A First-in-class Phase 1 Dose-escalation Study of the Novel Oral ERK - - PowerPoint PPT Presentation

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A First-in-class Phase 1 Dose-escalation Study of the Novel Oral ERK - - PowerPoint PPT Presentation

Feb 27, 2023 17 likes •228 views

A First-in-class Phase 1 Dose-escalation Study of the Novel Oral ERK 1/2 Kinase Inhibitor BVD-523 (ulixertinib) in Patients with Advanced Solid Tumors Jeffrey R. Infante, Filip Janku, Anthony W. Tolcher, Manish Patel, Ryan J. Sullivan, Keith T.

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SLIDE 1

A First-in-class Phase 1 Dose-escalation Study

  • f the Novel Oral ERK 1/2 Kinase Inhibitor

BVD-523 (ulixertinib) in Patients with Advanced Solid Tumors

Jeffrey R. Infante, Filip Janku, Anthony W. Tolcher, Manish Patel, Ryan J. Sullivan, Keith

  • T. Flaherty, Richard D. Carvajal, Anna M. Varghese, Deborah J. Wong, Mario Sznol,

Jeffrey A. Sosman, Andrea Wang-Gillam, Howard A. Burris, Antoni Ribas, Sapna Pradyuman Patel, Dean J. Welsch, Saurabh Saha

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SLIDE 2

Disclosures

ASCO 2015 Jeffrey R. Infante MD I have no personal financial relationship to disclose

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SLIDE 3
  • MAPK pathway mutations causally drive many cancers
  • RAF and MEK inhibitors are approved but limited by intrinsic and acquired resistance
  • ERK inhibition has the potential to overcome or avoid resistance from upstream mutations

dabrafenib RTKs vemurafenib trametinib BVD-523 RAS RSK ERK RAF MEK

Targeting the MAPK pathway

  • BVD-523 : Highly potent, selective and reversible ATP-competitive ERK1/2 inhibitor

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SLIDE 4

BVD-523 (ulixertinib): A Potent & Selective ERK Inhibitor

Highly potent

  • ERK1 Ki < 300 pM
  • ERK2 Ki = 40 pM

Highly selective

  • > 1,000-fold vs CDK1, CDK2, CDK5, CDK6, GSK3b
  • > 10,000-fold vs 70 other kinases

BVD-523

  • Tumor growth regression in BRAF and KRAS-mutant xenograft models
  • Single agent inhibition in patient-derived xenograft models cross-resistant to BRAFi and MEKi

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SLIDE 5

BVD-523: Patient-derived Xenografts that Progressed on BRAF and MEK Inhibitors

500 1000 1500 7 14 21 Day

Post BRAFi-Progression

Tumors that escape BRAFi and MEKi may remain sensitive to ERKi ¡

Vehicle Dabrafenib BVD-523 BVD-523 + Dabrafenib 5

Tumor Volume (mm3)

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SLIDE 6

RSK1/2 Phosphorylation as a BVD-523 Activity Clinical Biomarker

BVD-523

RTKs RAS RAF MEK ERK RSK

pRSK/total RSK

(%Control) 10 Human PBMC Donors

EC50 ~450 nM (200 ng/mL)

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BVD-523 inhibits RSK1/2 phosphorylation using an ex vivo human whole blood assay

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SLIDE 7

BVD-523: FIH Study Objectives

Primary objective: To define the safety and tolerability of BVD-523, the maximum tolerated dose (MTD), and the recommended Phase 2 Dose (RP2D). Secondary objectives: To determine the pharmacokinetic profile of BVD-523 and selected

  • metabolites. To investigate any preliminary clinical efficacy.

Exploratory objective(s): To evaluate pharmacodynamic marker (biomarker) measures. To investigate any preliminary clinical effects on tumor response assessed by FDG-PET as indicated.

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SLIDE 8

Accelerated Dose Titration (1 patient per cohort) First-in-human starting dose (10 mg, BID) > Grade 2 Related AE Standard “3 + 3” Dose Escalation Recommended Phase 2 Dose

Study Design: Dose Escalation Phase

  • PK collection, pre-dose through 12 hours post-dose, on Days 1 and 15
  • PD collection, at pre-dose and 4 hours post-dose, on Days 1 and 15

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SLIDE 9

BVD-523: Key Eligibility

  • Inclusion Criteria

– Patients with metastatic or advanced-stage malignant tumor, for whom no therapy exists that would be curative – ECOG performance status of 0 or 1 – Adequate renal, hepatic, bone marrow, and cardiac function

  • Exclusion Criteria

– A history or current evidence/risk of retinal vein occlusion or central serous retinopathy – Concurrent therapy with drugs known to be strong inhibitors of CYP1A2, CYP2D6, and CYP3A4, or strong inducers of CYP3A4

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SLIDE 10

BVD-523: Dose-Limiting Toxicity Criteria

  • BVD-523 related toxicity in the first 21 days (Cycle 1) of treatment

– ≥ Grade 4 hematologic toxicity > 1 day – Grade 3 hematologic toxicity with complications – ≥ Grade 3 non-hematologic toxicity (except untreated nausea, vomiting, constipation, pain and rash unless they persist with adequate treatment), including a doubling of AST/ALT in patients with grade 2 ALT/AST at baseline – A treatment interruption exceeding 5 days (or > 7 days for rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for ≥ 7 days) due to BVD-523- related toxicity

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SLIDE 11

BVD-523: Patient Characteristics

All Patients (n=27)

n (%)

Age (yr), median (range)

61 (33-86)

Sex

Female 13 Male 14

ECOG Performance Status (Initial)

10 (37) 1 17 (63)

Tumor Types

Melanoma BRAF mt Unknown 8 (30) 7 1 Colorectal Cancer 5 (18) Papillary Thyroid Cancer 4 (15) Non-small Cell Lung Cancer 2 (7) Others* 8 (30)

Prior Systemic Therapy

1 (4) 1 2 (7) 2-3 11 (41) >3 13 (48)

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*2 Pancreatic, 1 Appendiceal, 1 NSGCT, 1 Ovarian, 3 Unknown

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SLIDE 12

BVD-523: Dose Escalation and DLT

MTD defined as 600 mg po BID continuously

Dose-limiting Toxicities in Cycle 1 (21 days) Dose (mg, BID) DLT Frequency (%) DLT Description 10 0/1 20 0/1 40 0/1 75 0/1 150 0/1 300 0/4 600 1/7 (14)

  • Rash G3

750* 2/4 (50)

  • Rash G3, diarrhea G2
  • Hypotension G2, elevated creatinine G2, anemia G2, delay to cycle 2 dosing

900 2/7 (29)

  • Pruritis G3, elevated AST G3
  • Diarrhea G3, vomiting G3, dehydration G3, elevated creatinine G3

12 * Intermediate dose

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SLIDE 13

Adverse Events Possibly Related/Related to BVD-523 in ≥ 10% of Patients

Analysis cut-off date of 13 March 2015

All Patients (N=27)

All Grade (%) Grade 1/2 Grade 3/4 Blood and Lymphatic Anemia 5 (18) 3 2 Gastrointestinal Constipation 3 (11) 3 Diarrhea 14 (52) 12 2 Nausea 14 (52) 14 Vomiting 8 (30) 7 1 General Peripheral Edema 5 (18) 5 Fatigue 16 (59) 15 1 Fever 3 (11) 3 Laboratory Values Increased Creatinine 5 (18) 4 1 Increased LFTs (ALT/AST) 4 (15) 1 3 Metabolism and Nutrition Anorexia 6 (22) 3 3 Dehydration 4 (15) 2 2 Ophthamalogical Blurry/Dimmed Vision 3 (11) 3 Skin and Subcutaneous Erythema Multiforme 3 (11) 3 Rash 19 (70) 17 2 Pruritis 6 (22) 6

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SLIDE 14

GDC-0425 Cycle 1 Pharmacokinetics

EC50=200 ng/mL HWB

  • BVD-523 is absorbed slowly, Tmax 2 – 4 hours post dose
  • Cmax and AUC generally dose related, up to 600 mg BID
  • Moderate accumulation in plasma (1.3 to 4.0 fold at doses >75 mg BID)
  • Moderate inter-patient variability.

BVD-523: Pharmacokinetics (Cycle 1 Day 15)

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1 ¡ 10 ¡ 100 ¡ 1000 ¡ 10000 ¡ 0 ¡ 2 ¡ 4 ¡ 6 ¡ 8 ¡ 10 ¡ 12 ¡

Plasma ¡BVD-­‑523 ¡(ng/mL) ¡ Time ¡A=er ¡Dosing ¡(hours) ¡

900 ¡mg, ¡BID ¡ 750 ¡mg, ¡BID ¡ 600 ¡mg, ¡BID ¡ 300 ¡mg, ¡BID ¡ 150 ¡mg, ¡BID ¡ 75 ¡mg, ¡BID ¡ 40 ¡mg, ¡BID ¡ 20 ¡mg, ¡BID ¡ 10 ¡mg, ¡BID ¡

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SLIDE 15

BVD-523: Pharmacodynamic inhibition of ERK substrate phosphorylation

Concentration-dependent inhibition of ERK activity in whole blood; ≥80% target inhibition at tolerated doses/exposures

25 50 75 100 1000 2000 3000 150 300 450 600 750 900

[BVD-523] (ng/mL) pRSK/total RSK (% Baseline) 15 Dose (mg, BID)

Avg + Std Dev

(no error bars n < 2) Day 15 Trough Data

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SLIDE 16

BVD-523: Pharmacodynamic / Radiographic Response

Lesion Longest Diameter (cm)

8.8 cm 6.9 cm 5.6 cm 13.7 cm

Baseline Cycle 2 Cycle 4 Cycle 6 Cycle 8

4.7 cm 17

  • Metabolic response observed by FDG-PET in 5/16 evaluable patients
  • Patient: 61 y/o V600E BRAF mutant melanoma
  • Post-vemurafenib & dabrafenib progression
  • Confirmed CT Partial Response on BVD-523, on-study > 500 days
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SLIDE 17

BVD-523: Radiographic Response

54 ¡ 33 ¡ 51 ¡ 23 ¡ 32 ¡ 86 ¡ 43 ¡ 56 ¡ 45 ¡ 298 ¡ 42 ¡ 85 ¡ 90 ¡ 175 ¡ 141 ¡ 772 ¡ 113 ¡ 93 ¡ 190 ¡ 86 ¡ 174 ¡ 101 ¡ 190 ¡ 506 ¡ 394* ¡

  • ­‑80 ¡
  • ­‑60 ¡
  • ­‑40 ¡
  • ­‑20 ¡

0 ¡ 20 ¡ 40 ¡ 60 ¡ 80 ¡

Best ¡% ¡Change ¡of ¡SLD ¡from ¡Baseline ¡

10 ¡mg ¡BID, ¡BVD-­‑523 ¡ 40 ¡mg ¡BID, ¡BVD-­‑523 ¡ 75 ¡mg ¡BID, ¡BVD-­‑523 ¡ 150 ¡mg ¡BID, ¡BVD-­‑523 ¡ 300 ¡mg ¡BID, ¡BVD-­‑523 ¡ 450 ¡mg ¡BID, ¡BVD-­‑523 ¡ 600 ¡mg ¡BID, ¡BVD-­‑523 ¡ 750 ¡mg ¡BID, ¡BVD-­‑523 ¡ 900 ¡mg ¡BID, ¡BVD-­‑523 ¡

BRAF KRAS BRAF NRAS KRAS BRAF BRAF BRAF KRAS BRAF NRAS BRAF BRAF MEK1 BRAF BRAF KRAS BRAF BRAF BRAF

Melanoma CRC Melanoma Adenocarcinoma CRC Adenocarcinoma CRC Melanoma Melanoma Melanoma NSGCT CRC PTC PTC PTC NSCLC NSCLC NET PTC Unknown Ovarian PNET Melanoma Melanoma Melanoma * Evaluated with calipers

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Note: All patients with disease measured by RECIST v1.1 who received ≥ 1 dose of study treatment and had > 1 on-treatment tumor assessment (n=25 of 27: 2 did not receive both scans of target lesions)

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SLIDE 18

Analysis cut-off date of 13 March 2015

BVD-523: Duration on Study

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100 ¡days 200 ¡days 300 ¡days 400 ¡days 500 ¡days 600 ¡days 700 ¡days

10 ¡mg ¡BID 20 ¡mg ¡BID 40 ¡mg ¡BID 75 ¡mg ¡BID 150 ¡mg ¡BID 300 ¡mg ¡BID 450 ¡mg ¡BID

Melanoma; ¡BRAF ¡V600E; ¡Refractory

600 ¡mg ¡BID 750 ¡mg ¡BID 900 ¡mg ¡BID

Off-­‑study: ¡PD Off-­‑study: ¡other Partial ¡Response

Melanoma; ¡BRAF ¡V600K; ¡BRAF/MEK ¡Inhibitor ¡naïve ¡ Melanoma; ¡BRAF ¡V600E; ¡Intolerant ¡to ¡other ¡BRAF/MEK ¡Inhibitors

NSCLC/ERCC1 Appendiceal/KRAS Melanoma PTC/BRAF Ovarian/KRAS

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SLIDE 19

Conclusions

  • BVD-523 showed manageable tolerability in 27 patients with solid tumors
  • The MTD and preliminary RP2D is 600 mg BID
  • PK was generally linear and dose-dependent up to 600 mg BID
  • In patients’ peripheral blood, phosphorylation of the ERK substrates RSK1/2 was

shown to be inhibited at doses ≥75 mg BID

  • 3 PR and 7 SD >3 months

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SLIDE 20

Group 1: BRAF mutant cancers (except CRC and NSCLC), inhibitor naïve Group 2: BRAF mutant CRC, inhibitor naïve Group 3: BRAF mutant melanoma, progressed/refractory to BRAFi &/or MEKi Group 4: NRAS mutant melanoma, inhibitor naïve Group 5: MEK mutant cancers, inhibitor naïve Group 6: BRAF mutant NSCLC, inhibitor naïve Accelerated Dose Titration (1 patient per cohort) FIH (10 mg, BID) > Grade 2 Related AE Standard “3 + 3” Dose Escalation Solid Tumor RP2D Advanced Solid Tumor Protocol (NCT01781429)

BVD-523 Clinical Program

Current Status

Enrollment to Date Dose Escalation n=27, complete Cohort Expansion n=21, ongoing

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SLIDE 21

Thank You to the patients and their families

Mario Sznol

Harriet Kluger

Howard A Burris Todd Bauer

Johanna C. Bendell

Manish R. Patel

Terri Peterson Michael Shearer Melissa Rivera

Anthony W. Tolcher Amita Patnaik

Kyri Papadopoulos

Anna M. Varghese Richard D. Carvajal

Jyothi Sreekumar Juho Whang

Jeffrey Alan Sosman

Jordan Berlin Igor Puzanov

Filip Janku Sapna Patel

Divya Sakamuri Goran Cabilo Anne James

Antoni Ribas Deborah Jean Wong

John Glaspy Bartosz Chmielowski Christine Kivork

Keith Flaherty Ryan J. Sullivan

Rebecca Heist

Andrea Wang-Gillam

Craig Lockhart Rebecca Nieman

Amanda Collins, Gary DeCrescenzo, Anna Groover, Maria Miller, Saurabh Saha, Mary Varterasian, Dean Welsch

Key Partners

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