Azenosertib Clinical Update Dose Selection, Monotherapy and Chemotherapy Combinations Efficacy and Safety and Ongoing Development June 2023 Nasdaq: ZNTL
2 Forward Looking Statement and Disclaimer Zentalis Pharmaceuticals, Inc. (“we,” “us,” “our,” “Zentalis” or the “Company”) cautions that this presentation (including oral commentary that accompanies this presentation) contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995. 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3 Today’s Agenda 1 Review of Azenosertib Monotherapy Trial Results: Declaration of New Azenosertib Monotherapy Dose 2 Currently Accruing Trials in Ovarian Cancer and USC Review of Azenosertib + Chemotherapy in Platinum-Resistant Ovarian Cancer (Presented Yesterday: ASCO Abstract 5513)3 Proposed Phase 3 Chemotherapy Combination Trial4 Q&A5
Joining the Call Today 4 Kimberly Blackwell, MD Chief Executive Officer Zentalis Pharmaceuticals Carrie Brownstein, MD Chief Medical Officer Zentalis Pharmaceuticals Funda Meric-Bernstam, MD Chair of the Department of Investigational Cancer Therapeutics -- the Phase 1 Program at The University of Texas MD Anderson Cancer Center; Member, Zentalis Scientific. Advisory Board
5 Zentalis’ Clinical Transformation Has Yielded Significant Progress • To develop first in class and best in class therapies against known cancer targets Purpose Positioned to Execute and Deliver • Management team with deep oncology experience • Respected scientific and clinical advisors • Established partnerships with Pfizer, GSK • Multiple opportunities in hematologic malignancies • 100+ patients dosed to date Promising Programs: BCL-2i and Degrader • High potential, validated target in difficult-to-treat tumors • WEE1 inhibitor designed to have superior selectivity and pharmacologic properties • Monotherapy activity and favorable safety profile • 400+ patients dosed to date Azenosertib meets all the criteria People
6 Today’s Call - Two Large Phase 1 Data Sets: Four Critical Take Home Messages Around Azenosertib Combination With Single Agent Chemotherapy Improves Response Rates And Durability Over Chemotherapy Alone In Platinum-resistant/Refractory Ovarian Cancer: • 50% ORR, 5.6 month DOR and a 7.4 month mPFS with paclitaxel • 36% ORR, 11.4 month DOR and a 10.4 month mPFS with carboplatin Comprehensive and Ongoing Development Strategy In Ovarian Cancer and USC: • Phase 2 Monotherapy in USC (all patients) • Phase 2 Monotherapy in platinum-resistant ovarian cancer • Phase 1/2 Monotherapy or in combination/alternating with niraparib PARPi-resistant PROC • Proposed Phase 3 Study in Cyclin E1+ platinum sensitive ovarian cancer • Chemotherapy + azenosertib followed by azenosertib monotherapy maintenance compared to doublet chemotherapy followed by placebo Monotherapy Dose Optimization Has Been Successful: • Confirmed ORR of 36.8% in heavily pre-treated platinum-resistant ovarian cancer and USC • Improved tolerability over other WEE-1 Inhibitor and highly comparable to Antibody Drug Conjugates USC, Uterine Serous Carcinoma; ORR, Confirmed Objective Response Rate; DOR, Duration of Response; mPFS, Median Progression Free Survival.
AZENOSERTIB NEW INTERMITTENT MONOTHERAPY DOSE
8 Azenosertib Intermittent Monotherapy Dose Substantially Improves Antitumor Activity and Tolerability Compared to prior dosing regimen (300 mg continuous), intermittent dosing led to: • More than a doubling of exposures • A near doubling of response in both USC and HGSOC • Confirmed ORR of 36.8% in the patient population* • Maintains or improves safety and tolerability *Response evaluable: have baseline measurable disease by RECIST 1.1, at least one post baseline scan, and received at least o ne dose of drug; Abbreviations: 5:2, 5-days of treatment followed by 2-days off treatment; USC, Uterine Serous Carcinoma; HGSOC, High Grade Serous Ovarian Cancer; ORR, objective response rate Monotherapy Dose Selection: 400 mg intermittent (5 days on, 2 days off a week; 5:2)
9 • WEE1 phosphorylates CDK/Cyclin complexes to engage cell cycle checkpoints, allowing DNA repair to occur • Azenosertib inhibits WEE1: • Leads to dephosphorylation of CDK 1 and 2, activating the cdk/cyclin complexes • Removes 2 cell cycle checkpoints: G1/S and G2/M • Cell cycle progresses without sufficient DNA repair • Cancer cells accumulate DNA damage, resulting in apoptosis and mitotic catastrophe Azenosertib’sMOA and early monotherapy clinical activity made dose optimization critical WEE1 activity in untreated cancer cell Azenosertib blocks WEE1 resulting in cancer cell death Azenosertib Targets WEE1, a Critical Protein for Cancer Cell Survival CDK2/Cyclin E PhosphorylationP WEE1 P P P S G2 M G1 Cell survival Cancer progression P CDK1/Cyclin A Azenosertib WEE1 CDK2/Cyclin E Cell death S G2 M G1 CDK1/Cyclin A Luserna di Rora, et al. 2020. J Hem Onc. 13:126. Elbaek et al. 2022. Cell Reports. 38:110261. Abbreviations: MOA, mechanism of action
10 Increased exposures at steady state Maintained or improved tolerability Finding The Optimal Dose of Azenosertib A m o u n t o f D ru g in B lo o d 300 mg continuous dose demonstrated favorable safety profile and antitumor activity, but preclinical models and clinical data suggested that intermittent dosing would allow for: Therapeutic Index
11 Zentalis 001 Study: From First In Human to Dose Optimization Primary objectives: Safety, PK [Steady State Exposure (AUC0-24) & Concentration Maximum (Cmax)] Phase 1b expansion Intermittent Dosing Dose finding (CRM) Total daily dose, 5:2 or 4:3 schedule Phase 1a Dose Escalation Phase 1b Expansion 500mg 450mg 400mg 350mg 400mg qd 5:2 Continuous Dosing Phase 1a Dose Escalation 450mg 200mg Dose finding (CRM) Total daily dose, continuous schedule 400mg 350mg 300mg 300mg qd Lower doses Study Details: DLT period is 21 days • Tumor assessments (per RECIST 1.1) occur every 2 cycles (6 weeks) • Protocol permits “Backfill” enrollment of additional patients at the highest previously cleared dose level Abbreviations: CRM, continual reassessment method; qd, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; 4:3, 4-days of treatment followed by 3-days off treatment; DLT, dose limiting toxicity; RECIST, response evaluation criteria in solid tumors; PK, pharmacokinetics; AUC, area under the curve NCT04158336
12 Zentalis 001: Heavily Pretreated Patients With Advanced Solid Tumors Continuous N = 74 Intermittent N = 53 Total N = 127 Age Median 67 64 65 Range (Min-Max) (41 - 81) (35 - 83) (35 – 83) Measurable Disease (N, %) 70 (94.6) 53 (100) 123 (96.9) ECOG PS (N, %) ECOG 0 20 (27.0) 18 (34.0) 38 (29.9) ECOG 1 53 (71.6) 35 (66.0) 88 (69.3) ECOG 2 1 (1.4) - 1 ( 0.8) Prior Lines of treatment Mean (range) 4.33 (1-18) 4.71 (1-10) 4.37 (1-18) Prior Therapies (N, %) Prior PARPi 9 (12.2) 13 (24.5) 22 (17.3) Prior experimental agent 30 (40.5) 19 (35.8) 49 (38.6) Prior VEGF-inhibitor 42 (56.8) 31 (58.5) 73 (57.5) Prior anti-PD1/PDL1 35 (47.3) 18 (34.0) 53 (41.7) Data cut-off: April 24, 2023 Patients who received ≥300 mg; Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; PARPi, poly-ADP ribose polymerase inhibitor; VEGF, vascular endothelial growth factor; PD1/PDL1, programmed cell death protein 1/programmed death ligand 1
13 Zentalis 001: Multiple Tumor Types, No Biomarker Stratification N=127 • Clear Cell RCC • NSCLC • Gastric Cancer • Head and Neck SCC • Anal SCC • Melanoma • SCLC • Uterine stromal sarcoma • Small cell ovarian • Carcinosarcoma • Adenoid cystic carcinoma • Appendiceal (includes N ≤ 2) No biomarker, biopsy or prior therapy requirements for enrollment Patients who received ≥300 mg; Abbreviations: USC, uterine serous carcinoma; CRC, colorectal cancer; RCC, renal cell carcinom a; NSCLC, non-small cell lung cancer; SCC, squamous cell carcinoma; SCLC, small cell lung cancer Data cut-off: April 24, 2023
14 Patients who received ≥300 mg; Collected at Day 12 after 3 consecutive days of dosing Abbreviations: 5:2, 5-days of treatment followed by 2-days off treatment; AUC, area under the curve Intermittent Dosing Resulted In A Significant Increase In Steady State Exposure (AUC0-24 ) With intermittent dosing, more patients reach the projected target efficacious steady-state exposure (AUC0-24) Azenosertib (mg) 300 350 400 450 350 400 450 500 Continuous Intermittent 5:2 A U C 0 -2 4 (n g* h r/ m L) mean Intermittent 4:3 Data cut-off: April 24, 2023
15Data cut-off: April 24, 2023 Patients who received ≥300 mg; Collected at Day 12 after 3 consecutive days of dosing Intermittent Dosing Achieves Higher Maximal Concentration (Cmax) Levels
AZENOSERTIB MONOTHERAPY EFFICACY IN OVARIAN AND UTERINE SEROUS CARCINOMA
17 Zentalis 001: Patients With Uterine Serous Carcinoma And Ovarian Cancer After Multiple Prior Therapies 51 Patients Enrolled with Uterine Serous Carcinoma or High-Grade Serous Ovarian Cancer • Continuous and Intermittent dosing schedules • Heavily Pretreated Group of Patients: USC N = 26 HGSOC N = 25 Prior Lines of treatment Mean (Range) 3.4 (1-9) 5.3 (1-18) Platinum Resistant 26 (100%) 25 (100%) Prior Therapies Prior PARPi 2 (7.7) 17 (68.0) Prior experimental agent 5 (19.2) 7 (28.0) Prior VEGF-inhibitor 19 (73.1) 21 (84.0) Prior anti-PD1/PDL1 19 (73.1) 5 (20.0) Patients who received ≥300 mg; Abbreviations: USC, uterine serous carcinoma; HGSOC, high -grade serous ovarian cancer PARPi, poly-ADP ribose polymerase inhibitor; VEGF, vascular endothelial growth factor; PD1/PDL1, programmed cell death receptor 1/programmed death ligand 1 Data cut-off: April 24, 2023
18 Azenosertib Intermittent Dosing Schedule Doubles Objective Response Rate In Ovarian/USC Populations Data cut-off: June 2, 2023 *Response evaluable: have baseline measurable disease by RECIST 1.1, at least one post baseline scan, and received at least o ne dose of drug Patients who received ≥300 mg. Abbreviations: USC, uterine serous carcinoma; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; CI, confidence interval; +: Patients remain on the rapy at the time of data cut-off 0 20 40 60 80 100 120 140 160 180 200 -100 -80 -60 -40 -20 0 20 40 60 80 100 300 300 300 300 300 450 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 300 350 350 300 + + + + +U + + + + + + 0 20 40 60 80 100 120 140 160 180 200 350 500 500 400 500 400 350 400 400 400 400 450 450 450 500 350 350 350 450 B e st P e rc e n t C h an ge fr o m B as e li n e (% ) PR PD Continuous Intermittent CR /PR SD PD Best Overall Response Cohort N* ORR % (95% CI) Intermittent 19 36.8% (16.3, 61.6) Continuous 26 19.2% (6.5, 34.9) Overall 45 26.7% (14.6, 41.9) +
19 Azenosertib Monotherapy Intermittent Dosing: 89% of Ovarian and USC Patients Had Target Lesion Reductions from their Baseline Scans + + + + + ++ + + + + + Baseline Week 6 Week 12 Week 18 Week 24 Week 30 Week 36 PD PR -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 B e st P e rc e n tC h an ge Fr o m B as el in e (% ) Visit Tumor Type Ovarian USC Intermittent Dose Cohort N* ORR % (95% CI) Ovarian 13 30.8 % (9.09-61.4) Uterine Serous Carcinoma 6 50% (11.8-88.2) *Response evaluable: have baseline measurable disease by RECIST 1.1, at least one post baseline scan, and received at least o ne dose of drug; Patients who received ≥300 mg. Abbreviations: USC, uterine serous carcinoma; HGSOC, high-grade serous ovarian cancer SD, stable disease; PR, partial response; ORR, confirmed objective response rate; mPFS, median progression free survival; complete response; NR, Not reached, +: Patients remain on therapy at the time of data cut -off • 12/19 (63%) patients remain on therapy • Median follow up of 4.4 months • mPFS of 5.68 months (2.79, NR) • 10/13 (77%) of ovarian cancer patients had received a prior PARP inhibitor Data cut-off: June 2, 2023
20 Abbreviations: cPR, confirmed partial response; HGSOC, high-grade serous ovarian cancer; SD, stable disease; PD, progressive disease; PR, partial response. Azenosertib Patient Profile: Durable cPR In Cyclin E Amplified Platinum Resistant Ovarian Cancer Screening Timepoint 2 Prior lines of therapy: 1. Avelumab (SD) 2. Doxorubicin Liposomal (PD) 3. Topotecan/bevacizumab (PD) 4. Cyclophosphamide/bevacizumab (unknown) 5. XMT1536 (NaPi2b ADC) (PR) 6. APG115 (MDM2 inh) / Pembrolizumab (SD) 7. ABBV-155 (CD275 ADC) (PD) 8. NC318 (Siglec-15 mAB) (SD) 9. SM08502 (CLK inhibitor) (PD) 10. NBMBMX (HDAC8 inh) (SD) TL1: Baseline TL1: Timepoint6 73-year-old female w/ HGSOC CCNE1amp (Foundation) Response cPR (-71%) Treatment Length 11 months Current Status Off treatment Baseline 12 weeks
21 Azenosertib Patient Profile: Durable cPR In HRD+ PARPi Platinum Resistant Ovarian Cancer Screening Screening Timepoint 2 Target Lesion No Longer Visualized Prior lines of therapy 1. Carbo/taxol/abraxane/bev/Olaparib (PD) 2. Pembrolizumab (PD) 3. NaPi2b targeting-ADC (XMT-1536) (PD) 4. Carbo/gem/bevacizumab (PD) 5. Pegylated doxorubicin (PD) 6. Topotecan (PD) 7. PABP-1 RNP (ATRC-101) (PD) 64-year-old female HGSOC; BRCA1m (Foundation) Response cPR (-48%) Treatment Length 5 months Current Status On treatment Abbreviations: cPR, confirmed partial response HGSOC, high-grade serous ovarian cancer; HRD+, homologous recombination repair deficiency; PARPi, poly-ADP ribose polymerase inhibitor; high-grade serous ovarian cancer; BRCA1m, BRCA1 mutant; PD, progressive disease Baseline
AZENOSERTIB MONOTHERAPY SAFETY IN PATIENTS FROM ZENTALIS 001
23 Intermittent Dosing Maintains Safety And Improves Tolerability Over Continuous Dosing Continuous (n=67) Intermittent (n=27) Total* (n=94) Treatment Related AEs, N (%) All Grade Grade 3/4 All Grade Grade 3/4 All Grade Grade 3/4 Gastrointestinal Nausea 46 (68.7) 2 (3.0) 9 (33.3) - 55 (58.5) 2 (2.1) Diarrhea 31 (46.3) 4 (6.0) 11 (40.7) 3 (11.1) 42 (44.7) 7 (7.4) Vomiting 28 (41.8) - 3 (11.1) - 31 (33.0) - Decreased appetite 20 (29.9) 1 (1.5) 4 (14.8) 1 (3.7) 24 (25.5) 2 ( 2.1) Dehydration 6 (9.0) - 3 (11.1) - 9 (9.6) - Fatigue 30 (44.8) 8 (11.9) 11 (40.7) 2 (7.4) 41 (43.6) 10 (10.6) Hematologic Anemia 6 (9.0) 2 (3.0) 6 (22.2) 3 (11.1) 12 (12.8) 5 (5.3) Thrombocytopenia 4 (6.0) 3 (4.5) 2 (7.4) - 6 (6.4) 3 (3.2) Neutropenia** 1 (1.5) 1 (1.5) 4 (14.8) 3 (11.1) 5 (5.3) 4 (4.3) *Safety Evaluable Population: Received at least one dose of drug; **No incidence of febrile neutropenia in either dosing group Continuous 300, 350, 400; Intermittent 350 5:2 and 400 5:2 Treatment Related AEs > 10% and treatment related AEs of interest: All Tumor Types Abbreviations: AE, adverse event Data cut-off: April 24, 2023
24 *Safety Evaluable Population: Received at least one dose of drug; Continuous 300, 350, 400; Intermittent 350 5:2 and 400 5:2 Abbreviations: SAEs, serious adverse events Azenosertib At Intermittent Schedules Reduces Dose Modifications And Serious Adverse Events Continuous N = 67 Intermittent N = 27 Total* N =94 Treatment Related AEs leading to, N (%): Dose reduction 19 (28.4) 4 (14.8) 23 (24.5) Dose interruption 17 (25.4) 9 (33.3) 26 (27.7) Discontinuation 4 (6.0) - 4 (4.3) Death - - - Treatment Related SAEs 5 (7.5) - 5 (5.3) Data cut-off: April 24, 2023
25 Azenosertib: Tolerability* Compared To Adavosertib and Mirvetuximab 14 .8 % 33 .3 % 0. 0% 55 .0 % 57 .0 % 15 .0 % 5 4 .0 % 72 .0 % 5. 0% 2 0 .0 % 3 3 .0 % 9. 0 % Reduction Interruption Discontinuation Azenosertib-Intermittent (ZENTALIS001) Adavosertib (ADAGIO) Adavosertib (EFFORT) Mirvetuximab (SORAYA) 1 2 4 3 Data cut-off: April 24, 2023 *Attributable to Treatment Related AEs. Not direct head-to-head comparisons. 1. ZENTALIS 001: data on file 2. (ADAGIO Study) Liu et. al. Presented at the Society of Gynecologic Oncology Annual Meeting, March 23 –28, 2023 3. (EFFORT Study) Westin et. al. DOI: 10.1200/JCO.2021.39.15_suppl.5505 Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 5505-5505. 4. (SORAYA Study) Matulonis et al. DOI: 10.1200/JCO.22.01900 Journal of Clinical Oncology 41, no. 13 (May 01, 2023) 2436-2445.
AZENOSERTIB MONOTHERAPY ONGOING STUDIES IN USC AND OVARIAN CANCER
27 Monotherapy Dose and Biomarker Enrichment Is Foundational To Our Clinical Strategy Cyclin E1 0 0.1 0.3 1 µM Azenosertib p-CHK1 Cleaved Caspase-3 γH2AX p-H3 Azenosertib induces markers of DNA damage, replicative stress, and apoptosis* *OVCAR3 Cyclin E1 positive cells, 16-hour treatment High genomic instability can be caused by: Cyclin E1+ Tumors • Cyclin E1+ drives accelerated entry into S-phase through its partnership with CDK2 • Replication machinery is overloaded, resulting in genomic instability Homologous Recombination Repair Defective (HRD+) Tumors • Results in genomic instability through tumors inability to repair double stranded DNA breaks. Tumors with High Genomic Instability are Sensitive to Azenosertib
28 Zentalis 004 (TETON): Azenosertib Monotherapy In Women With ≥2L Advanced Uterine Serous Carcinoma Endpoints NCT04814108 Patients (N=130) Azenosertib 400 mg QD 5:2 Key Eligibility: Recurrent or persistent USC; ≥1 prior platinum-based chemotherapy regimen; Prior HER-2 directed therapy for known HER-2+; Prior anti-PDL-1; Measurable disease; ECOG PS 0-1; No prior WEE1 inhibitor; No prior cell cycle checkpoint inhibitor. DOR Safety and Tolerability ORR CURRENTLY ACCRUING- FDA Fast track designation Abbreviations: 2L, two lines; USC, uterine serous carcinoma; ECOG PS, Eastern Cooperative Oncology Group performance score; QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; ORR, objective response rate; DOR, duration of response
29 Zentalis 005 (DENALI): Evaluating Impact of CCNE1 Amplification and Cyclin E1+ in Platinum-Resistant High-Grade Serous Ovarian Cancer Endpoints (ICR) Cohort 2B (N=80) CCNE1 Non-amplified & Cyclin E1+ Cohort 2C (N=40) CCNE1 Non-Amplified & Cyclin E1- Cohort 2A (N=60) CCNE1 Amplified NCT05128825 Cohort 1 (N=30) CCNE1 amplified and/or Cyclin E1+ Azenosertib 400 mg QD 5:2 Key Eligibility: High-Grade Serous Ovarian Cancer; ECOG PS 0-1; Platinum-resistant (excluding Platinum-refractory); 1-3 prior lines of chemotherapy; Measurable disease per RECIST v 1.1; Cyclin E1 IHC+ and/or CCNE1 amplified. CURRENTLY ACCRUING ORR DOR ORR DOR ORR DOR Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance score; RECIST, response evaluation criteria in solid t umors; QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; ORR, objective response rate; DOR, Duration of Response; ICR, Independent Central Review
30 Abbreviations: PARPi, poly-ADP ribose polymerase inhibitor; QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; PFS, progression free survival; ORR, objective response rate Zentalis 006 (MAMMOTH): Revised Phase 1/2 Study Of Azenosertib In Combination With Niraparib Or Alternating With Niraparib Or As A Monotherapy in Patients With PARP-resistant Ovarian Cancer Endpoints Azenosertib + niraparib alternating schedule Azenosertib monotherapy 400 mg QD 5:2 Azenosertib + niraparib administered concurrently NCT05198804 Enrollment* (N=138) * Enrollment Based on Slot Availability Key Eligibility: Recurrent high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer (serous, clear cell or endometrioid); 1 – 5 prior lines for advanced/metastatic disease; Relapsed within 6 months of platinum therapy (platinum resistant), progressed after taking at least 3 months of PARPi as maintenance treatment. ORR Safety and Tolerability PFS, DOR CURRENTLY ACCRUING
31 • Recommended Phase 2 dose of 400 mg at 5:2 schedule selected based on clinical safety and efficacy • Update on monotherapy efficacy data, and clinical trial timelines in 2H23 36.8% Confirmed Response Rate in Ovarian and Uterine Serous Carcinomas with intermittent dosing* Majority of patients remain on intermittent treatment Azenosertib is Highly Active Agent in Ovarian Cancer and USC and has Favorable Safety Profile *Response evaluable patients (having received at least one scan) USC, Uterine Serous Carcinoma
AZENOSERTIB CHEMOTHERAPY COMBINATIONS
33 Correlation of Cyclin E1 expression and clinical outcomes in a Phase 1b dose-escalation study of Azenosertib (ZN-c3), a WEE1 inhibitor, in combination with chemotherapy (CT) in patients (pts) with platinum- resistant or refractory (R/R) epithelial ovarian, peritoneal, or fallopian tube cancer (EOC) Joyce Liu1, Siqing Fu2, Gary Richardson3, Zivko Vranjes4, Tarek Meniawy5, Catherine Shannon6, Erika P. Hamilton7, Stephanie Blank8, Cara Mathews9, Jasmina Alidzanovic10, Rossitza Krasteva11, Qing Shi13, Olivier Harismendy13, Mieke Ptaszynski14, Shannon N. Westin2, Funda Meric-Bernstam2, Premal H.Thaker15 1Dana Farber Cancer Institute, Boston, MA 2The University of Texas MD Anderson Cancer Center, Houston, TX; 3Cabrini Hospital, Malvern, Australia; 4University Clinical Center of Republic of Srpska, Bosnia and Herzegovina; 5Linear Cancer Research, University of Western Australia, Perth, Australia; 6Mater Hospital, Brisbane, Australia; 7Tennessee Oncology, Sarah Cannon Research Institute, Nashville, TN; 8Icahn School of Medicine at Mount Sinai, New York City, NY; 9Women & Infants Hospital of Rhode Island, Providence, RI; 10University Clinical Center Tuzla, Bosnia and Herzegovina; 11Uni Hospital, Panagyurishte, Bulgaria; 13Zentalis Pharmaceuticals, New York, NY; 14FormerlyZentalis Pharmaceuticals, New York, NY; 15Siteman Cancer Center, Washington University, St Louis, MO Abstract #5513 Poster Bd #208
34 *Gemcitabine + Azenosertib has exciting and durable activity-a MTD has not been determined, further dose cohorts are ongoing. Abbreviations: RP2D, recommended phase 2 dose; PLD pegylated liposomal doxorubicin; QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; D, day; AUC, area under the curve; mg/mL*min Main Takeaways • Strong and durable efficacy signal across chemotherapy backbones - cORR of 34%; cDOR of 8.3 months; mPFS of 9.0 months (response evaluable=94) • Cyclin E1 status predicts benefit of azenosertib addition to chemotherapy • Suggests azenosertib restores chemotherapy sensitivity in heavily pre-treated platinum- resistant ovarian cancer RP2D Azenosertib Chemotherapy Paclitaxel 300 mg QD 5:2 80 mg/m2 on D1, D8, D15 (28-day cycles) Carboplatin 200 mg QD 5:2 AUC=5 on D1 (21-day cycles) Gemcitabine TBD* TBD* PLD 400 mg QD 5:2 40 mg/m2 D1 (28-day cycles) Data cut-off: April 10, 2023 RP2D established for paclitaxel, carboplatin and PLD combinations Azenosertib Is Active With Favorable Tolerability Profile in Combination with Chemotherapy
35 Phase 1b combination study to define RP2D dosing Azenosertib + Paclitaxel 200 mg QD 5:2 2 dose levels 300 mg QD 5:2 Azenosertib + Gemcitabine Azenosertib + PLD 200 mg QD 3 dose levels Cohort assignment by availability and investigator preference Paclitaxel: 80 mg/m2 on D1, D8, D15 (28-day cycles) Objectives Azenosertib + Carboplatin 300 mg QD Gemcitabine: D1, D8 (21-day cycles) 4 dose levels 200 mg QD 5:2 Carboplatin: AUC 5 mg/mL*min on D1 (21-day cycles) G: 1000 mg/m2 A: 200 mg QD 3 dose levels G: 600 mg/m2 A: 200 mg QD 5:2 400 mg QD 5:2 PLD: 40 mg/m2 D1 (28-day cycles) Dose Finding guided by a CRM Key Eligibility: High-Grade Serous Ovarian Cancer; ECOG Performance Status 0-2; Platinum-resistant/refractory; Up to 3 prior lines of chemotherapy; Measurable disease per RECIST v 1.1 Primary: Safety and Tolerability MTD and/or RP2D Key Secondary: Clinical Activity (Endpoints: ORR, DOR, PFS, CA125) NCT04516447 Abbreviations: ; ECOG, Eastern Cooperative Oncology Group; RECIST, response evaluation criteria in solid tumors; 5:2, 5 -days of treatment followed by 2-days off treatment; CRM, continuous reassessment model; QD, once daily; D, day; AUC, area under the curve; G, gemcitabine; A, azenosertib; PLD, pegylated liposomal doxorubicin; MTD, maximum tolerated dose; RP2D, recommended Phase 2 dose; ORR, objective response rate; DOR, duration of response; PFS, progression -free survival; Data cut-off: April 10, 2023
36 *Safety Evaluable Population: Received at least one dose of drug. Abbreviations: PLD, pegylated liposomal doxorubicin; NR, not reported; ECOG, Eastern Cooperative Oncology Group Patient Characteristics* Characteristic Azenosertib + Paclitaxel (N=26) Azenosertib + Carboplatin (N=36) Azenosertib + Gemcitabine (N=18) Azenosertib + PLD (N=35) Total (N=115) Age, years Median (Range) 61.5 (45-83) 61.0 (48-77) 62.5 (47-77) 56.0 (34-75) 61.0 (34-83) Race and Ethnicity, N (%) White 24 (92.3) 34 (94.4) 16 (88.9) 34 (97.1) 108 (93.9) Black or African-American 0 0 0 0 0 Asian 1 (3.8) 1 (2.8) 1 (5.6) 1 (2.9) 4 (3.5) Other / NR 1 (3.8) 1 (2.8) 1 (5.6) 0 3 (2.6) Hispanic (Yes/No/NR) 1/25/0 (3.8/96.2/0) 0/34/2 (0/94.4/5.6) 1/17/0 (5.6/94.4/0) 1/33/1 (2.9/94.3/2.9) 3/109/3 (2.6/94.8/2.6) ECOG Performance Status, N (%) 0 21 (80.8) 21 (58.3) 12 (66.7) 24 (68.6) 78 (67.8) 1 5 (19.2) 15 (41.7) 6 (33.3) 11 (31.4) 37 (32.2) Geographic Region, N (%) US 6 (23.1) 10 (27.8) 10 (55.6) 5 (14.3) 31 (27.0) Europe 10 (38.5) 10 (27.8) 6 (33.3) 27 (77.1) 53 (46.1) Australia 9 (34.6) 15 (41.7) 1 (5.6) 3 (8.6) 28 (24.3) Korea 1 (3.8) 1 (2.8) 1 (5.6) 0 3 (2.6) Platinum Status Refractory, n (%) 5 (19.2) 9 (25.0) 3 (16.7) 7 (20.0) 24 (20.9) Prior Lines of Therapy 1-2, n (%) 22 (84.6) 30 (83.3) 18 (100) 33 (94.3) 103 (89.6) 3-4, n (%) 4 (15.4) 6 (16.7) - 2 (5.7) 12 (10.4) Prior PARP Inhibitor n (%) 8 (30.8) 10 (27.8) 5 (27.8) 5 (14.3) 28 (24.3) Prior Bevacizumab n (%) 8 (30.8) 18 (50.0) 6 (33.3) 15 (42.9) 47 (40.9) Data cut-off: April 10, 2023
37 High Response of Azenosertib Doublets Endpoint Azenosertib + Paclitaxel (N=26) Azenosertib + Carboplatin (N=36) Azenosertib + Gemcitabine (N=18) Azenosertib + PLD (N=35) Total (N=115) Response-Evaluable* (N) 22 28 13 31 94 ORR (confirmed), N (%) 11 (50.0) 10 (35.7) 5 (38.5) 6 (19.4) 32 (34.0) Median DOR (95% CI) in months 5.6 (3.8-NE) 11.4 (8.3-NE) 6.2 (NE) 7.3 (1.5-NE) 8.3 (5.6-12.4) Clinical Benefit Rate (CR + PR + SD for ≥ 16 weeks), N (%) 18 (81.8) 16 (57.1) 6 (46.2) 24 (77.4) 64 (68.1) Median PFS (95% CI) in months 7.4 (5.5-NE) 10.4 (3.3-14.5) 8.3 (3.3-NE) 6.3 (3.7-11.0) 9.0 (5.8-13.7) *Response evaluable subjects are treated subjects with baseline measurable disease per RECIST version 1.1 and at least one po st-baseline assessment. All objective responses were confirmed per RECIST v 1.1. Abbreviations: ; PLD, pegylated liposomal doxorubicin; ORR, objective response rate; DOR, duration of response; CI, confidence interval; NE, not estimable; CR, complete response; PR, partial response; SD, stable disease; PFS, progression-free survival; RECIST, response evaluation criteria in solid tumors Data cut-off: April 10, 2023
38 Abbreviations: PLD, pegylated liposomal doxorubicin; PFS, progression free survival; m, months. Kaplan-Meier Curves of Progression-Free Survival: Durable Responses 0 0.0 0.2 0.4 0.6 0.8 1.0 5 10 15 20 25 P ro gr es si o n -F re e Su rv iv al P ro b ab ili ty Median PFS (months) Azenosertib combined with Time (months) Patients at risk 35 36 26 18 18 8 11 4 7 4 1 1 4 1 0 0 0 1 Paclitaxel PLD Carboplatin Gemcitabine 6.28 m PLD (N=35) Paclitaxel (N=26) 7.36 m Gemcitabine (N=18) 8.31 m Carboplatin (N=36) 10.35 m Data cut-off: April 10, 2023
39 21 30 25 29 29 32 42 50 0 10 20 30 40 50 O R R ( % ) The Activity of Azenosertib + Paclitaxel is Robust and Durable Compared to Historical Reports of Single Agent Paclitaxel, Adavosertib + Paclitaxel and Mirvetuximab in Platinum-Resistant Ovarian Cancer 3.9 3.5 4.1 5.5 5.5 5.6 7.4 0 2 4 6 8 Paclitaxel (N=55) Paclitaxel (N=36) Paclitaxel (N=68) Adavosertib + Paclitaxel (N=38) Mirvetuximab (N=105) Mirvetuximab (N~225) Azenosertib + Paclitaxel (N=26) mPFS (m) Objective Response Rate (ORR) Median Progression Free Survival (mPFS) References: 1. Markman et al. Gynecol Oncol 2006;101:436-40. 2. AURELIA: Avastin USPI 3. MITO11: Pignata et al. Lancet Oncol 2015;16:561-68. 4. OCTOPUS: Banerjee et al. ESMO 2019. 5. GYN49: Moore et al. Clin Cancer Res 2022;28:36-44. 6. SORAYA: Matulonis et al. J Clin Oncol 2023;41:2436-45. 7. MIRASOL: Immunogen Press Release May 3, 2023. Abbreviations: ORR, objective response rate; mPFS, median progression free survival; m, months. Not direct head-to-head comparisons. Data cut-off: April 10, 2023 7 6 5 4 3 2
40 References: 1. Leitao et al. Gynecol Oncol 2003;91:123-9. 2. CARTAXHY: Lortholary et al. Ann Oncol 2012;23:346-52. 3. Pectasides et al. Gynecol Oncol 2010;118:52-7. 4. Brewer et al. Gynecol Oncol 2006;103:446-50. 5. MK-1775-009: Leijen et al. J Clin Oncol 2016;34:4354-61. 6. GYN-49: Moore et al. Clin Cancer Res 2022;28:36-44. 7. SORAYA: Matulonis et al. J Clin Oncol 2023;41:2436-2445. 8. MIRASOL: Immunogen Press Release May 3, 2023. Abbreviations: ORR, objective response rate; mPFS, median progression free survival; m, months. Not direct head-to-head comparisons. The Activity of Azenosertib + Carboplatin is Robust and Durable Compared to Historical Reports of Single Agent Paclitaxel, Adavosertib + Paclitaxel and Mirvetuximab in Platinum-Resistant Ovarian Cancer 23 37 39 16 43 30 32 42 36 0 10 20 30 40 50 ORR (%) 4.8 7.1 5.3 4.2 5.5 5.6 10.4 0 2 4 6 8 10 12 Carboplatin + Weekly Paclitaxel (N=51) Alternating Platinum Doublets (N=45) Adavosertib + Carboplatin (N=21) Adavosertib (5 doses) + Carboplatin (N=23) Mirvetuximab (N=105) Mirvetuximab (N~225) Azenosertib + Carboplatin (N=36) mPFS (m) Objective Response Rate (ORR) Median Progression Free Survival (mPFS) Data cut-off: April 10, 2023 8 7 6 5 3 2
41 Abbreviations: RFS, recurrence free survival, CSS; cancer specific survival, OS; overall survival; PFS, Progression free survival; DMFS; distant metastasis free survival, Patients With Cyclin E1+ Tumors Consistently Have Worse Outcomes On Chemotherapy Hazard Ratio Worse outcome Chappuis PO (2005) [CSS] Desmedt C (2006) [RFS] Jansen MP (2012) [PFS] Luhtala S (2016) [RFS] Lundgren C (2015) [CSS] Lundgren C (2015) [DMFS] Sieuwerts AM (2006) [DMFS] Sieuwerts AM (2006) [OS] Nakayama K (2016) [OS] Nakayama K (2016) [OS] Nakayama K (2016) [PFS] Zhou Z (2014) [OS] Ayahn A (2017) [OS] Chan A MY (2020) [OS] Kang E (2023) [OS] Nakayama N (2010) [OS] Petersen S (2020) [OS] Petersen S (2020) [PFS] Pils D (2014) [OS] Stronach E (2018) [OS] Stronach E (2018) [PFS] Lotan Y (2013) [CSS] Lotan Y (2013) [RFS] Matsushita R (2015) [OS] Shariat SF (2006) [CSS] Shariat SF (2006) [RFS] 1 4 16 Haz ti N 100 500 1000 3000 CCNE1 alteration type Amplification Amplification+Overexpression Overexpression Cancer Type Breast Cancer Endometrial Cancer Esophageal Cancer Ovarian Cancer Urothelial Cancer
42 *Timing of tissue collection was not disclosed. Abbreviations: PFS: progression free survival, OS; overall survival Ovarian Cancer Patients with CCNE1 Amplified and/or Cyclin E1 + Cancers have a Worse Outcome Following Platinum-Based Chemotherapy Treatment Independent of Platinum- Sensitivity Status Hazard Ratio Cyclin E1 Alteration Worse outcome • 6 Studies; n=5404 • 4 Studies where timing of tissue collection was available-all were platinum sensitive tissue collected after ≤ 1 course of chemotherapy; 3533/5404 (65%) • Other 2 Studies did not disclose timing of tissue collection 1 2 4 53 Chan* (2020) [OS] Nakayama (2010) [OS] Petersen* (2020) [OS] Petersen* (2020) [PFS] Pils (2014) [OS] Stronach (2018) [OS] Stronach (2018) [PFS] N 500 100 1000 Amplification Amplification + Overexpression Kang (2023) [OS] han [ ] Kan [ ] Nakaya a [ ] etersen [ ] t r en ( ) ] Pils [ ] Stronac [ ] Stronach ( ) ] 1 2 3 4 5 Hazard Ratio N 100 500 1000 Cyclin E1 Alteration Amplification Amplification+ Overexpression
43 Zentalis 002: Majority of Ovarian Cancers are Cyclin E1 + IHC H-Score* >150 ≤ 150 to > 50 ≤ 50 CCNE1 Amplified 5 0 0 CCNE1 Not Amplified 25 15 6 Tissue Not Evaluated for Amplification 16 21 6 • H-score > 50 includes all CCNE1 amplified tumors • Prevalence of Cyclin E1-IHC+, H-score > 50 of all safety evaluable patients with tissue is 82/94 (87%); • Prevalence of Cyclin E1+ in the response evaluable patients with tissue is 70/82 (85%). C yc lin E 1 IH C H -S co re * CCNE1 Status Amplified Not amplified Not Evaluated for Amplification 0 Patients 100 200 300 50 150 *H-scores calculated by multiplying the percentage of cells (0 to 100%) with intensity of Cyclin E1 expression (0 to 3); IHC: Im munohistochemistry Safety evaluable: received at least one dose of drug; Response evaluable: have baseline measurable disease by RECIST 1.1, at least one post baseline scan, and received at least one dose of drug Data cut-off: April 10, 2023 250
44 Progression Free Survival is Significantly Improved in Cyclin E1+, Cohort compared to Cyclin E1- Independent of Chemotherapy Backbone *Response evaluable subjects are treated subjects with baseline measurable disease per RECIST version 1.1 and at least one pos t-baseline assessment. Abbreviations: IHC, immunohistochemistry ; CI, confidence interval H-Score ≤ 50 (N=12) H-Score > 50 (N=78) Median PFS (months) 3.25 9.86 Hazard Ratio (95% CI) 0.37 (0.18 – 0.79) Log-rank p-value 0.0078 0 0.0 0.2 0.4 0.6 0.8 1.0 5 10 15 20 25 Patients at risk 78 12 36 2 12 1 4 1 1 0 P ro g re ss io n -F re e S u rv iv a l P ro b ab ili ty Time (months) H-Score > 50 H-Score ≤ 50 Data cut-off: April 10, 2023
45 Abbreviations: C, Continuous azenosertib dosing; I, Intermittent azenosertib dosing; MTD, maximum tolerated dose; PLD, pegylated liposomal doxorubicin *All doses were at or below the MTD **A MTD for Gemcitabine + Azenosertib has not been determined, further dose cohorts are ongoing. *** Safety evaluable: received at least one dose of drug Treatment-related Adverse Events: All Doses Moving Forward Involve Intermittent Dosing Treatment-Related Adverse Event ≥20% N (%) Azenosertib + Paclitaxel (Continuous, N=7; Intermittent, N=19) Azenosertib + Carboplatin (Continuous, N=22; Intermittent, N=14) Azenosertib + Carboplatin (Continuous, N=14; Intermittent, N=8) Azenosertib + Gemcitabine (Continuous N=8; Intermittent, N=10) Azenosertib + PLD (Continuous N=27; Intermittent, N=8) Total*** (Continuous, N=64; Intermittent, N=51) All Doses* All Doses Doses ≤ MTD All Doses** All Doses* Grade All Gr Gr ≥3 All Gr Gr ≥3 All Gr Gr ≥3 All Gr Gr ≥3 All Gr Gr ≥3 All Gr Gr ≥3 Hematologic Neutropenia C 5 (71.4) 5 (71.4) 9 (40.9) 7 (31.8) 4 (28.6) 3 (21.4) 7 ( 87.5) 6 (75.0) 19 (70.4) 17 (63.0) 40 (62.5) 35 (54.7) I 11 (57.9) 5 (26.3) 7 (50.0) 1 (7.1) 4 (50.0) - 7 (70.0) 4 (40.0) 3 (37.5) 3 (37.5) 28 (54.9) 13 (25.5) Thrombo- cytopenia C 4 (57.1) 2 (28.6) 16 (72.7) 11 (50.0) 11 (78.6) 6 (42.9) 8 (100.0) 5 (62.5) 9 (33.3) 2 (7.4) 37 (57.8) 20 (31.3) I 4 (21.1) - 9 (64.3) 5 (35.7) 4 (50.0) 2 (25.0) 8 (80.0) 6 (60.0)* 3 (37.5) 3 (37.5) 24 (47.1) 14 (27.5) Anemia C 5 (71.4) - 10 (45.5) 3 (13.6) 5 (35.7) 1 (7.1) 6 (75.0) 2 (25.0) 11 (40.7) 4 (14.8) 32 (50.0) 9 (14.1) I 8 (42.1) 1 (5.3) 10 (71.4) 4 (28.6) 4 (50.0) 1 (12.5) 5 (50.0) 2 (20.0) 2 (25.0) 1 (12.5) 25 (49.0) 8 (15.7) Gastro- intestinal Nausea C 4 (57.1) - 15 (68.2) 1 (4.5) 10 (71.4) 1 (7.1) 5 (62.5) - 16 (59.3) 2 (7.4) 40 (62.5) 3 (4.7) I 7 (36.8) 1 (5.3) 6 (42.9) - 3 (37.5) - 5 (50.0) - 4 (50.0) 1 (12.5) 22 (43.1) 2 (3.9) Vomiting C 3 (42.9) 1 (14.3) 8 (36.4) - 6 (42.9) - 1 (12.5) - 11 (40.7) 2 (7.4) 23 (35.9) 3 (4.7) I 2 (10.5) 1 (5.3) 2 (14.3) - 2 (25.0) - 1 (10.0) - 4 (50.0) 1 (12.5) 9 (17.6) 2 (3.9) Diarrhea C 4 (57.1) 1 (14.3) 4 (18.2) - 1 (7.1) - 1 (12.5) - 8 (29.6) - 17 (26.6) 1 (1.6) I 6 (31.6) 1 (5.3) 5 (35.7) - 3 (37.5) - 6 (60.0) - 2 (25.0) - 19 (37.3) 1 (2.0) Other Fatigue C 6 (85.7) 1 (14.3) 8 (36.4) - 3 (21.4) - 3 (37.5) 1 (12.5) 8 (29.6) 3 (11.1) 25 (39.1) 5 (7.8) I 8 (42.1) 2 (10.5) 5 (35.7) 1 (7.1) 4 (50.0) - 6 (60.0) 2 (20.0) 2 (25.0) - 21 (41.2) 5 (9.8) Data cut-off: April 10, 2023
46 Proposed Randomized Phase 3 Trial Design of Azenosertib + Chemotherapy in Recurrent Platinum-Sensitive Ovarian Cancer that is Cyclin E1+ Key Eligibility: High-Grade Serous Ovarian Cancer; ECOG performance status 0-1; ≥1L Prior Line of Platinum-based chemotherapy; Platinum-Sensitive (Platinum-free interval ≥ 6 months); Prior Bevacizumab & PARPi if eligible and per regional standard of care; Cyclin E1 + (either CCNE1 amplified and/or Cyclin E1 IHC-Positive) Physician’s Choice Carboplatin-Doublet** (6 cycles) Endpoints Primary Progression-Free Survival by BICR No Maintenance Stratification Factors • Prior lines of therapy (1 v 2-3) • Prior PARPi (Yes v No) • CCNE1 amplification (Yes v No) Azenosertib + Chemotherapy* (6 cycles) Azenosertib*** Maintenance Key Secondary Overall Survival R 2:1 *Paclitaxel or Carboplatin **Paclitaxel or Pegylated Liposomal Doxorubicin ***Azenosertib, 400 mg QD 5:2 Abbreviations: ECOG, Eastern Cooperative Oncology Group; 1L, 1 line; PARPi, poly-ADP ribose polymerase inhibitor; IHC, immunohistochemistry; BICR, blinded independent central review.
47 *Gemcitabine + Azenosertib has exciting and durable activity-a MTD has not been determined, further dose cohorts are ongoing. Abbreviations: RP2D, recommended phase 2 dose; PLD pegylated liposomal doxorubicin; QD, once daily; 5:2, 5-days of treatment followed by 2-days off treatment; D, day; AUC, area under the curve; mg/mL*min Conclusions: Data Supports Dose and Advancement of Azenosertib- Chemotherapy Combination into Platinum-Sensitive Ovarian Cancer Main Takeaways • Strong and durable efficacy signal across chemotherapy backbones • Cyclin E1 status predicts benefit of azenosertib addition to chemotherapy • Suggests azenosertib restores chemotherapy sensitivity in heavily pre-treated platinum- resistant ovarian cancer • Plans to initiate Phase 3 study of azenosertib in combination with chemotherapy in Cyclin E1+ platinum sensitive ovarian cancer RP2D Azenosertib Chemotherapy Paclitaxel 300 mg QD 5:2 80 mg/m2 on D1, D8, D15 (28-day cycles) Carboplatin 200 mg QD 5:2 AUC=5 on D1 (21-day cycles) Gemcitabine TBD* TBD* PLD 400 mg QD 5:2 40 mg/m2 D1 (28-day cycles) Data cut-off: April 10, 2023 RP2D established for paclitaxel, carboplatin and PLD combinations
48 Potential to Transform Treatment Paradigm for Patients and Capture Significant Market Share in Ovarian Cancer Cyclin E1+ HRP Cyclin E1+ HRD Cyclin E1 low HRD Others 30% 24% 12% 34% High Grade Serous Ovarian Cancer Patient Segments • Ongoing clinical programs address Cyclin E1+ and HRD+ patient populations • Opportunity is much larger than recently approved therapies • Data support potential role for Azenosertib at every stage of metastatic therapy: • Platinum sensitive: combination with chemotherapy • Platinum resistant: monotherapy and combination with chemotherapy Potential to transform standard of care Azenosertib Monotherapy Potentially Addresses 88% Of High Grade Serous Ovarian Cancer Sources: 1. HRD prevalence derived from Konstantinopoulos, et al Cancer Discov (2015) 2. CCNE1 amplification prevalence of ~20% reported in Aziz et al Gynecol Oncol (2018) and TGCA Network Nature volume 474 (2011) 3. Cyclin E1 expression and copy number extracted from the digital analysis of Aziz et al Figure 3A to infer full distribution of Cyclin E1 H-scores and overlap with CCNE1 amplification based on Cyclin E1 high definition of H-score >50 4. HRD prevalence and proportion of overlap with CCNE1 amplification from Konstantinopoulos et al, Figure 2 5. Total HGSOC incidence estimates (US, EU5) sourced from SEER and ECIS are 35, 388 individuals/year HRD: Homologous recombination deficient HRP: Homologous recombination proficient
49 Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC Platinum Resistant HRD+ or Cyclin E1+ HGSOC 2L+ USC 2L+ USC 2L+ USC 2L+ USC 2L+ USC 2L Pt. Sensitive, HGSOC 2L Pt. Sensitive, HGSOC 2L Pt. Sensitive, HGSOC 2L Pt. Sensitive, HGSOC 1L+ bRAF CRC 1L+ bRAF CRC 1L+ bRAF CRC HRD+ post-PARPi HRD+ post-PARPi Other Cyclin E+ Tumor Types 38,214 42,077 57,807 77,093 89,027 140,950 P o te n ti al U S + EU 5 P at ie n ts Gynecologic malignancies Non-Gynecologic malignancies Legend Azenosertib monotherpy Azenosertib + chemotherapy Azenosertib + BEACON Indications Over Time Addressable Patient Population More than Doubles as Franchise Expands to Non- Gynecological Malignancies Source: Used ‘drug-treatable’ estimates from DRG Clarivate for all Ovarian, USC, CRC, Breast, Prostate and Pancreatic. For ‘Other Cyclin-E1 driven solid tumors’ used incidence reported by SEER and ECIS. Cyclin E1 prevalence in platinum sensitive ovarian cancer derived from Petersen, et al CCNE1 and BRD4 co-amplification in high-grade serous ovarian cancer is associated with poor clinical outcomes, Gynecologic Oncology,Volume 157, Issue 2, 2020 Abbreviations: bRAF+ CRC: bRAF mutant Colorectal Cancer; HRD+ : Homologous Recombinant Repair Deficiency; HGSOC: High Grade Serous Ovarian Cancer; 2L: Secon d Line HRD+ Post PARPi tumor types: Prostate, Pancreas and Breast; Other Cyclin E+ Tumor Types include bladder, stomach, esophageal, lung squamous, lung adenocarcinoma, and breast cancer
50 Today’s Conclusions: Great Progress in Advancing Azenosertib’s Potential to Transform Cancer Care Solid efficacy with multiple chemotherapy combinations • Significant improvements in ORR and mPFS over chemotherapy alone or chemotherapy + adavosertib • Opportunity to use Cyclin E+ as biomarker to identify patients who would benefit from azenosertib addition to chemo Abbreviations: RP2D, recommended Phase 2 dose; ORR, confirmed objective response rate; HGSOC, High Grade Serous Ovarian Cancer; USC, Uterine Serous Carcinoma of the Endometrium; 2H23, second half of 2023; mPFS, media progression free survival Comprehensive Clinical Strategy • All lines of therapy for ovarian cancer, both as a monotherapy and in combination with chemotherapy • Post-pembro (≥2 L) therapy for USC • Clinical trial timelines to be updated in 2H23 Azenosertib monotherapy RP2D dose: 400 mg intermittent (5 days on, 2 days off a week; 5:2) • Increased exposures with intermittent dosing led to an ORR of 36.8% in Ovarian Cancer and USC • Strong safety profile: no treatment-related discontinuations • Majority of patients remain on therapy; update in 2H23
51 Our Thanks And Deepest Appreciation To All Patients, Caregivers, Families, And Investigators KBC Bežanijska kosa A hospital you can trust.
Question & Answer Session 52 Kimberly Blackwell, MD Chief Executive Officer Zentalis Pharmaceuticals Carrie Brownstein, MD Chief Medical Officer Zentalis Pharmaceuticals Funda Meric-Bernstam, MD Chair of the Department of Investigational Cancer Therapeutics -- the Phase 1 Program at The University of Texas MD Anderson Cancer Center; Member, Zentalis Scientific. Advisory Board
Backup: Data Breakdown for ASCO Disclosures N, ORR (%) Azenosertib + Paclitaxel Azenosertib + Carboplatin Azenosertib + Gemcitabine Azenosertib + PLD Total Efficacy Evaluable in Abstract* 9/18 (50.0) 9/27 (33.3) 2/14 (14.3) 5/35 (14.3) 25/94 (26.6) Efficacy Evaluable ASCO Poster Data Cut** 11/26 (42.3) 10/29 (34.5) 5/18 (27.8) 6/35 (17.1) 32/104 (30.8) Response Evaluable on ASCO Poster** 11/22 (50.0) 10/28 (35.7) 5/13 (38.5) 6/31 (19.4) 32/94 (34.0) Definitions: • Efficacy evaluable: received at least 1 dose of study drug, measurable disease at baseline • Response evaluable: received at least one dose of study drug, measurable disease at baseline AND at least one follow-up scan *Data Cut Off of January 17, 2023 **Data Cut Off of April 10, 2023 Reasons for 21 patients not being evaluable: No post-baseline scan yet (n=11); AE (n=4); Subject decision (n=4); Withdrawal of consent (n=1); Clinical progression (n=1)