNOTE-426 Subgroup Analysis: Baseline Characteristics All Pembrolizumab + Axitinib (n = 432) Completers (n = 103) Median age, yrs (range) § < 65 yrs, n (%) 62 (55 -68) 260 (60. 2) 61 (36 -82) 72 (69. 9) Male, n (%) 308 (71. 3) 76 (73. 8) Region, n (%) § North America § West Europe § Rest of world 104 (24. 1) 106 (24. 5) 222 (51. 4) 20 (19. 4) 23 (22. 3) 60 (58. 3) IMDC risk category, n (%) § Favorable § Intermediate § Poor 138 (31. 9) 238 (55. 1) 56 (13. 0) 36 (35. 0) 63 (61. 2) 4 (3. 9) ≥ 2 metastatic sites, n (%) 315 (72. 9) 66 (64. 1) Previous nephrectomy, n (%) 357 (82. 6) 92 (89. 3) Sarcomatoid features, n (%) 51 (11. 8) 17 (16. 5) PD-L 1 CPS ≥ 1, * n (%) 242 (56. 0) 56 (54. 4) Characteristic *Centrally assessed using PD-L 1 IHC 22 C 3 pharm. Dx assay. Plimack. ASCO GU 2021. Abstr 327. Slide credit: clinicaloptions. com

KEYNOTE-426 Subgroup Analysis: OS and PFS in Completers OS 100 PFS Probability (%) 100 OS Probability (%) PFS 94. 7% Median OS: NR 80 60 40 20 0 0 6 Patients at Risk, n 103 12 103 18 Mos 103 24 102 Plimack. ASCO GU 2021. Abstr 327. Reproduced with permission. 30 52 36 6 42 0 74. 8% 80 Median PFS: NR 60 40 20 0 0 6 12 18 Patients at Risk, 103 n 97 94 91 Mos 24 30 36 42 73 24 2 0 Slide credit: clinicaloptions. com

KEYNOTE-426 Subgroup Analysis: ORR and Safety in Completers Outcome, n (%; 95% CI) Completers (n = 103) ORR (CR + PR) 88 (85. 4; 77. 1 -91. 6) DCR (CR + PR + SD) 98 (95. 1; 89. 0 -98. 4) Best response § CR § PR § SD § PD† § NE‡ 16 (15. 5; 9. 1 -24. 0) 72 (69. 9; 60. 1 -78. 5) 11 (10. 7; 5. 5 -18. 3) 2 (1. 9; 0. 2 -6. 8) § All 103 patients (100%) experienced at least 1 treatment-related AE ‒ Grade 3/4 treatment-related AEs occurred in 62 patients (60. 2%) ‒ No patients died of a treatment-related AE § 15 patients (14. 6%) discontinued axitinib due to a treatment-related AE *Based on binomial exact CI method for binomial data. † 2 patients completed 2 yrs of pembrolizumab without PD and then continued axitinib after PD for 2 mos (n = 1) and 4 mos (n = 1). ‡Postbaseline assessments available; nonevaluable (eg, all postbaseline assessments with insufficient data for assessment of response per RECIST, version 1. 1, or CR, PR, or SD < 6 weeks from randomization). Plimack. ASCO GU 2021. Abstr 327. Slide credit: clinicaloptions. com

KEYNOTE-426 Subgroup Analysis: Univariate Analysis of Patients Most Likely to Complete 2 Yrs of Therapy Characteristic Odds Ratio (95% CI) P Value Sex § Male vs female 1. 18 (0. 71 -1. 94) . 522 Age group, yrs § < 65 vs ≥ 65 1. 74 (1. 08 -2. 80) . 022 Characteristic Odds Ratio (95% CI) P Value Metastases § Liver/bone vs other § Lung/LN vs other 1. 77 (0. 68 -4. 56) 1. 41 (0. 89 -2. 23) . 236 No. of organs with mets § 1 vs ≥ 2 1. 74 (1. 08 -2. 81) . 023 Sum of longest diameter of target lesion by tertiles § Lower 3 rd vs upper 3 rd § Middle 3 rd vs upper 3 rd 2. 36 (1. 33 -4. 21) 1. 31 (0. 71 -2. 43) . 008 1. 48 (0. 55 -3. 99) . 441 Race § White vs all others 1. 16 (0. 65 -2. 10) . 614 Karnofsky PS score § 90/100 vs 70/80 2. 44 (1. 24 -4. 79) . 010 IMDC risk group 1 § Favorable vs poor § Intermediate vs poor 4. 59 (1. 55 -13. 59) 4. 68 (1. 63 -13. 47) . 015 RCC histology § Clear cell vs clear cell component 1. 20 (0. 75 -1. 21) . 454 Sarcomatoid features § Yes vs no § Unknown vs no 2. 10 (1. 08 -4. 09) 1. 64 (1. 01 -2. 67) . 037 1. 13 (0. 72 -1. 80) . 592 Nephrectomy § Yes vs no 2. 02 (1. 02 -4. 00) . 043 IMDC risk group 2 § Favorable vs intermediate/poor PD-L 1 status § CPS < 1 vs CPS ≥ 1 Plimack. ASCO GU 2021. Abstr 327. Slide credit: clinicaloptions. com

KEYNOTE-426 Subgroup Analysis: Multivariate Analysis of Patients Most Likely to Complete 2 Yrs of Therapy Characteristic Odds Ratio (95% CI) P Value Age group, yrs § < 65 vs ≥ 65 1. 76 (1. 07 -2. 90) . 025 Karnofsky PS score § 90/100 vs 70/80 2. 10 (1. 04 -4. 24) . 039 IMDC risk group § Favorable vs poor § Intermediate vs poor 4. 99 (1. 63 -15. 27) 4. 90 (1. 67 -14. 41) . 014 Sarcomatoid features § Yes vs no § Unknown vs no 2. 19 (1. 04 -4. 24) 1. 75 (1. 06 -2. 90) . 028 Plimack. ASCO GU 2021. Abstr 327. Slide credit: clinicaloptions. com

Belzutifan in Advanced Clear-Cell RCC: Study Design § Dose-escalation*/expansion phase I/II study of belzutifan (MK-6482), a potent, selective, oral smallmolecule HIF-2α inhibitor with antitumor activity in clear-cell RCC[1] ‒ Current analysis: updated follow-up of dose-expansion cohort in advanced clear-cell RCC [2] Adult patients with previously treated advanced clear-cell RCC with ≥ 1 previous therapy; ECOG PS 0/1 (N = 55) § Belzutifan 120 mg PO QD‡ Median previous/current follow-up: 16. 7 mos/27. 7 mos Primary endpoint: safety Previous/current data cutoff: July 2, 2019/June 1, 2020 ‒ Belzutifan at 120 mg dose was shown to be well tolerated with a favorable safety profile[1] § Until PD or unacceptable toxicity Key secondary endpoints: ORR, Do. R, PFS § Out of 55 patients enrolled, 44 (80%) had d/c therapy ‒ Most common reason for d/c was PD ‒ 11 (20%) patients remained on treatment *Dose-escalation cohort in other solid tumors. ‡ 21 -day DLT period in dose-escalation. 1. Choueiri. ASCO GU 2020. Abstr 611. 2. NCT 02974738. 3. Bauer. ASCO GU 2021. Abstr 273. Slide credit: clinicaloptions. com

Belzutifan in Advanced RCC: Baseline Characteristics Characteristic Median age, yrs (range) Patients (n = 55) 62 (39 -75) Male, n (%) 44 (80) ECOG PS, n (%) § 0 § 1 § 2 20 (36) 34 (62) 1 (2) IMDC risk category, n (%) § Favorable § Intermediate/poor 13 (24) 42 (76) § 39 patients (71%) received both PD-1 inhibitors and VEGF inhibitors Bauer. ASCO GU 2021. Abstr 273. Characteristic Patients (n = 55) Median previous systemic therapies, n (range) 3 (1 -9) Previous systemic therapies, n (%) § 1 § 2 §≥ 3 8 (15) 13 (24) 34 (62) Previous anticancer therapies, n (%) § Anti-VEGF/VEGFR § Checkpoint inhibitor § Investigational/other § m. TOR inhibitor § Cytokine 50 (91) 44 (80) 16 (29) 13 (24) 10 (18) Slide credit: clinicaloptions. com

Belzutifan in Advanced RCC: Safety Outcome, n (%) Patients (n = 55) Any grade AEs 55 (100) Grade 3 -5 AEs 39 (71) Any grade TRAEs 53 (96) Grade 3 -5 TRAEs 22 (40) Discontinuation due to AEs* 5 (9) Discontinuation due to TRAEs† 2 (4) Death due to AEs 4 (7) Death due to TRAEs 0 (0) § 96% had TRAEs ‒ Grade 4/5 TRAEs: 0 § 40% experienced a grade 3 TRAE § Discontinuations after TRAE hypoxia: 2 (4%) *5 patients experienced 7 adverse events (hypoxia, n =2), abdominal pain (n =1), cardiac arrest (n = 1), decrease appetite (n = 1), PD (n = 1), and fatigue (n = 1). †One patient discontinued treatment due to grade 2 hypoxia and 1 due to grade 3 hypoxia. Bauer. ASCO GU 2021. Abstr 273. Slide credit: clinicaloptions. com

Belzutifan in Advanced RCC: All-Cause AEs Any Grade 3 Grade 4/5 All-Cause AEs in > 20% (N = 55), n (%) Any Grade 3 Grade 4/5 Any 55 (100) 33 (60) 6 (11) Arthralgia 14 (25) 0 (0) Anemia 42 (76) 15 (27) 0 (0) Blood creatinine increased 14 (25) 1 (2) 0 (0) Fatigue 39 (71) 3 (5) 0 (0) Headache 14 (25) 1 (2) 0 (0) Dyspnea 27 (49) 3 (5) 0 (0) Dizziness 13 (24) 0 (0) Nausea 20 (36) 1 (2) 0 (0) Back pain 12 (22) 1 (2) 0 (0) Cough 17 (31) 0 (0) Diarrhea 12 (22) 0 (0) Hypoxia 17 (31) 9 (16) 0 (0) Hyperkalemia 12 (22) 1 (2) 0 (0) Vomiting 16 (29) 0 (0) Constipation 12 (22) 0 (0) Edema, peripheral 15 (27) 0 (0) Dehydration 11 (20) 1 (2) 0 (0) All-Cause AEs in > 20% (N = 55), n (%) § Grade 5 AEs: 4 events in 4 patients (7%) ‒ Acute kidney injury, disease progression, malignant neoplasm progression, cardiac arrest, one patient each Bauer. ASCO GU 2021. Abstr 273. § Grade 4 AEs: 4 events in 2 patients (4%) ‒ Sepsis (2), hypercalcemia (1), respiratory failure (1) Slide credit: clinicaloptions. com

Belzutifan in Advanced RCC: ORR (Clear-Cell RCC Cohort) Best Confirmed Objective Response, * n (%) All Patients (N = 55) IMDC Risk Category Favorable (n = 13) Intermediate/Poor (n = 42) 14 (25) [95% CI: 15 -39] 4 (31) [95% CI: 9 -61] 10 (24) [95% CI: 12 -39] 0 14 (25) 0 4 (31) 0 10 (24) 30 (54) 8 (62) 22 (52) 44 (80) [95% CI: 67 -90] 12 (92) [95% CI: 64 -100] 32 (76) [95% CI: 61 -88] PD 8 (15) 1 (8) 7 (17) Not evaluable 3 (5) 0 3 (7) ORR § CR § PR SD DCR (CR + PR + SD) *Per investigator assessment using RECIST v 1. 1. Bauer. ASCO GU 2021. Abstr 273. Slide credit: clinicaloptions. com

Belzutifan in Advanced RCC: Best Tumor Change From Baseline per Investigator Assessment Change From BL in Sum of Target Lesion Diameter (%) 100 § 35 (64%) patients had a reduction in target lesion size* 80 60 40 20 0 -20 -40 -60 -80 -100 PD SD PR *3 patients were not evaluable. Bauer. ASCO GU 2021. Abstr 273. Reproduced with permission. Patients Slide credit: clinicaloptions. com

Belzutifan in Advanced RCC: Do. R Patients § 19 (35%) patients continued treatment beyond 12 months § Median Do. R was not reached § 10 of 14 (71%) responders experienced response that lasted ≥ 6 mos NE PD SD PR Treatment ongoing 0 5 10 Data cutoff: June 1, 2020 Bauer. ASCO GU 2021. Abstr 273. Reproduced with permission. 15 20 25 30 35 Mos of Treatment Slide credit: clinicaloptions. com

Belzutifan in Advanced RCC: PFS Probability (%) 100 80 60 40 20 Median, mos (95% Cl) 0 0 Patients at Risk, n 55 5 31 All Patients N = 55 IMDC Favorable (n = 13) IMDC Intermediate/Poor (n = 42) 14. 5 (7. 3 -NR) NR (3. 4 -NR) 11. 0 (5. 4 -22. 1) 10 15 19 14 Bauer. ASCO GU 2021. Abstr 273. Reproduced with permission. Mos 20 25 30 35 11 5 3 0 Slide credit: clinicaloptions. com

Belzutifan (MK-6482) + Cabozantinib in Advanced Clear-Cell RCC § Multicenter, 2 -cohort, open-label phase II trial ‒ Belzutifan: potent, selective, oral small-molecule HIF-2α inhibitor Adult patients with advanced/metastatic clearcell RCC; either treatmentnaive or previously treated with anti–PD-(L)1 and ≤ 2 regimens for advanced disease; ECOG PS 0/1 Cohort 1 Treatment naive (n = 50) Cohort 2 Prior anti–PD-(L)1 (n = 52) The current analysis presents data from cohort 2 § Primary endpoint: ORR Belzutifan 120 mg/day + Cabozantinib 60 mg/day Assessments Q 8 W after Wk 9 for 12 mos, then Q 12 W Posttreatment 28 -day safety follow-up; follow-up visits every 6 mos § Key secondary endpoints: PFS, TTR, Do. R, OS, safety, PK/PD Choueiri. ASCO GU 2021. Abstr 272. NCT 03634540. Slide credit: clinicaloptions. com

Belzutifan + Cabozantinib in Advanced RCC: Baseline Characteristics Prior Treatment, n (%) Patients (n = 52) 63 (43 -79) Anti–PD-(L)1 + anti–CTLA-4 34 (65) Male sex, n (%) 38 (73) 18 (35) ECOG PS, n (%) § 0 § 1 Anti–PD-(L)1 + anti-VEGF/ VEGFR TKI 23 (44) 29 (56) IO combination + anti-VEGF/ VEGFR TKI 0 (0) IO followed by anti-VEGF/ VEGFR TKI or anti-VEGF/VEGFR TKI followed by IO 7 (14) Characteristic Median age, yrs (range) Number of previous lines of anticancer therapy, n (%) § 1 § 2 Choueiri. ASCO GU 2021. Abstr 272. Patients (n = 52) 28 (54) 23 (44) Slide credit: clinicaloptions. com

Belzutifan + Cabozantinib in Advanced RCC: ORR Outcome, n (%) Patients (n = 41) ORR (CR + PR) 9 (22) DCR (CR + PR + SD) 37 (90) Best response § CR § PR § Unconfirmed PR* § SD § PD § Not evaluable 0 (0) 9 (22) 5 (12) 28 (68) 3 (7) 1 (2) *Documented at 1 time point and to be confirmed at a subsequent time point. Choueiri. ASCO GU 2021. Abstr 272. Slide credit: clinicaloptions. com

Belzutifan + Cabozantinib in Advanced RCC: Best Tumor Change From Baseline Change From BL in Sum of Target Lesion Diameter (%) 100 80 60 40 § 36/41 patients (88%) had a decrease in target lesion size* PD Unconfirmed PR† SD Confirmed PR 20 0 -20 -40 -60 -80 -100 *Response in 1 patient not available, recorded as no change from BL. †Documented at 1 time point, yet to be confirmed at a subsequent time point. Choueiri. ASCO GU 2021. Abstr 272. Reproduced with permission. Slide credit: clinicaloptions. com

Belzutifan + Cabozantinib in Advanced RCC: TTR and Do. R Patients • Median TTR: 1. 9 mos (range: 1. 5 -9. 2) • Median Do. R: not reached (range: 3. 7 -14. 8+) • All confirmed responses ongoing at data cutoff (Oct 15, 2020) PD SD Death 0 5 10 Mos Choueiri. ASCO GU 2021. Abstr 272. Reproduced with permission. 15 Unconfirmed PR* Confirmed PR Treatment ongoing 20 25 *Documented at 1 time point, yet to be confirmed at a subsequent time point. Slide credit: clinicaloptions. com

Belzutifan + Cabozantinib in Advanced RCC: PFS and OS PFS Probability (%) 100 80 60 40 PFS Rate 6 mos 20 0 1 2 OS Rate 12 mos 78% 0 16. 8 mos 65% 3 4 5 6 7 6 mos 12 mos 95% 81% 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Patients at Risk, n Mos 41 40 33 33 28 27 20 20 15 14 10 9 8 Choueiri. ASCO GU 2021. Abstr 272. Reproduced with permission. 8 6 6 6 1 1 Data cutoff: Oct 15, 2020 1 1 0 Slide credit: clinicaloptions. com

Belzutifan + Cabozantinib in Advanced RCC: Safety AEs, n (%) Patients (N = 52) Outcome, n (%) Patients (N = 52) Any grade TEAE 52 (100) Deaths due to a TEAE (PD) 1 (2) Any grade TRAE § Related to belzutifan § Related to cabozantinib 51 (98) Deaths due to a TRAE 0 (0) Grade 3 -5 TEAE 35 (67) Grade 3 TRAE § Related to belzutifan § Related to cabozantinib 31 (60) 17 (33) 28 (54) Serious TEAE 16 (31) Serious TRAE § Related to belzutifan § Related to cabozantinib 7 (13) 4 (8) Choueiri. ASCO GU 2021. Abstr 272. Belzutifan dose reduced* 10 (19) Cabozantinib dose reduced† 25 (48) Discontinued any drug due to a TEAE § Discontinued belzutifan‡ § Discontinued cabozantinib§ 8 (15) 6 (12) 8 (15) *14 AEs in 10 patients: fatigue, ALT increase, decreased appetite, anemia, diarrhea, headache, hypoxia, oral pain). † 37 AEs in 25 patients, including: fatigue, hand-foot syndrome, ALT increase, decreased appetite, nausea, platelets decreased, stomatitis. ‡ 6 AEs in 6 patients: fatigue, ALT increase, anemia, PD, mental changes. § 9 AEs in 8 patients: ALT increase, fatigue, PD, exertional dyspnea, mental changes, myocardial infarction. Slide credit: clinicaloptions. com

Belzutifan + Cabozantinib in Advanced RCC: TRAEs in ≥ 15% of Patients, % (N = 52) Any Grade 3 Any 98 60 Anemia 77 12 § Of 742 AEs, 92% were grade 1/2 Fatigue 67 12 Hand-foot syndrome 54 2 Diarrhea 44 4 § Treatment-related hypoxia, considered an on-target AE for belzutifan (n = 2; 4%) Hypertension 44 23 Nausea 35 2 ALT increased 33 6 AST increased 33 4 Decreased appetite 29 2 Dysgeusia 23 2 Headache 19 0 Hypophosphatemia 17 4 Stomatitis 15 0 Choueiri. ASCO GU 2021. Abstr 272. § No grade 4/5 TRAEs ‒ Both grade 3 events Slide credit: clinicaloptions. com

SWOG 1500: Cabozantinib, Crizotinib or Savolitinib vs Sunitinib in Metastatic Papillary RCC § Multicenter, randomized, open-label phase II trial[1 -3] Stratified by subtype (type 1 vs type II vs NOS by local review), number of prior therapy (0 vs 1) Cabozantinib* 60 mg PO QD + (n = 44) Patients with confirmed metastatic papillary RCC; Zubrod PS 0/1; measurable disease; ≤ 1 prior therapy; no prior sunitinib (N = 147) § Primary endpoint: PFS Crizotinib† 250 mg PO BID + (n = 28) Savolitinib‡ 600 mg PO QD (n = 29) Crizotinib and savolitinib arms closed for futility (December 2018) Sunitinib§ 50 mg PO QD 4 wks on/2 wks off (n = 46) *Reduction to 40 mg and 20 mg allowed. †Reduction to 200 mg BID and 250 mb QD allowed. ‡Reduction to 400 mg and 200 mg allowed. §Dose reductions to 37. 5 mg and 25 mg allowed. § Secondary endpoints: OS, ORR, safety, exploratory evaluation of MET mutational status and MET expression Pal. ASCO GU 2021. Abstr 270. NCT 02761057. Slide credit: clinicaloptions. com

SWOG 1500: Baseline Characteristics Cabozantinib (n = 44) Crizotinib (n = 28) Savolitinib (n = 29) Sunitinib (n = 46) 65 (29 -81) 68 (51 -84) 67 (29 -82) 65 (32 -89) Male sex, % 82 79 66 76 Race, % § White § Black § Other § Unknown 73 20 7 5 79 14 8 4 72 10 16 10 85 11 4 0 Previous systemic therapy, % 5 7 10 7 Histologic subtype (local assessment), % § Type II § NOS 20 57 23 18 54 29 17 52 31 17 52 30 Histologic subtype (central assessment), % § Type II § Mixed/other 32 46 18 21 45 24 26 46 24 32 36 27 Characteristic Median age, yrs (range) Pal. ASCO GU 2021. Abstr 270. Slide credit: clinicaloptions. com

SWOG 1500: Baseline Characteristics (cont’d) Cabozantinib (n = 44) Crizotinib (n = 28) Savolitinib (n = 29) Sunitinib (n = 46) IMDC risk group § Favorable § Intermediate § High 23 64 14 29 57 14 30 66 14 30 57 13 Zubrod PS § 0 § 1 66 34 64 36 52 48 63 37 Mixed histology 18 21 24 15 Prior nephrectomy 73 72 72 74 Metastatic site § Bone § CNS 14 0 18 <1 28 0 15 0 Characteristic, % Pal. ASCO GU 2021. Abstr 270. Slide credit: clinicaloptions. com

SWOG 1500: PFS and OS Cabozantinib (n = 44) Crizotinib (n = 28) Savolitinib (n = 29) Sunitinib (n = 46) PFS* § Failed, n § Median PFS, mos § 95% CI 32 9. 0 6. 0 -12. 0 26 2. 8 3. 0 -4. 0 28 3. 0 -7. 0 38 5. 6 3. 0 -7. 0 OS § Deaths, n § Median OS, mos § 95% CI 22 20. 0 11. 0 -NR 16 19. 9 11. 0 -NR 21 11. 7 7. 0 -29. 0 24 16. 4 13. 0 -22. 0 Outcome *Cabozantinib significantly prolonged PFS compared with sunitinib (HR: 0. 60; 95% CI: 0. 37 -0. 97; P =. 019). Pal. ASCO GU 2021. Abstr 270. Slide credit: clinicaloptions. com

SWOG 1500: ORR Cabozantinib (n = 44) Crizotinib (n = 28) Savolitinib (n = 29) Sunitinib (n = 46) ORR* § CR § PR § Unconfirmed PR § SD § PD 23 5 18 5 51 9 0 0 0 4 25 43 3 0 3 7 28 28 4 0 4 2 50 24 Symptomatic deterioration 2 11 3 2 Early death 2 0 0 2 Assessment inadequate 7 18 31 15 Outcome, % *Confirmed ORR with cabozantinib was significantly higher than with sunitinib (23% vs 4%, respectively; P =. 010). Pal. ASCO GU 2021. Abstr 270. Slide credit: clinicaloptions. com

SWOG 1500: Safety (Clinical Toxicity) AE, % Cabozantinib (n = 44) Crizotinib (n = 28) Savolitinib (n = 29) Sunitinib (n = 46) Any Grade Grade 3/4 Any 97 74 92 37 92 39 93 68 Fatigue 69 13 48 7 50 0 57 6 Diarrhea 55 4 44 0 10 0 48 6 Nausea 34 0 25 0 42 8 Hypertension 65 32 11 0 21 3 35 17 Anorexia 44 2 18 0 21 0 31 0 Oral mucositis 37 2 3 0 0 0 28 0 Hand–foot syndrome 48 20 0 0 24 0 Vomiting 13 0 7 0 24 2 Dehydration 2 0 0 0 3 3 11 2 Abdominal pain 13 6 3 0 6 2 Dyspnea 11 0 14 0 7 3 6 0 Edema limbs 6 0 22 3 28 7 6 0 Other GI disorders 16 2 0 0 6 0 Pal. ASCO GU 2021. Abstr 270. Slide credit: clinicaloptions. com

SWOG 1500: Safety (Laboratory Abnormalities) AE, % Cabozantinib (n = 44) Crizotinib (n = 28) Savolitinib (n = 29) Sunitinib (n = 46) Any Grade Grade 3/4 Thrombocytopenia 18 0 0 0 3 0 40 4 Anemia 23 0 22 3 7 0 33 13 Leukopenia 20 0 0 28 11 Neutropenia 16 0 3 0 0 0 24 8 Lymphocytopenia 13 0 7 0 10 0 22 4 AST increased 32 0 25 3 7 0 17 2 Proteinuria 16 2 0 0 3 0 15 2 ALT increased 30 2 29 7 10 0 13 2 Hypoalbuminemia 13 0 14 3 17 0 13 2 Hyponatremia 6 6 0 0 25 10 8 4 Hypophosphatemia 25 9 3 0 0 0 6 0 Hypocalcemia 23 2 11 0 10 0 2 0 Hypomagnesemia 20 4 0 0 0 Pal. ASCO GU 2021. Abstr 270. Slide credit: clinicaloptions. com

Kidney Cancer Studies: Summary § CLEAR: pembro + len was superior to sunitinib in ORR, PFS, and OS, and the combination of len + eve was superior to sunitinib in ORR and PFS but not OS; investigators propose pembro + len as new first-line tx for advanced clear-cell RCC[1] § KEYNOTE-426 subgroup analysis: patients who completed 2 yrs of treatment with pembro and axitinib had ongoing clinical benefit (3 -yr OS: 94. 7%) and most had IMDC favorable or intermedia/poor risk disease[2] § Belzutifan in advanced RCC: single-agent belzutifan and combination therapy of belzutifan + cabozantinib showed promising activity in previously treated patients with advanced clear-cell RCC[3, 4] ‒ Grade 3 on-target AEs of anaemia and hypoxia were observed in 27% and 16% of patients, respectively § SWOG 1500: compared with sunitinib, cabozantinib significantly improved PFS (HR: 0. 6; P =. 019) and ORR (23% vs 45; P =. 010); investigators propose cabozantinib as the new reference standard for systemic tx in metastatic papillary RCC[5] 1. Motzer. ASCO GU 2021. Abstr 269. 2. Plimack. ASCO GU 2021. Abstr 327. 3. Choueiri. ASCO GU 2021. Abstr 272. 4. Bauer. ASCO GU 2021. Abstr 273. 5. Pal. ASCO GU 2021. Abstr 270. Slide credit: clinicaloptions. com

Go Online for More CCO Coverage of Genitourinary Cancers! CME-certified text module with expert commentary on all the key studies from ASCO GU 2021 (coming soon!) Genitourinary Cancers Decision Support Tool featuring the latest management recommendations from 5 GU experts (coming soon!) clinicaloptions. com/oncology