Phase Ib/II ECHO-202/KEYNOTE-037: Epacadostat + Pembrolizumab in Pts With Advanced Urothelial Carcinoma CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois *Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

Epacadostat + Pembrolizumab in Advanced Urothelial Carcinoma: Background Multiple immune checkpoint inhibitors (atezolizumab, avelumab, durvalumab, nivolumab, pembrolizumab) recently approved for pts with advanced UC after platinum-based chemotherapy[1-6] Pembrolizumab FDA approved in this setting based on phase III KEYNOTE-045 data[6] Atezolizumab, pembrolizumab also approved for first-line therapy in cisplatin- ineligible pts[7,8] Epacadostat: potent, selective, PO inhibitor of tryptophan-degrading enzyme IDO1; promotes immunosurveillance in tumor microenvironment[9] Current analysis from multicohort phase Ib/II trial evaluating safety, efficacy of epacadostat + pembrolizumab focuses on advanced UC cohort in phase II portion of study[10] UC, urothelial carcinoma. References: 1. Rosenberg JE, et al. Lancet. 2016;387:1909-1920. 2. Patel MR, et al. ASCO GU 2017. Abstract 330. 3. Powles T, et al. ASCO GU 2017. Abstract 286. 4. Sharma P, et al. Lancet Oncol. 2017;18:312-322. 5. Apolo AB, et al. J Clin Oncol. 2017;[Epub ahead of print]. 6. Bellmunt J, et al. N Engl J Med. 2017;376:1015-1026. 7. Balar AV, et al. Lancet. 2017;389:67-76. 8. Balar AV, et al. ASCO GU 2017. Abstract 284. 9. Liu X, et al. Blood. 2010;115:3520-3530. 10. Smith DC, et al. ASCO 2017. Abstract 4503. Slide credit: clinicaloptions.com References in slidenotes.

ECHO-202/KEYNOTE-037: Study Design Open-label dose escalation phase Ib study: adults with histologically or cytologically confirmed advanced/recurrent cancer, ECOG PS 0/1, and no prior immune checkpoint inhibitor or IDO1 inhibitor Phase II: PD during/following platinum-based therapy in adjuvant or advanced disease setting; tumor cohorts included melanoma, SCCHN, UC, NSCLC, RCC, TNBC, OC, MSI-high CRC, DLBCL, GC, and HCC Current analysis in UC (N = 40): ORR, change in target lesions, TTR, DoR, safety, PD-L1 biomarker analysis Phase Ib Phase II CRC, colorectal cancer; DLBCL, diffuse large B-cell lymphoma; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; GC, gastric cancer; MSI, microsatellite instability; NSCLC, non-small-cell lung cancer; PD, progressive disease; PS, performance status; RCC, renal cell carcinoma; SCCHN, squamous cell carcinoma of the head and neck; TNBC, triple-negative breast cancer; TTR, time to response; UC, urothelial carcinoma. Dose Escalation Safety Expansion Cohort Expansion Epacadostat 25, 50, 100, or 300 mg BID + Pembrolizumab 2 mg/kg or 200 mg Q3W Epacadostat 50, 100, or 300 mg BID + Pembrolizumab 200 mg Q3W Epacadostat 100 mg BID + Pembrolizumab 200 mg Q3W Slide credit: clinicaloptions.com Smith DC, et al. ASCO 2017. Abstract 4503.

ECHO-202/KEYNOTE-037: Baseline Characteristics UC Pts (N = 40) Median age, yrs (range) 67 (43-87) Male, n (%) 30 (75) White, n (%) 35 (88) ECOG PS 0/1, n (%) 16 (40) / 24 (60) Bellmunt risk score,* n (%) 1 ≥ 2 5 (13) 21 (53) 14 (35) Common sites of metastases Lymph node Lung Bone Liver Skin or subcutaneous tissue Other 23 (58) 16 (40) 9 (23) 8 (20) 1 (3) Characteristic, n (%) UC Pts (N = 40) Prior radiation tx 10 (25) Prior surgery 37 (93) Prior tx for advanced disease 0† or 1 ≥ 2 32 (80) 8 (20) Prior platinum-based tx Cisplatin Carboplatin 31 (78) 12 (30) PD-L1 expression Positive (CPS ≥ 1%) Negative (CPS < 1%) NE, missing, or not done 11 (28) 21 (53) CPS, combined positive score; ECOG, Eastern Cooperative Oncology Group; Hb, hemoglobin; NE, not evaluable; PS, performance status; tx, treatment; UC, urothelial carcinoma. *Based on presence of liver mets, ECOG PS ≥ 1, Hb < 10 g/dL, time from last chemotherapy < 3 mos. †Platinum-based adjuvant/neoadjuvant therapy given to pts with no prior tx for advanced UC.. Slide credit: clinicaloptions.com Smith DC, et al. ASCO 2017. Abstract 4503.

ECHO-202/KEYNOTE-037: Pt Disposition Median follow-up: 33.8+ wks (range: 3.6 to 131.0+ wks) Median epacadostat exposure: 20.1 wks (range: 1 to 132+ wks) Disposition, n UC Pts (N = 40) Treatment completed* 2 Treatment ongoing 11 Treatment discontinued Disease progression Adverse events Patient decision Death 27 18 5 3 1 UC, urothelial carcinoma. *Treatment completed after 24 mos of therapy or in pts who elected to discontinue after CR following a minimum of 24 wks of therapy and ≥ 2 cycles of additional treatment beyond the date of CR. Slide credit: clinicaloptions.com Smith DC, et al. ASCO 2017. Abstract 4503.

ECHO-202/KEYNOTE-037: Best Objective Response (RECIST v1.1) Outcome, n (%) UC Pts (N = 40) Prior Lines of Tx PD-L1 Expression 0-1 (n = 32) ≥ 2 (n = 8) CPS ≥ 1% (n = 11) CPS < 1% Unknown (n = 21) ORR CR PR 14 (35) 3 (8) 11 (28) 12 (38) 3 (9) 9 (28) 2 (25) 7 (64) 1 (13) 6 (29) 3 (14) SD 7 (18) 7 (22) 1 (9) 5 (24) DCR 21 (53) 19 (59) 8 (73) 11 (52) PD 10 (31) 4 (50) 2 (18) 6 (75) NE 5 (13) 4 (19) CPS, combined positive score; DCR, disease control rate; ir, immune related; NE, not evaluable; PD, progressive disease; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. By irRECIST, ORR: 38% (4 CR, 11 PR); DCR: 60% (9 SD) Slide credit: clinicaloptions.com Smith DC, et al. ASCO 2017. Abstract 4503.

ECHO-202/KEYNOTE-037: Efficacy 44% of evaluable pts had ≥ 25% reduction in baseline target lesions 46% of pts with 0-1 prior lines of therapy 33% of pts with ≥ 2 prior lines of therapy Responses seen in majority of PD-L1+ pts (CPS ≥ 1%) Most responses durable, occurred early in course of tx Ongoing responses: 10/14 Included 2 pts who completed tx, 3 pts with CR Median DoR: 30.6+ wks (range: 9.7 to 93.1+ wks) CPS, combined positive score; DoR, duration of response; tx, treatment. Slide credit: clinicaloptions.com Smith DC, et al. ASCO 2017. Abstract 4503.

ECHO-202/KEYNOTE-037: TRAEs TRAE Occurring in ≥ 5% of Pts, n (%) UC Pts (N = 40) Any Grade Grade 3/4 Any 28 (70) 9 (23) Fatigue 13 (33) 1 (3) Rash 8 (20) 3 (8) Amylase increase 5 (13) Pruritis 4 (10) ALT increase Chills Lipase increase Nausea Arthralgia 2 (5) AST increase Dysgeusia Flushing Hyperglycemia Dose interruption due to TRAEs: 11/40 (28%); none in > 1 pt Dose reduction due to tx-related rash: 2/40 (5%) D/c due to TRAE: 3/40 (8%) Colitis, rash, COPD exacerbation, n = 1 each AEs manageable with supportive care No tx-related deaths ALT, alanine aminotransferase; AST, aspartate aminotransferase; COPD, chronic obstructive pulmonary disorder; D/c, discontinuation; TRAE, treatment-related adverse events; tx, treatment; UC, urothelial carcinoma. Slide credit: clinicaloptions.com Smith DC, et al. ASCO 2017. Abstract 4503.

ECHO-202/KEYNOTE-037: AEs of Special Interest AE of Special Interest,* n (%) UC Pts (N = 40) Any Grade Grade 3/4 Any 6 (15) 3 (8) Severe skin reaction† Colitis 1 (3) Hypothyroidism Pneumonitis Type I diabetes mellitus AE, adverse event; UC, urothelial carcinoma. *Immune-related AEs, regardless of investigator attribution to study treatment. †Includes grade ≥ 3 rash and rash macular. Slide credit: clinicaloptions.com Smith DC, et al. ASCO 2017. Abstract 4503.

ECHO-202/KEYNOTE-037: Conclusions In pts with advanced urothelial carcinoma, combination epacadostat + pembrolizumab active and well tolerated ORR: 35%; DCR: 53%; median DoR: 30.6+ wks; 10/14 ongoing responses Higher response rate in PD-L1–positive pts, those with 0-1 vs ≥ 2 prior lines of treatment Safety profile consistent with prior phase I/II data; greater frequency of grade 3/4 rash with combination vs pembrolizumab monotherapy Study investigators suggest that data supports phase III trial of epacadostat + pembrolizumab in pts with urothelial carcinoma DCR, disease control rate; DoR, duration of response. Slide credit: clinicaloptions.com Smith DC, et al. ASCO 2017. Abstract 4503.

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