Hanmi Pharmaceutical Co., Ltd. · KRX:128940
Hanmi Pharmaceutical — Technical Presentation (2019)
18 slides from Hanmi Pharmaceutical's technical presentation, 2019
Slide 1: Belvarafenib, a novel pan-RAF inhibitor, in solid tumor patients: Phase I study
Belvarafenib, a novel pan-RAF inhibitor, in solid tumor patients harboring BRAF, KRAS, or NRAS mutations: Phase I study (RAFI-101, RAFI-102) Tae Won Kim1, Jeeyun Lee2, Sang Joon Shin3, Jin-Soo Kim4, Yu Jung Kim5, Hye Sook Han6, Soo Jung Lee7, Hyeong-Seok Lim8, Yoon-hee Hong9, Young Su Noh9, 10, Yuju
Slide 2: Background
Background • The RAF kinase, consisted of three subtypes (A-RAF, B-RAF, C-RAF), is a key component of the MAPK signaling pathway that regulates cell proliferation and survival in various tissues1 • Dysregulation of B-RAF and C-RAF are known to be associated with various cancers • There is growing ev
Slide 3: Belvarafenib (HM95573)
Belvarafenib (HM95573) Belvarafenib showed potent anti-tumor activity in BRAF, KRAS and NRAS mutant model in vivo Xenograft model in nude mice Belvarafenib VS. Dabrafenib A highly potent and selective type II pan-RAF inhibitor Orally available A potential novel option for various solid tumor 3 T
Slide 4: Objectives & Methods
Objectives & Methods Dose escalation study (RAFI-101) Dose expansion study (RAFI-102) (NCT02405065) (NCT03118817) Primary objective/ Safety, tolerability, MTD, RP2D Efficacy (ORR) endpoint Secondary objective/ Efficacy (ORR, PFS, maximal tumor shrinkage, Safety, efficacy endpoint DOR) Cut-off date 1
Slide 5: Study Design
Study Design Dose escalation Dose expansion Part A1 PK-guided escalation scheme Part A2 Modified Fibonacci scheme (N ≥3 per cohort) (N= 3 or 6 per cohort: rolling 6) Cohort 1 Cohort 8 NRASm Melanoma 800mg BID N=10 N=6 Cohort 2 Dose escalation cohort Cohort 7 Back filled 650mg BID 650mg BID * BRAFm M
Slide 6: Patient Demographics
Patient Demographics Baseline Dose-escalation Dose-expansion Baseline Dose-escalation Dose-expansion Characteristic study (N=72) study (N=63) Characteristic study (N=72) study (N=63) Age (years) Primary site of tumor, n (%) Median (Min, Max) 58 (31, 78) 57 (24, 75) CRC 42 (58.3) 20 (31.8) Sex, n (%)
Slide 7: Efficacy summary
Efficacy summary Dose-escalation study Dose-expansion study NRASm NRASm BRAFm BRAFm All pts All pts melanoma melanoma melanoma CRC (N=67) (N=57) (N=9) (N=10) (N=6) (N=6) BORR (unconfirmed), n (%) 4 (44.4) 7 (10.5) 2 (20.0) 2 (33.3) 2 (33.3) 7 (11.9) ORR (confirmed), n (%) 1 (11.1) 3 (4.5) 2 (20.0) 1
Slide 8: Best target percentage change from Baseline: dose escalation study
Best target percentage change from Baseline: dose escalation study Mutant Cancer Dose Best Type Type change KRAS Sarcoma 450 mg -50.5% (G12V) BID NRAS Melanoma 650 mg -44.0% (G12D) BID BRAF GIST 200 mg -38.1% (V600E) BID NRAS Melanoma 200 mg -36.2% (Q61K) BID NRAS Melanoma 300 mg -33.8% (Q61K) & BID
Slide 9: Best target percentage change from Baseline: dose expansion study
Best target percentage change from Baseline: dose expansion study Others include gallbladder, bladder, nephroblastoma, thymic, endometrial, PDAC, amulla of vater, malignant neoplasm, NSCLC, breast, cholangiocarcinoma 9 Tae Won Kim, MD
Slide 10: Responder Cases MAF (% of Screening)
ctDNA from plasma samples were analyzed by FoundationACT Responder Cases NRAS Q61R, Melanoma, PR (-84.8%) BRAF V600E, CRC, PR (-39%) 120 BRAF_V600E 100 MAF (% of Screening) CDKN2A_V82M 80 TP53_R248Q 60 PTEN_L247fs*6 40 PR PR (Week 8) PD (Week 12) PD 20 (D278) (D125) 0 0 20 40 60 80 100 120 Treatme
Slide 11: Treatment Duration: dose escalation study
Treatment Duration: dose escalation study Mutation Cancer Dose Duration Type Type (days) BRAF (V600E) Melanoma 800 mg BID 702 NRAS (G12C) Melanoma 800 mg BID 611 BRAF (V600E) GIST 200 mg BID 512 KRAS (G12C) CRC 100 mg QD 437 BRAF (V600E) Melanoma 450 mg BID 377 KRAS (G12V) Bladder 300 mg BID 311 NRA
Slide 12: Treatment Duration: dose expansion study
Treatment Duration: dose expansion study Mutation Cancer Dose Duration Type Type (days) BRAF (V600E) Melanoma 450 mg BID 563 KRAS (G12D) Gallbladder 450 mg BID 331 KRAS (G12D) Bladder 450 mg BID 284 NRAS (Q61R) Melanoma 450 mg BID 278 KRAS (Q61H) CRC 450 mg BID 229 KRAS (G12D) CRC 450 mg BID 225 BRA
Slide 13: Safety summary
Safety summary This result is analyzed with pooled data of dose escalation and expansion studies. Total 450 mg BID (N=135) (N=74) All Grades Grade ≥3 All Grades Grade ≥3 Any TEAEs, n (%) 127 (94.1) 45 (33.3) 72 (97.3) 30 (40.5) Any ADRs, n (%) 113 (83.7) 26 (19.3) 62 (83.8) 16 (21.6) AE leading to d
Slide 14: TEAEs occurring in ≥ 10% of patients
TEAEs occurring in ≥ 10% of patients This result is analyzed with pooled data of dose escalation and expansion studies. Total 450 mg BID TEAEs reported (N=135) (N=74) in ≥ 10% of subjects All Grades Grade ≥3 All Grades Grade ≥3 Dermatitis acneiform 50 (37.0) 4 (3.0) 34 (46.0) 4 (5.4) Rash 32 (23.7)
Slide 15: Pharmacokinetics
Pharmacokinetics Plasma AUC of Belvarafenib on multiple doses by cohort In dose escalation study, Single dose median Tmax • 3.0~4.5 h (QD) • 15.5~24.0 h (BID) Median t1/2 • 65.1~106.1h (QD) • 32.3~66.4 h (BID) Target exposure was achieved from 200 mg BID Mean concentration showed linearity f
Slide 16: Summary and Conclusions
Summary and Conclusions • Belvarafenib was well tolerated and exhibited anti-tumor activity in patients with advanced solid tumors harboring BRAF, KRAS or NRAS mutations • RP2D was declared as 450mg BID • Targeted exposure was achieved from 200 mg BID • NRAS-mutant melanoma patients had 44.4% of BOR
Slide 17: Acknowledgements
Acknowledgements • We would like to thank all of the participating patients and their families • Study sites participated: Asan Medical Center Samsung Medical Center Severance Hospital Seoul National University Boramae Medical Center Seoul National University Bundang Hospital Chungbuk National Unive
Slide 18: Thank You
THANK YOU TED BY: Tae Won Kim, MD.