Loxo Oncology — 2017 ASCO Annual Meeting
24 slides from Loxo Oncology's conference presentation, Jun 5, 2017
Slide 1: Role of TRK in normal biology and cancer
Role of TRK in normal Neurotrophin family of receptors biology and cancer TRK fusions • • TRKA (NTRK1) Pain, thermoregulation Ligand binding domain (LBD) replaced by 5’ fusion partner Drives overexpression and ligand-independent activation TRKB (NTRK2) Movement, memory, mood, appetite, body weight N
Slide 2: TRK fusions found in diverse histologies
TRK fusions found in diverse Brain cancers (glioma, GBM, astrocytoma) Salivary (MASC) Thyroid cancer Lung cancer Secretory breast cancer Pancreatic cancer histologies Common cancer with low TRK fusion frequency Rare cancer with high TRK fusion frequency Cholangiocarcinoma GIST Colon Melanoma Gliomas
Slide 3: Detecting TRK fusions
Detecting TRK fusions • Several modalities: – DNA & RNA NGS, FISH, IHC Large NTRK introns (compared to ALK, ROS1, RET) make DNA-based detection challenging • • Loxo/Ventana developing Pan-TRK IHC companion diagnostic (CDx) • NGS “universal” CDx tests under FDA review include TRK fusion detection* Mo
Slide 4: Larotrectinib TRKA/B/C
Larotrectinib TRKA/B/C • Larotrectinib is the first and only selective pan-TRK inhibitor in clinical development • Highly potent against TRKA, TRKB, TRKC –5–11 nM IC50 in cellular assays Highly selective • • Development timeline – – – March 2015: 1st TRK-fusion patient treated July 2016: breakthroug
Slide 5: Larotrectinib TRK fusion development program
Larotrectinib TRK fusion development program • Age >18 years N=55 TRK fusion patients n=12 • Advanced solid tumors Data cut-off: April 14, 2017 6 Hyman, LBA2501 NAVIGATE: adult/adolescent phase II ‘basket’ trial • Age >12 years • TRK fusion positive SCOUT: pediatric phase I/II • Age <21 years • Adva
Slide 6: Patient demographics
Patient demographics 7 Hyman, LBA2501 Characteristic Total (n=55) Gender, n (%) Male29 (53) Female26 (47) Median age (range), years45.0 (0.3–76.0) Age group, n (%) <2 years6 (11) 2–6 years5 (9) 6–15 years1 (2) 15–39 years12 (22) >40 years31 (56) ECOG PS, n (%) 027 (49) 122 (40) 26 (11) No. of prior
Slide 7: Diversity of cancers treated - unique types
Diversity of cancers treated - 17 unique types Inflammatory myofibroblastic kidney tumor 2% Salivary gland 22% Breast 2% Infantile Appendix 2% Pancreatic myofibromatosis Peripheral nerve sheath tumor 4% Sarcoma, NOS 4% Myopericytoma 4% 2% 2% Cholangiocarcinoma 4% Infantile fibrosarcoma (IFS) 13% Spi
Slide 8: Clinical activity of larotrectinib in patients with TRK fusion cancers
Clinical activity of larotrectinib TRK fusion cancers in patients with *Includes unconfirmed responses with confirmatory scans pending (4 PR, 1 CR). All remain in response and ongoing on study. 9 Hyman, LBA2501 Enrolled patients with confirmatory response data available (n=50) All enrolled patients
Slide 9: Efficacy of larotrectinib in TRK fusion cancers
Efficacy of larotrectinib in TRK fusion cancers 93.2 50 40 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 Partial response Complete response 64% 12% * # # *Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due to prior therapy; #Pathologic CR Note: One patient not show
Slide 10: Efficacy regardless of age
Efficacy 93.2 50-.- regardless of age •Adultpatients 40 30-20 - 10 -;-h cu ·u; 5 0 -10 -u---m----u-------;----.Ea .!: -20--30 -40 -50--60 -70--80 -90-cu Cl - ---r--c -;------------c:: (IJ ..r::. <> E ::::1 E ')( (IJ ........-........ .......... -100-.....n....n._.. # # 'Patient had TRK solvent front
Slide 11: Efficacy regardless of tumor type
Efficacy regardless of tumor type 93.2 50 40 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 * Thyroid Colon Melanoma Soft tissue sarcoma Lung GIST Appendix IFS Breast Salivary gland Cholangiocarcinoma Pancreas # # *Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due
Slide 12: Efficacy regardless of NTRK gene
Efficacy regardless of NTRK gene 93.2 50-40 30-• NTRK1 • NTRK2 NTRK3 r-......., 20" ,_ ,_ ---------------------------------------------------------------------i<1) -30 r--------------------u---------E----------:---------------------E-----r-.... ......_ .... .., E ::::1 -40 -50--60 -70--80 -90--100-E
Slide 13: Efficacy regardless of fusion partner
Efficacy regardless of fusion partner 93.2 NTRK1 NTRK2 NTRK3 LMNA STRN ETV6 TPM3 TPR CTRC PDE4DIP IRF2BP2 SQSTM1 PPL TRIM63 50 40 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 TPM4 * # # *Patient had TRK solvent front resistance mutation (NTRK3 G623R) at baseline due to prior therapy; #Patholo
Slide 14: Duration of larotrectinib therapy
Duration of larotrectinib therapy progression surgery going esponse 93% of esponding tients and 75% of all patients remain n t atment or underwent surgery with curative ent 0 Median time 3 to response = 1.8 months 6 9 12 15 18 21 24 27 Overall treatment duration (months) No progressions in central n
Slide 15: Median duration of response not reached
Median duration of response not reached 1.00 91% 0.75 dian follow-up 5.8 months 0.50 0.25 0.00 0 6 12 18 24 30 Months from start of response N=38 3/38 2/17 0/7 0/3 0/0 In patients with confirmed complete or partial response (n=38) 16 Hyman, LBA2501 Probability 79% Me
Slide 16: Median progression-free survival not reached
Median progression-free survival not reached 1.00 75% 0.75 63% Median follow-up 7.7 months 0.50 0.25 0.00 0 6 12 18 24 30 Months from initiation of treatment N=55 12/55 3/27 0/11 0/6 0/1 17 In primary analysis population (n=55) Hyman, LBA2501 Probability
Slide 17: SQSTM1-NTRK1 lung cancer patient
SQSTM1-NTRK1 lung cancer patient Baseline Cycle 4 Courtesy of S. Kummar, Stanford University 18 Hyman, LBA2501 45F NSCLC & paraneoplastic hypertrophic osteoarthropathy Prior therapy: platinum/pemetrexed Larotrectinib ongoing in month 8, resolution of paraneoplastic symptoms
Slide 18: ETV6-NTRK3 infantile fibrosarcoma patient
ETV6-NTRK3 infantile fibrosarcoma patient Baseline Cycle 3 19 Courtesy of L. Mascarenhas, CHLA Hyman, LBA2501 2F infantile fibrosarcoma 2 cycles of vincristine/ actinomycin-D/ cyclophosphamide progression leg amputation was only alternative option 4 cycles larotrectinib referred for surgery Patholog
Slide 19: ETV6-NTRK3 secretory breast cancer patient
ETV6-NTRK3 secretory breast cancer patient Baseline Day 6 Day 20 14F, prior therapy: 4 lines of chemotherapy and repeated resections Treated with larotrectinib under expanded access Courtesy of N. Shukla, Memorial Sloan Kettering 20 Hyman, LBA2501
Slide 20: Adverse events
Adverse events 7 (13%) patients required dose reductions – all maintained tumor regression (1 CR, 5 PR, 1 SD) on reduced dose. No discontinuations for adverse events. Entire safety database (n=125) *TEAEs shown as reported by >15% of patients 21 Hyman, LBA2501 Treatment-related AEs (%) Grade 3 Grade
Slide 21: LOXO-195 to Address TRK Acquired Resistance
LOXO-195 TRKA G595R to Address TRK Acquired Resistance LOXO-195 Treatment Colorectal TPM3-NTRK1 TRKA G595R NSCLC TPR-NTRK1 TRKA G595R IFS ETV6-NTRK3 TRKC G623R On Treatment Baseline TRKA F589L + Cholangio LMNA-NTRK1 TRK solvent front mutations detected in 5 of 6 patients with acquired resistance. Fi
Slide 22: Larotrectinib conclusions
Larotrectinib conclusions • Consistent and durable antitumor activity in TRK fusion cancers – – – ORR: 76% (12% CRs) 6-month landmark DOR: 91% Minimal side effects for patients • Notable elements of larotrectinib program – – – – – Potentially the first new targeted therapy developed in a tissue type
Slide 23: Acknowledgements
Acknowledgements • Patients and their families, many of whom traveled long distances to participate in these studies • National Institutes of Health P30 CA008748 • Marie-Josée and Henry R. Kravis Center for Molecular Oncology 24 Hyman, LBA2501
Slide 24: Acknowledgements
Acknowledgements * Patients and their families, many of whom traveled long distances to participate in these studies * National Institutes of Health P30 CA008748 * Marie-Josée and Henry R. Kravis Center for Molecular Oncology