Approaches to the Treatment of Metastatic Bladder Cancer

Daniel P. Petrylak, MD Professor of Medicine and Urology Director, GU Translational Working Group Co Director, Signal Transduction Program Smilow Cancer Center, Yale University

M-VAC vs Cisplatin Phase III Long term survival

Cisplatin M-VAC Evaluable 122 133 3 years 4 17 6 years* 2 9

*6 patients died of TCC, 1 2nd Ca, 2 other, 1 lost to F/U

Saxman, JCO, 15:2564, 1997 M-VAC: EORTC Dose Intensification

HD M-VAC: Methotrexate 30 mg/m2 Day 1; Vinblastine 3 mg /m2 Day 2 Adriamycin 30 mg / m2 Cisplatin 70 mg/m2 G-CSF Classic M-VAC: Methotrexate 30 mg/m2 Day 1, 14, 21 Vinblastine 3 mg /m2 Day 1, 14, 21 Adriamycin 30 mg / m2 Day 2 Cisplatin 70 mg/m2 Day 2 Accrual :263 patients

Sternberg, C. N. et al. J Clin Oncol; 19:2638-2646 2001 Mechanism of Immune Checkpoint Inhibitors

• Cancer cells develop many mutations that can make them appear foreign to the immune

IFNg-mediated system upregulation of tumor PD-L1 PD-L1/PD-1-mediated inhibition of • T cells can recognize, attack tumor cell killing and kill these “foreign” cancer

B7.1 Priming and cells Key Attributes of activation of T cells the Immune System • Cancer cells can evade immune attack by expressing • Specificity PD-L1 • Memory • Adaptive • Adaptive tumor expression of PD-L1 turns the immune

Immune cell system OFF modulation of T cells • Clinically, we want to block PD-1 or PD-L1 to reactivate Stromal PD-L1 modulation of T cells PD-L2-mediated the immune system

inhibition of TH2 T cells • PD-L1 plays an important role in dampening the anti-tumor immune response Herbst RS et al. J Clin Oncol . 2013;31(suppl; abstr 3000) Checkpoint Inhibitors Approved for Use in Urothelial Carcinoma 7 US FDA Approvals May 2016-May 2017 Setting Antibody Approval Status First-line Atezolizumab • Accelerated approval granted in April 2017. (cisplatin- Pembrolizumab • Accelerated approval granted in May 2017. ineligible) Atezolizumab • Accelerated approval granted in May 2016. • In May 2017, the subsequent phase 3 IMvigor211 trial did not meet primary endpoint of Platinum- overall survival. pretreated Nivolumab • Accelerated approval granted in February 2017. Durvalumab • Accelerated approval granted in May 2017. Avelumab • Accelerated approval granted in May 2017. Pembrolizumab • Full approval granted in May 2017. Approvals: First-line, Cisplatin- Ineligible Apr 2017 May 2017

Above agents are indicated in patients with locally advanced or metastatic urothelial carcinoma not eligible for cisplatin-containing chemotherapy. Definition of the Medically Unfit Patient • Concurrent renal insufficiency limits the administration of drugs such as cisplatin • Cardiac dysfunction and third space accumulation of fluids limit hydration of patients • Performance status predisposes to neutropenia and dose adminstration • No consisteentstandard definition of “unfit” based on objective criteria Treatment of the Medically Unfit Patient • Treatment goals shift to palliation of symptoms rather than response/survival • Single agent vs non cisplatin containing doublets • Immune therapy for first line treatment IMvigor210 (Cohort 1)

IMvigor210: Cohort 1 (N = 119): Atezolizumab 1200 mg IV q3w • Inoperable locally advanced 1L cisplatin-ineligible until RECIST v1.1 progression or metastatic urothelial carcinoma • Predominantly UC histology • Tumor tissue evaluable for Cohort 2 (N = 310): Atezolizumab 1200 mg IV q3w PD-L1 testinga Platinum-treated mUC until loss of clinical benefit

Cohort 1–specific inclusion criteria Key primary endpoint : •No prior treatment for mUC (>12 mo since perioperative chemo) •ECOG PS 0-2 • Confirmed ORR: RECIST v1.1 •Cisplatin ineligibility1 based on ≥1 of the following: (per central IRF) − Renal impairment: GFR <60 and >30 mL/min − Grade ≥2 hearing loss or peripheral neuropathy Key secondary endpoints : − ECOG PS 2 • DOR, PFS, OS, safety

Balar et al. Lancet. 2017;389:67 IMvigor210 (Cohort 1)

• N = 119 • ORR = 23% (9% CR) Overall Survival

Balar et al. Lancet. 2017;389:67 KEYNOTE-052: Pembrolizumab as 1st-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Cancer Patients (N = 350) Primary Endpoints • ORR in all patients •Advanced urothelial cancer Pembrolizumab • ORR in patients with •No prior chemotherapy for 200 mg Q3W metastatic disease PD-L1–positive •ECOG PS 0-2 tumors •Ineligible for cisplatin based Primary Endpoints: on ≥1 of the following: – CrCl <60 mL/min • Planned interim analysis in first 100 patients – ECOG PS 2 • Determine the PD-L1–high expression cutpoint – Grade ≥2 neuropathy or • ORR in all patients and PD-L1‒positive population hearing loss Secondary Endpoints: DOR, PFS, OS, and ORR in all patients, – NYHA class III CHF PD-L1‒positive and PD-L1–high-expressing patients; safety and tolerability

Balar et al. ESMO 2016; abstract LBA32_PR. KEYNOTE-052 (ASCO17 Update)

N = 370 ORR: 29% CR: 7%

O’Donnell et al. ASCO 2017; Abstract 4502. Sequence of Therapy for Cisplatin-Eligible Patients

Cisplatin-based PD-1 or PDL-1 Single Agent chemotherapy Inhibitor Chemotherapy Sequence of Therapy for Cisplatin-Ineligible Patients

Carboplatin- Checkpoint Single Agent based Inhibitor Chemotherapy chemotherapy

Carboplatin- Pembrolizumab/ Single Agent based atezolizumab Chemotherapy chemotherapy

Comorbidity/patient choice‒directed (no validated biomarkers) First-Line Therapy for Cisplatin-Ineligible Metastatic UC PD-1/PD-L1 Inhibitor OR Gemcitabine-Carboplatin Based on Activity?

Gem-Carbo (Ph III)1 Atezolizumab (Ph II)2 Pembrolizumab (Ph II)3

Number of patients 119 119 370

% with PS 2 44.5% 20% 42%

% CrCl <60 mL/min 55.5%a 70% 49%

% PS 2 + CrCl <60 mL/min 26.9%a 7% 9%

ORR 41.2% 23% 24%

Median PFS 5.8 mo 2.7 mo 2 mo; 3 mo on therapy

Median OS 9.3 mo 15.9 mo Not reported

Duration of response Not reported Not reached Not reached (median f/u 17.2 mo) (78% ≥6 months)

aGFR 30-60 mL/min. 1. De Santis M, et al. J Clin Oncol. 2012;30(2):191-199; 2. Balar AV, et al. Lancet. 2017;389(10064):67-76; 3. Balar AV; et al. Lancet Oncol. 2017;18:1483-1492. Use PD-L1 expression to select therapy for cisplatin-ineligible patients?

5/18/2018 FDA Alert •In two ongoing clinical trials (KEYNOTE-361 and PD-L1 (IHC) IMVIGOR-130), the Data Monitoring Committees’ (DMC) found patients in the monotherapy arms of both trials with PD-L1 low status had decreased survival compared to patients who received cisplatin- or Low High carboplatin-based chemotherapy. •Both trials have stopped enrolling patients whose tumors have PD-L1 low status to the Keytruda or Carboplatin- Tecentriq monotherapy arms. Pembrolizumab/ based •The monotherapy arms remain open only to patients atezolizumab chemotherapy whose tumors have PD-L1 high status. First Line Chemotherapy +Checkpoint Therapy trials in Metastatic Urothelial Cancer

CT ID Phase Target Experimental Arm(s) Standard Arm NCT02807636 III PD-L1 Atezo Placebo + Gem-Plat IMvigor130 OR Atezo + Gem-Plat NCT02853305 III PD-1 Pembro Gem-Plat KEYNOTE-361 OR Pembro + Gem-Plat NCT02516241 III PD-L1 +/- Durvalumab Gem-Plat DANUBE CTLA-4 OR Durva + Treme NCT03036098 III PD-1 + CTLA Nivo + Ipi* Gem-Plat CM-901

*This trial includes a substudy for cisplatin-eligible patients comparing gemcitabine + cisplatin +/- nivolumab. Approvals: Previously-treated Disease May 2016 Feb 2017 May 2017

Atezolizumab Nivolumab Durvalumab Avelumab Pembrolizumab

Above agents are indicated in patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with (platinum-containing) chemotherapy. IMvigor210 (Cohort 2)

Key primary endpoint : Cohort 2-Specific Inclusion Criteria •Confirmed ORR: RECIST v1.1 • Progression during/following platinum (per central IRF) (no restrictions on # prior lines of therapy) • ECOG PS 0-1 Key secondary endpoints : • CrCl ≥ 30 mL/min •DOR, PFS, OS, safety Rosenberg et al. Lancet. 2016; 387:1909. IMvigor210 (Cohort 2)

All patients: • ORR = 15% (5% CR) • mOS = 7.9 months

Rosenberg et al. Lancet. 2016; 387:1909. Phase Ia Trial of Atezolizumab in Pretreated Bladder Cancer

• N = 92 • 72% with ≥2 prior systemic therapies • ORR 50% in PD-L1 high (IC2/3) • ORR 17% in PD-L1 low (IC0/1)

Petrylak et al. ASCO 2015; Abstract 4501. OS by PD-L1 Status

Petrylak et al. ASCO 2015; Abstract 4501. Median Survival by Baseline Characteristics

Petrylak et al. ASCO 2015; Abstract 4501. Patterns of AE Occurrence

Petrylak et al. ASCO 2015; Abstract 4501. IMvigor211 Phase III Trial in Previously-treated Urothelial Cancer

Vinflunine, paclitaxel, or docetaxel Patients with previously treated IV q3w until progression relapsed UBC (n = 767 [230 PD-L1+]) Atezolizumab 1200 mg IV q3w • Primary endpoint: OS in IHC 2/31/2/3ITT • Secondary endpoints: PFS, ORR, DOR • FPI: Q4 2014 .

FPI=first patient in; ITT=intent-to-treat. http://www.clinicaltrials.gov/ct2/show/NCT02108652. 27 IMvigor211 Study Design

a Key Eligibility Criteria Atezolizumab Loss of • mUC with progression during or 1200 mg q3w clinical benefit following platinumPrimary-based endpoint: chemotherapy Key secondary endpoints: – ≤ 2 prior lines of therapy OS R ORR,No crossover then PFS permitted Survival • Measurable disease per RECIST v1.1 2-sided  = 0.05 per protocol • ECOG PS 0-1 1:1 follow-up • Evaluable sampleOS: for PD IC2/3-L1 testing ORR: IC2/3 PFS: IC2/3 • TCC histology as primary component Chemotherapy RECIST v1.1 (N = 931) (investigator’s choice) progression • Vinflunine q3w StratificationOS: IC1/2/3 Factors ORR:• DocetaxelIC1/2/3 q3w PFS: IC1/2/3 • No. of risk factorsb (0 vs. 1/2/3) • Paclitaxel q3w • Liver metastases (yes vs. no) • PD-L1 status (0/1 vs. 2/3) • Chemotherapy (vinflunineOS: ITT vs. taxanes) ORR: ITT PFS: ITT ▪ Primary endpoint ▪ Additional endpoints – OS, tested hierarchically – Efficacy: RECIST v1.1 ORR, PFS and DORc in pre-specified populations – Safety – PROs: EORTC QLQ-C30 DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment of Cancer; PRO, patient-reported outcome; q3w, every three weeks; RECIST, Response Evaluation Criteria In Solid Tumors; TCC, transitional cell carcinoma. a ClinicalTrials.gov, NCT02302807. b Defined by time from prior chemotherapy < 3 mo, ECOG performance status > 0 and hemoglobin < 10 g/dL. c Confirmed response was not required 27 for secondary efficacy endpoints. This analysis reports exploratory confirmed responses. Powles T, et al. EAS 2017, IMvigor211. OS Analysis: IC2/3 Population

Events/ Median OS 12-mo OS Rate Patients (95% CI) (95% CI) 100 Atezolizumab 72/116 11.1 mo (8.6, 15.5) 46% (37, 56) Chemotherapy 88/118 10.6 mo (8.4, 12.2) 41% (32, 50) 80

40 OverallSurvival 20 HR = 0.87 (95% CI: 0.63, 1.21) 0 P = 0.41 0 2 4 6 8 10 12 14 16 18 20 22 24

No. at Risk Months Atezolizumab 116 100 85 77 71 58 51 39 27 19 11 6 0 Chemotherapy 118 100 91 82 71 61 47 32 24 15 9 5 1

28 HR, hazard ratio. Powles T, et al. EAS 2017, IMvigor211. OS Analysis: IC1/2/3 Population

Events/ Median OS 12-mo OS Rate Patients (95% CI) (95% CI) 100 Atezolizumab 220/316 8.9 mo (8.2, 10.9) 40% (35, 46) Chemotherapy 232/309 8.2 mo (7.4, 9.5) 33% (28, 39) 80

40 OverallSurvival 20 HR = 0.87 (95% CI: 0.71, 1.05) 0 P = 0.14 0 2 4 6 8 10 12 14 16 18 20 22 24

No. at Risk Months Atezolizumab 316 274 232 198 175 141 122 97 64 41 23 9 1 Chemotherapy 309 273 228 188 153 121 95 66 46 31 15 7 1

29 Powles T, et al. EAS 2017, IMvigor211. OS Analysis: ITT Population

Events/ Median OS 12-mo OS Rate Patients (95% CI) (95% CI) 100 Atezolizumab 324/467 8.6 mo (7.8, 9.6) 39% (35, 44) Chemotherapy 350/464 8.0 mo (7.2, 8.6) 32% (28, 37) 80

OverallOverallSurvivalSurvival 20 HR = 0.85 (95% CI: 0.73, 0.99) 0 P = 0.038 0 2 4 6 8 10 12 14 16 18 20 22 24

No. at Risk Months Atezolizumab 467 405 327 280 245 201 177 138 90 59 34 13 1 Chemotherapy 464 397 330 268 219 175 140 99 60 42 17 7 1

▪ Median follow-up duration in ITT population: 17.3 mo (range, 0 to 24.5 mo)

30 Powles T, et al. EAS 2017, IMvigor211. OS by Chemotherapy Type

▪ OS was also examined in 100 subgroups based on chemotherapy 80 ITT With Taxane type at randomization 60 – Improved OS was observed 40 with atezolizumab vs. taxanes 20

Overall Survival Overall HR = 0.73 (95% CI: 0.58, 0.92) 0 Median OS 0 2 4 6 8 10 12 14 16 18 20 22 24 Subgroup (95% CI) No. at Risk Months Atezolizumab 8.3 mo (6.6, 9.8) Atezolizumab 215 186 153 125 106 89 81 66 45 34 19 7 0 Taxane 214 179 147 122 94 74 58 35 20 16 4 3 1 Taxane 7.5 mo (6.7, 8.6)

31 Powles T, et al. EAS 2017, IMvigor211. Phase Ib JAVELIN Solid Tumor Trial of Avelumab: Trial Schema

• Open-label, multicenter phase Ib study in pts with confirmed solid tumors Advanced UC Cohort: Pts with histology or cytology confirmed Treated until PD, unacceptable metastatic UC after progression on Avelumab AE, or investigator decision or ineligible for platinum-based 10 mg/kg IV Q2W chemotherapy for metastatic disease; ECOG PS 0-1 (N = 241) ▪ Primary endpoint: ORR, safety ▪ Secondary endpoints: PFS, OS, and association of PD-L1 expression on tumor cells with clinical activity of avelumab

Patel M, et al. ASCO GU 2017. Abstract 330. Phase Ib JAVELIN Solid Tumor Trial of Avelumab (ASCO17 Update) ORR in patients with ≥6 months follow-up (N = 161): 17% (6% CR)

N = 242

mOS 7.4 mo

1.5 mo mPFS (6.6 wk)

Apolo, et al. ASCO17; Abstract 4528. KEYNOTE-045: Phase III Study Design

CPS, combined positive score; PD, progressive disease. Bellmunt et al. SITC 2016; Abstract 02. Median OS HR P Value Median PFS HR P Value Pembro 10.3 mo Pembro 2.1 mo 0.70 .0004 0.96 .32 Chemo 7.4 mo Chemo 3.3 mo

Pembrolizumab Chemotherapy Data cutoff: Jan 18, 2017 ORR 21% 11% Median follow-up: 18.5 mo CR 8% 3%

Bajorin et al. ASCO 2017, Abstract 4501. Future Directions

Non Muscle Invasive Disease Combinations Adjuvant therapy Biomarkers Addition of Ipilimumab to Nivolumab at Progression • 10 patients who evidenced progression of disease on nivolumab. • 1 PR, 4 SD after addition of ipilimumab. • Modest increase in grade 3/4 toxicities.

Callahan et al. ASCO GU 2017; Abstract 384. Checkmate 032 Checkmate 032 Ipilimumab(Ipi) +Nivolumab(N) ORR PFS OS N 3 mg/kg 26% 2.8 9.9

N+ Ipi 3 mg/kg 27% 2.6 7.4

N+ Ipi 1 mg/kg 38% 4.9 15.3 PDL-1 Expression and ORR Adjuvant PD-1/PD-L1 Inhibitor Phase III Trials

PI Population Control Experimental Primary Arm Arm Endpoint Industry All-comers MIUC No therapy Atezolizumab PFS Prior NAC- ≥pT2 No AC ≥pT3 Industry All-comers MIUC Placebo Nivolumab PFS Prior NAC- ≥pT2 No AC ≥pT3 Intergroupa All-comers MIUC No therapy Pembrolizumab PFS/OS Prior NAC- ≥pT2 No AC ≥pT3

aPI: Apolo; SWOG PI: Sonpavde; ECOG PI: Srinivas. Neoadjuvant Therapy With IO Agents Selected Phase I-II Trials

Trial ID Phase Regimen Primary Endpoint

NCT03294304 II GC-Nivolumab pCR

Chemo-IO NCT02690558 II GC-Pembrolizumab pCR

NCT02365766 I/II G/GC-Pembrolizumab Feasibility, pCR

NCT02451423 II Atezolizumab pCR, immune response IO NCT02736266 II Pembrolizumab pCR

NCT02812420 II Durvalumab + Tremelimumab Feasibility

NCT02845323 II Nivolumab +/- Urelumab Immune response IO-IO Pending I Durvalumab +/- CD73i Feasibility, Immune response Planned Phase III Trial by NRG, SWOG ChemoRT +/- Concurrent  Adjuvant Atezolizumab

ATEZOLIZUMAB x 1 year

RT + Chemotherapy (5-FU-MMC, Survival Cisplatin +/- 5-FU) PFS

OBSERVE Targeted Therapy in Urothelial Cancer

Atezolizuma b Vinflunin 1.Immunotherapy is active only in a small subset of patients Accelerated 2.Resistance to immunotherapyMVAC is often seen. Gem/Ci s 3.SignificantStandard MVAC percentage of patients are not fit enough to receive Cisplatin-combination chemotherapy.

1978:4.In Cisplatin this era of precision medicine, there is no FDA approved, US FDA biomarker-selected targeted therapy for 2009:mUC . Approved 2009: Vinflunine EMA Approved 2016: Atezolizumab US FDA Approved UC is molecularly heterogeneous

• While multiple pathways are altered, the frequency of mutation in any one gene/ pathway is modest, at best • Unselected trials with targeted agents unlikely to yield positive results

TCGA Network, Nature 2014 Multiple alterations in kinase signaling pathways

TCGA Network, Nature 2014 TSC1 mutations in TCC

Frequency of TSC1 or TSC2 mutations: 8 to 15%.*

* Sjödahl G et al. PLoS One. 2011 Knowles MA et al. Cancer Metastasis Rev 2009 Pymar LS et al. Hum Mol Genet 2008; Personalized medicine in UC: mTOR/TSC1

• Whole genome sequencing revealed TSC1 and NF2 inactivating mutations • In vitro evaluation shows TSC1 sensitizes urothelial cancer cells to mTOR inhibition

G Iyer et al. Science 2012;338:221 Personalized medicine in UC: mTOR/TSC1

• Patient treated on phase I study of everolimus/ pazopanib • CR lasting 14 months • WES showed activating mTOR mutations

Mutations are activating, and can be inhibited by rapamycin in vitro Wagle, et al. Cancer Discovery 2014 MLN-0128 (aka. TAK228): NCI Protocol 9767

• Potent, highly selective ATP-competitive inhibitor of mTOR kinase that exhibits dual specificity against both TORC1 and TORC2 complexes. • Dual TORC1/2 inhibition mitigates the feedback activation of AKT, known to cause resistance to TORC1 selective inhibitors. • Displays cellular inhibition of TORC1 and TORC2 pathways with IC50 less than 10 nM. • Potential of greater clinical activity than the currently available rapalogs. Schema (NCI Protocol 9767)

TSC1 / TSC2 mutation sequencing to be done at Yale Profiling Lab by Dr. Primary Jeff Sklar Endpoint: ORR N=25 FGFR-3(Fibroblast Growth Factor Receptor)

• A membrane based tyrosine kinase receptor involved in cellular proliferation, differentiation, and steroid biosynthesis.17 FGFR-3(Fibroblast Growth Factor Receptor)

• In addition to activating mutations, FGFR over- expression has been implicated in bladder cancer with Turo et al. noting up-regulated FGFR expression via IHC in 53 and 56 of 106 matched pairs of primary tumors and metastases. 18

• FGFR inhibitors and anti-FGFR antibody-drug conjugates are in ongoing and upcoming trials in advanced urothelial carcinoma. BISCAY – Umbrella Study A biomarker-directed study in patients with muscle-invasive bladder cancer Treatment option MOA Biomarkers Adjusted Prev Module A: Durvalumab* +AZD4547 OR FGFR FGFR3 mutations/ ~11% AZD4547 inhibitor fusions

PARP ATM, BRCA1/2, Module B: Durvalumab* + Lynparza HRR gene trunc or ~19%  inhibitor missense mut/del

Dx sample Module B2: Durvalumab + Treme + Lynparza analysed CDKN2A loss WEE1 RB1 loss Module C: Durvalumab* + AZD1775 CCNE1 ampl ~46% inhibitor MYC ampl Module C2: Durvalumab + Treme + AZD1775 PD-L1 Module D: Durvalumab* None ~22% only

Assignment to module dependent on presence of biomarker *PD-L1 54 Binding of Ramucirumab to VEGFR-2 and Icrucumab to VEGFR-1 Inhibits Subsequent Signaling Rationale for VEGF Blockade in Bladder Cancer • Antiangiogenic agents, particularly anti-VEGFR-2 monoclonal antibodies (MAbs), may be capable of acting as chemosensitizing agents when given in combination with docetaxel, since this effect was demonstrated in mice when an anti-VEGFR-2 MAb, DC101, was combined with paclitaxel. • Anti-VEGFR-1 MAbs may inhibit metastasis, based on the observed impact of the anti-VEGFR-1 MAb, MF1, on VEGFR-1-positive circulating hematopoietic progenitor cells in mice. Enfortumab Vedotin: Proposed Mechanism of Action

Enfortumab Vedotin is being co-developed by Seattle Genetics, Inc. and Astellas Pharma Inc.

Presented by: Daniel P. Petrylak Study Design

• This phase 1, 3-part study (NCT02091999) enrolled patients with metastatic malignant solid tumors treated with ≥1 prior chemotherapy regimen • IV administration over 30 minutes on Days 1, 8, and 15 every 28 days • Study enrollment in Parts B and C ongoing

Part B (enrolling) Part A (closed) Dose expansion: 3 cohorts (n=15/cohort) Dose escalation/expansion, adaptive trial • Cohort 1: Urothelial Cancer-Cis-ineligible design utilizing a Continual Reassessment (1 mg/kg escalating to 1.25 mg/kg) Method, to determine RP2D RP2D • Cohort 2: NSCLC (1.25 mg/kg) • Cohort 1: 0.5 mg/kg 1.25 • Cohort 3: Ovarian Cancer (1.25 mg/kg) • Cohort 2: 0.75 mg/kg mg/kg • Cohort 3: 1 mg/kg Part C (enrolling) • Cohort 4: 1.25 mg/kg Dose expansion: 1 cohort (n=60) Nectin-4 expressing tumors, including mUC • CPI-treated mUC patients (1.25 mg/kg)

https://www.clinicaltrials.gov. Accessed 12 May 2017.

Presented by: Daniel P. Petrylak Screening of Nectin-4 Expression in mUC

• At screening, patients with mUC had samples that were centrally assessed 300 by immunohistochemistry (IHC) for 250 Nectin-4 – Almost all patient (97%) samples 200 showed Nectin-4 expression

– Expression of Nectin-4 was high 150

score -

(median H-score 280 out of a 300 H 100 maximum score) • Due to the above findings, pre- 50 screening for Nectin-4 is no longer an 0 eligibility requirement for subjects with Patients mUC Gray bars indicate patients with Nectin-4 H-score <150 Blue bars indicate patients with H-scores of ≥150 Note: data cutoff November 2016, N=186

Presented by: Daniel P. Petrylak EV-101: Disposition of Patients With Metastatic Urothelial Cancer

Patients With mUC Patients with mUC All Doses 1.25 mg/kg EV (N=155) (N=112 )

Subjects continuing treatment, n (%) 29 (19) 27 (24) Treatment discontinuations, n (%) 126 (81) 85 (76) Disease progression (radiographic) 83 (53.5) 56 (50) Disease progression (clinical symptoms) 11 (7) 7 (6) Adverse event 18 (12) 12 (11) Subject withdrew consent 5 (3) 3 (3) Investigator’s decision 7 (4.5) 5 (4) Other 2 (1) 2 (2) 22.6 23.7 Median time on treatment, weeks (range) (1.1, 89) (1.1, 78) Data presented as n (%). mUC, metastatic urothelial cancer. Data cut-off date is April 9, 2018.

Jonathan E. Rosenberg

6 0 EV–101: Demographics and Disease Characteristics

Patients With mUC Patients With mUC 1.25 mg/kg 1.25 mg/kg (N=112) (N=112) Median age, years (range) 67 (24–86) Primary tumor site bladder, n (%) 86 (77) Male, n (%) 82 (73) Site of metastases at baseline, n (%) Race, n (%) Liver 33 (29) Caucasian 103 (92) Lung 54 (48) Asian 5 (5) Lymph node only 21 (19) Other 3 (3) ≥2 prior therapies in the metastatic 71 (63) ECOG Score setting, n (%) 0 36 (32) Prior platinum-based therapy, n (%) 105 (94) 1 76 (68) Prior taxane treatment, n (%) 32 (29) Hemoglobin levels <10 g/dL, n (%) 23 (21) Prior CPI treatment, n (%) 89 (79) GFR <60 mL/min 56 (50) CPI was most recent therapy 65 (73*) Data cut-off date is April 9, 2018. Data cut-off date is April 9, 2018. ECOG, Eastern Cooperative Oncology Group; GFR, Glomerular filtration rate; *Percentage based on number of patients with prior CPI. mUC, metastatic urothelial cancer. CPI, checkpoint inhibitors; mUC, metastatic urothelial cancer.

Jonathan E. Rosenberg

6 1 Enfortumab Vedotin Toxicity Profile

• Consistent with previous reports, EV Patients With mUC 1 1.25 mg/kg was generally well tolerated (N=112) Treatment-Related Adverse Events in ≥25% of Patients With mUC All Grade Grade ≥3 • The majority of adverse events Fatigue 60 (54) 1 (1) considered at least possibly related Alopecia 50 (45) 0 to EV were mild-to-moderate in Decreased appetite 45 (40) 1 (1) severity Dysgeusia 43 (38) 0 Nausea 40 (36) 1 (1) Pruritus 39 (35) 1 (1) Peripheral neuropathy 39 (35) 0 Diarrhea 36 (32) 1 (1) Maculo-papular rash 28 (25) 3 (3) Data cut-off date is April 9, 2018. Data presented as n (%). Adverse events listed are individual preferred terms. mUC, metastatic urothelial cancer.

Jonathan E. Rosenberg

1Petrylak DP et al. J Clin Oncol. 2017;35:106–106.

6 2 Grade ≥3 Adverse Events Regardless of Treatment Attribution Patients With mUC 1.25 mg/kg (N=112) Grade ≥3 Adverse Events in ≥5% Patients with mUC Regardless of Treatment Attribution Anemia 9 (8) Hyponatremia 8 (7) Urinary tract infection 8 (7) Hyperglycemia 7 (6) Grade 5 Adverse Events Regardless of Treatment Attribution Diabetic ketoacidosis* 1 (0.9) Dyspnea 1 (0.9) Multiple organ dysfunction syndrome* 1 (0.9) Progressive disease 1 (0.9) Sepsis 1 (0.9) Small intestinal perforation 1 (0.9) Respiratory failure* 1 (0.9) Urinary tract obstruction* 1 (0.9) Data cut-off date is April 9, 2018. Data presented as n (%). Adverse events listed are individual preferred terms. *Fatal AEs that were considered at least possibly related to enfortumab vedotin. mUC, metastatic urothelial cancer.

Jonathan E. Rosenberg

6 3 Investigator-Assessed Response in Patients With mUC on Enfortumab Vedotin

1.25 mg/kg (N=112)a

Confirmed CR 4% Confirmed PR 37% Confirmed ORRb (95% CI) 41% (31.9, 50.8) SD 30% DCRb (95% CI) 71% (62.1, 79.6)

Data cut-off date is April 9, 2018. CR, complete response; DCR, disease control rate (DCR=CR+PR+SD); overall response rate (ORR=CR+PR); PR, partial response; SD, stable disease. aPatients must have at least one post-baseline assessment; responses assessed per RECIST 1.1. b95% CI based on the Clopper-Pearson method.

Jonathan E. Rosenberg

1 0 Duration of Response in Patients With Metastatic Urothelial Carcinoma

Median duration of confirmed 5.75 response, months (range) (1.8, 12.9)

Jonathan E. Rosenberg

6 5 Clinical Response With Enfortumab Vedotin in mUC Patients With or Without Prior CPI or Liver Metastases

Prior CPI Treatmenta CPI-Naïvea Liver Metastasesa 1.25 mg/kg 1.25 mg/kg 1.25 mg/kg (n=89) (n=23) (n=33) Confirmed CR 3.4% 9% 0 Confirmed PR 37% 35% 39% 40% 44% 39% Confirmed ORRb (95% CI) (30.2, 51.4) (23.2, 65.5) (22.9, 57.9) SD 34% 17% 21% 74% 61% 60% DCRb (95% CI) (63.8, 82.9) (38.5, 80.3) (42.1, 77.1) Data cut-off date is April 9, 2018. Data presented as n (%), unless otherwise indicated. CR, complete response; CPI, checkpoint inhibitor, DCR, disease control rate (DCR=CR+PR+SD); PR, partial response; ORR, overall response rate (ORR=CR+PR); SD, stable disease. aEvaluable patients must have at least one post-baseline assessment; responses assessed per RECIST 1.1. bData presented as % (95% CI); 95% CI based on the Clopper-Pearson method.

Jonathan E. Rosenberg

6 6 Clinical Response With Enfortumab Vedotin in mUC Patients With or Without Prior CPI or Liver Metastases

Jonathan E. Rosenberg

6 7 Progression-Free Survival in Patients With mUC Treated With Enfortumab Vedotin 1.25 mg/kg

Median PFS, Months (95% CI)

All patients with mUC 5.4 (5.1, 6.2) Patients with prior 5.4 (5.1, 6.2) CPI

Jonathan E. Rosenberg

6 8 Preliminary Overall Survival in Patients With mUC Treated With Enfortumab Vedotin 1.25 mg/kg

Overall Survival OS at 6 Months, % All patients with mUC 74.4 Patients with prior 75.6 CPI OS at 12 Months, % All patients with mUC 56.3 Patients with prior 54.2 CPI Data cut-off date is April 9, 2018.

Jonathan E. Rosenberg

6 9 Trials in Progress

• Phase II trial of Enfortumab Vedotin – Platinum treated cohort: 100 patients closed to accrual – Cisplatin ineligible, carboplatin naïve: Accruing, targeting 100 patients

• Phase I trial of Enfortumab Vedotin +pembrolizumab

• Phase III trial of Enfortumab Vedotin vs chemotherapy (paclitaxel, docetaxel, vinflunine)in checkpoint failures Sacituzumab Govitecan (IMMU- 132) in Patients With Previously Treated Metastatic Urothelial Cancer (mUC): Results From a Phase I/II Study

Scott T. Tagawa1, Bishoy Faltas1, Elaine T. Lam2, Philip Saylor3, Aditya Bardia3, Julio J. Hajdenberg4, Alicia K. Morgans5, Emerson Lim6, Kevin Kalinsky6, Pamela Simpson7, Matthew D. Galsky8, Robert M. Sharkey9, David M. Goldenberg9†, Trishna Goswami9, William A. Wegener9, Daniel Petrylak10 1Weill Cornell Medicine, New York, NY; 2University of Colorado Cancer Center, Aurora, CO; 3Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA; 4University of Florida Health Cancer Center, Orlando, FL; 5Vanderbilt Ingram Cancer Center, Nashville, TN; 6Columbia University Irving Medical Center-Herbert Irving Comprehensive Cancer Center, New York, NY; 7Helen F. Graham Cancer Center, Christiana Care Health System, Newark, DE; 8Icahn School of Medicine Mount Sinai, Tisch Cancer Institute, New York, NY; 9Immunomedics, Inc., Morris Plains, NJ; 10Yale School of Medicine, Yale Cancer Center, New Haven, CT. *Work done while Chairman and Chief Scientific Officer of Immunomedics, Inc.

View Poster Board #B5; Feb 15th 5:15 PM mUC results in IMMU-132-01 Study

Sacituzumab Govitecan is a Trop-2-Directed Antibody-Drug Conjugate (ADC)

• Trop-2 is an epithelial cell surface antigen highly expressed in UC1. Linker for SN-38 • Hydrolysable linker for Humanized anti-Trop-2 payload release antibody • Sacituzumab govitecan is distinct from • High drug-to-antibody • Directed towards Trop- other ADCs:2-6 ratio (7.5:1)5 2, an epithelial antigen 5 − High drug-to-antibody ratio expressed on many − Hydrolysis of the linker releases the solid cancers SN-38 cytotoxic intracellularly and in the tumor microenvironment. Thus, SN-38 payload Sacituzumab govitecan-bound tumor • SN-38 more potent than cells are killed by intracellular uptake parent compound, of SN-38, and adjacent tumor cells are irinotecan killed by SN-38 released • In xenograft models, extracellularly6 ADC delivers up to 136- fold more SN-38 than • Sacituzumab govitecan has shown irinotecan preclinical and clinical activity.3,7,8 Trop-2: trophoblast cell surface antigen 2; 1. Avellini et al. Oncotarget 2017;8:58642.. 2. Starodub et al. Clin Cancer Res 2015;21:3870. 3. Cardillo et al. Clin Cancer Res. 2011;17:3157-3169. 4. Sharkey et al. Clin Cancer Res. 2015;21:5131- 5138. 5. Cardillo et al. Bioconjugate Chem. 2015;26:919-931. 6.Govindan et al. Mol Cancer Ther. 2013;12:968-978. 7. Faltas et al. Nat Genet. 2016;48:1490-1499. 8. Bardia et al. J Clin Oncol. 2017;35:2141-2148

72 mUC results in IMMU-132-01 Study

Demographic and Baseline Characteristics

Characteristic N=45 Characteristic N=45 Age (y), median (range) 67 (49, 90) Median prior anticancer regimens, range 2 (1-6) Male, n (%) 41 (91) Median prior anticancer regimens in CPI-treated 3 (1-6) Race, n (%) pts (n=17), range White 39 (87) Lines of prior therapies, n, (%) Black 2 (4) ≤2 prior lines 28 (62) Asian 1 (2) ≥3 prior lines 17 (38) Other 2 (4) Bellmunt risk groups*, n, (%) Not reported 1 (2) Low 25 (56) ECOG PS, n (%) Intermediate 16 (36) 0 14 (31) High 4 (9) 1 31 (69) Visceral metastatic sites, n (%) 33 (73) Lung 27 (60) Liver 15 (33) Other 5 (11) *Placeholder for Bellmunt risk groups description. Nonvisceral metastatic sites, n (%) 12 (27) *Risk factors are ECOG PS >0, presence of liver metastases, and hemoglobin <10 g/dL

73 mUC results in IMMU-132-01 Study

Adverse Events (Worst Grade CTCAE) ≥20% or 5% grade ≥3 (Regardless of Causality; N=45)

• Most frequent SAEs included: Event All Grades (%) Grades 3 (%) Grade 4 (%) – Febrile neutropenia, diarrhea and Diarrhea 69 9 0 neutrophil count decreased in 2 pts each Nausea 67 2 0 Fatigue 58 9 0 – 24% of pts used GCSF Neutropenia* 51 22 16 Constipation 44 0 0 • No treatment-related deaths Alopecia 40 0 0 Decreased appetite 38 0 0 Anemia 33 13 0 • 6/45 pts discontinued due to AE not related to Cough 31 0 0 Vomiting 31 2 0 progressive disease Pyrexia 24 0 0 – No patient discontinued due to Back pain 22 0 0 neutropenia Dizziness 22 0 0 Rash 22 0 0 – And one patient discontinued due to Hypophosphatemia 20 11 0 diarrhea Febrile neutropenia 7 7 0 *Combined terms of Neutropenia' or 'Neutrophil count decrease'. GCSF, granulocyte colony-stimulating factor; SAE, serious adverse event.

74 mUC results in IMMU-132-01 Study

Objective Response Rate by Subgroup

Objective Response Rate, % (n/N) [95% CI]

Overall cohort 31.1 (14/45) [18.2, 46.6]

Lines of prior therapies ≤2 prior lines 39.3 (11/28) [21.50, 59.42] ≥3 prior lines 17.6 (3/17) [3.80, 43.43]

Prior checkpoint inhibitors 23.5 (4/17) [6.81, 49.90] (median of 3 prior lines of therapy)

Prior platinum and checkpoint 26.7 (4/15) [7.79, 55.10] inhibitors

Visceral involvement at study entry Yes 27.3 (9/33) [13.30, 45.52] Liver 33.3 (5/15) [11.82, 61.62] No 41.7 (5/12) [15.17, 72.33]

75 mUC results in IMMU-132-01 Study

Best Percent Change From Baseline in Tumor Size*

† Target Lesions Target

‡ Best Percent Change FromBaseline Change PercentBest ** • Excludes 5 pts with no post-baseline scans CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. *Based on the sum of the diameters of the target lesions (longest for non-nodal, short axis for nodal lesions); †pt had % change of 0 with best overall response of PD; ‡qualified for CR based on lymph node target lesion shrinkage to <10 mm. **One subject had 100% reduction of target lesions, but limited response in non-target lesions, hence classified as PR.

76 mUC results in IMMU-132-01 Study

Patients With Objective Responses (n=14/45) and all three of them are still on treatment

Overall Endpoint (N=45) 14 (31) ORR (CR or PR), n (%) [95% CI] [18.2, 46.6] CR, n (%) 2 (4) PR, n (%) 12 (27) Time to onset of response (mo), Median 1.9 (Range) (1.7, 7.4) Duration of response (mo), Median 12.9 (Range) (1.3, 29.4+)

• 50% of responders demonstrated Censored: subjects whose duration of responses are censored due to missing 2 tumor assessments or a DoR of ≥ 12 mo discontinuation Three patients have ongoing response with durations of 16.9+, 18.7+, and 29.4+ months and all three of them are still on treatment

77 mUC results in IMMU-132-01 Study

Progression-Free and Overall Survival*

Progression-Free Survival Overall Survival

1.0 1.0 0.9 MedianMedian PFS PFS 0.9 Median OS 0.8 7.37.3 months months 0.8 16.3 months 0.7 (95%(95% CI: CI: 5.0, 5.0, 10.7) 10.7) 0.7 (95% CI: 9.0, 0.6 0.6 31.0) 0.5 0.5 0.4 0.4 0.3 0.3

0.2 0.2 Probability of OS of Probability Probability of PFS of Probability 0.1 0.1 0.0 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 At risk: 45 29 19 13 8 6 5 3 2 2 1 0 45 40 32 30 25 23 17 12 9 7 6 3 2 1 0 Time (months) Time (months)

*Data as of Sept 1, 2018; PFS: 3 progression-free pts have an ongoing response and on treatment; OS: 5 live pts still on treatment. OS, overall survival; PFS, progression-free survival.

78 mUC results in IMMU-132-01 Study

Summary

• Sacituzumab govitecan, a novel Trop-2-directed ADC, demonstrated clinically significant activity in pts with heavily pre-treated relapsed/refractory mUC – ORR: 31% (2 CR, 12 PR) overall with an ORR of 39% in those with ≤2 prior lines of treatment • 26.7% in CPI- and platinum-treated pts • 33.3% in pts with liver metastases – Median duration of response: 12.9 months – Median PFS: 7.3 months – Median OS: 16.3 months • Sacituzumab govitecan was well tolerated, with a predictable safety profile – Most common treatment-emergent AEs were neutropenia and diarrhea, which were manageable – Low rate of patient discontinuation due to AEs • No patients discontinued due to neutropenia and 1 patient discontinued due to diarrhea – No treatment-related deaths • In conclusion, sacituzumab govitecan demonstrated significant clinical activity in pts with relapsed/refractory mUC, including pts with prior CPI + platinum treatment and visceral disease

79 mUC results in IMMU-132-01 Study TROPHY-U-01 (IMMU-132-06) Study A Phase II Open Label, Study of IMMU-132 in Metastatic Urothelial Cancer After Failure of Platinum-based Regimen or Anti-PD-1/ PD-L1 Based Immunotherapy

• Results from the Study-01 basket trial warranted further investigation in a dedicated phase 2 trial.

• TROPHY-U-01 (NCT03547973) is an international, single-arm, open-label, phase 2 trial evaluating the antitumor activity and safety of sacituzumab govitecan in 140 pts with advanced UC.

Cohort 1 (100 patients): pts who Objectives: progressed after prior platinum- • Overall response rate based and anti PD-1/anti PD-L1 Continue (ORR) will be centrally Sacituzumab Govitecan 10 mg/kg based therapies. Days 1 and 8, every 21 days treatment in the reviewed absence of • Duration of response Cohort 2 (40 patients): pts ineligible unacceptable (DOR) for platinum-based therapy and who toxicity or PD • Progression-free survival progressed after prior anti PD-1/anti (PFS) PD-L1 based therapies. • Overall survival (OS)

NCT Trial Number: 03547973 PD-1, programmed cell death-1; PD-L1, programmed death ligand-1. View TROPHY-U-01 Poster on Feb 15th TPS #495; Poster Board #N5