And Salivary Gland Cancers

Home , Larotrectinib

Larotrectinib is highly active in patients with advanced recurrent TRK fusion thyroid (TC) and salivary gland cancers (SGC) Wirth L, 1 Drilon A, 2 Albert CM, 3 Farago A, 1 el-Diery W, 4 Ma P, 5 Sohal D, 6 Raez L, 7 Baik C, 8 Brose MS, 9 Doebele R, 10 Cox MC, 11 Ku N, 11 Hong D 12 1Massachusetts General Hospital, Boston, MA; 2Memorial Sloan Kettering Cancer Center, New York, NY; 3Seattle Children’s Hospital, Seattle, WA; 4Fox Chase Cancer Center, Philadelphia, PA; 5West Virginia University, Morgantown, WV; 6Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, 7Memorial Cancer Institute, Pembroke Pines, FL; 8University of Washington/Seattle Cancer Care Alliance, Seattle, WA; 9University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA; 10 University of Colorado, Aurora, CO; 11 Loxo Oncology, South San Francisco, CA; 12 M.D. Anderson Cancer Center, Houston, TX Abstract # 20570

Introduction Patient and disease characteristics Adverse events with larotrectinib: ≥15% in safety database (n=125) n TRK fusions, involving the genes NTRK1, NTRK2, and NTRK3 , occur in a broad range of solid Characteristic Total N=19 Treatment-emergent AEs (%) Treatment-related AEs (%) tumors and are oncogenic: Median age (range), years 59 (15 –75) Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 3 Grade 4 Total – Targeted inhibition of TRK can be an effective antitumor approach Female, n 7 (37%) Fatigue 15 18 5–38 1–18 ECOG 0 –1 19 (100%) n Larotrectinib is the first selective pan-TRK inhibitor in clinical development and has demonstrated Dizziness 22 42–27 1–20 1 Tumour type/histology,* n (%) 19 (100%) Nausea 20 52–26 2–18 an overall response rate of 76% by investigator assessment Thyroid 7 (37%) Anemia 89 9 –26 3–10 n The incidence of TRK fusions in TC has been reported to be as high as 27% in pediatric patients Differentiated 6 Vomiting 18 6––24 ––13 and 12% in adult patients, especially in tumors with papillary histology 2,3 Follicular 1 Papillary 5 Increased AST 16 43–23 1–18 4 n In SGCs, TRK fusions define mammary analog secretory cancers (MASC) Anaplastic 1 Constipation 20 21–22 ––12 Salivary gland 12 (63%) n Here we provide the first report summarizing the activity and safety of TRK-directed therapy with Acinar/MASC 8 Cough 18 2––21 ––2 larotrectinib in the treatment of advanced, recurrent TRK-fusion TCs and SGCs including non- Adenoid cystic 1 Increased ALT 14 24–20 4–17 papillary and non-MASC histologies Adenocarcinoma 1 Diarrhea 14 51–20 ––6 Mucoepidermoid 1 Dyspnea 10 62–18 ––– TRK fusions are rare but recurrent oncogenic drivers Sarcomatoid 1 Disease status at enrollment • 7 (13%) of 55 patients with TRK fusion cancers required dose reductions Metastatic 18 • No discontinuations for adverse events n Beyond embryogenesis, tropomyosin receptor kinase (TRK) protein expression is primarily limited Locally advanced 1 AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase to the nervous system 5 Median number of prior systemic therapies, n=19 1 TC, n=7 3 n 3 neurotrophin receptors encoded by 3 distinct genes that regulate specific normal functions 6-10 SGC, n=12 0.5 Durable response in ETV6-NTRK3 fusion papillary TC – NTRK1 encodes TRKA → Pain, thermoregulation Previously treated 19 (100%) Previous treatment type (n=19) 33-year-old – NTRK2 encodes TRKB → Movement, memory, mood, appetite, body weight male progressed Surgery 18 (95%) through RAI, – NTRK3 encodes TRKC → Proprioception External beam radiation 18 (95%) pazopanib, trametinib Systemic treatment 12 (63%) n Recurrent chromosomal fusion events have been identified across diverse pediatric and adult Confirmed partial TC specific therapy (n=7) response with 11-17 cancers Iodine-131 3 (43%) larotrectinib 100 mg BID; Kinase inhibitor 4 (57%) Rapid improvement in cervical lymphadenopathy NTRK1/2/3 *Local pathology results Duration of treatment Promoter 5’ partner LBD Kinase domain Study baseline Study cycle 3 day 1 Study cycle 7 day 1 >21 months and ongoing at Larotrectinib is highly effective in TRK fusion TC and SGC July 17, 2017 data cut-off

Tyr Tyr ERK Investigator response Independent radiology Durable response in ETV6-NTRK3 fusion MASC of the salivary gland 5’ partner TRK kinase domain assessment (n=19) response assessment (n=19) Measurable disease at baseline Tyr Tyr Tyr Tyr AKT Yes 89.5% 89.5% No 10.5% 10.5% 5’ partner TRK kinase domain 5’ partner TRK kinase domain Best overall response for patients with 66-year-old male progressed through radiotherapy, LBD, ligand binding domain measurable disease at baseline dasatinib, GDC-0941 + erlotinib, Overall response rate 88.2% 88.2% and ABBV-399 TRK fusions are found in diverse cancer histologies Complete response 17.6% 17.6% Best response of PR with Partial response 70.6% 70.6% larotrectinib 100 mg QD* Progressive disease 11.8% 11.8% Duration of treatment >21 months and ongoing at July 17, 2017 data cut-off Larotrectinib is efficacious regardless of tumor type (INV)

40 Study baseline Study cycle 3 day 1 Study cycle 7 day 1 ) 30 * % *Patient enrolled at 100 mg BID and dose reduced to 100 mg QD on C1D2 due to transient dizziness possibly related to drug (

e 20 PR, partial response; QD, once daily; BID, twice daily; RAI, radioactive iodine z i 10 s

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m –10 u t –20 Conclusions n i

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n –40 a n h –50 TRK fusions can occur in non-papillary TC, and non-MASC SGC c –60 m n TRK inhibition with larotrectinib yields high response rates, including complete responses, u –70 m i

x –80 in adolescents and adults with recurrent pre-treated TRK fusion TC and SGC

a Thyroid M –90 n –100 Salivary gland Responses with larotrectinib therapy are generally durable GIST, gastrointestinal stromal tumors *Patient had a mutation at enrollment known to confer resistance to TRK inhibition due to prior TRK inhibitor therapy n Prolonged larotrectinib therapy is associated with minimal toxicity and no drug discontinuations **Patient with anaplastic TC who achieved a complete response in target lesions 2 patients with TC (not shown) had non-measurable disease at baseline for TEAEs Larotrectinib is the first and only selective pan-TRK inhibitor in INV, Investigator response assessment n Genomic profiling with assays capable of identifying TRK fusions should be strongly considered clinical development Larotrectinib efficacy regardless of NTRK fusion (INV) in patients with TC and SGC of all histologies when determining systemic treatment options, especially in the setting of recurrence TRKA/B/C 19 40 n Larotrectinib is a highly potent small-molecule inhibitor of TRKA, ) 30 * % ( References TRKB, and TRKC (5–11 nM IC 50 in cellular assays) e 20 z i 10 s n Highly selective, with little or no interaction with other kinase and r o 0 ** 1. Hyman et al. J Clin Oncol . 2017; 35 (suppl; abstr LBA2501). 11. Chen et al. Anticancer Res . 2014; 34:1595-600. 18 m –10 non-kinase targets u t

2. Prasad et al. Cancer . 2016; 122:1097-107. 12. Fujimoto et al. Proc Natl Acad Sci U S A . 1996; 93:4181-6. –20 n i 3. Greco et al. Mol Cell Endocrinol . 2010; 321:44-9. 13. Dupain et al. Mol Ther Nucleic Acids . 2017; 6:315-26. n Liquid formulation allows dosing of children as young as 1 month e –30 g

n –40 4. Skalova. Head Neck Pathol . 2013; 7:S30-6. 14. Wang et al. Comput Math Methods Med . 2015; 2015:912742.

of age and delivers equivalent PK to capsules a h –50 5. Vaishnavi et al. Cancer Discov . 2015; 5:25-34. 15. Tognon et al. Cancer Res . 2001; 61:8909-16. c –60 n Larotrectinib is highly active against TRK fusion cancers with m 6. Crowley et al. Cell . 1994; 76:1001-11. 16. Roccato et al. Br J Cancer . 2002; 87:645-53. 1 u –70 m ETV6-NTRK3 7. Smeyne et al. Nature . 1994; 368:246-9. 17. Ardini et al. Mol Oncol . 2014; 8:1495-507. durable responses in both children and adults i

x –80

a PPL-NTRK1 8. Skaper. CNS Neurol Disord Drug Targets . 2008; 7:46-62. 18. Doebele et al. Cancer Discov . 2015; 5:1049-57.

M –90 9. Ammendrup-Johnsen et al. J Neurosci . 2015; 35:12425-31. 19. Chartier et al. PeerJ . 2013; 1:e126. –100 IRF2BP2-NTRK1 *Patient had a mutation at enrollment known to confer resistance to TRK inhibition due to prior TRK inhibitor therapy 10. Huang and Reichardt. Annu Rev Neurosci . 2001; 24:677-736. PK, pharmacokinetics **Patient with anaplastic TC who achieved a complete response in target lesions 2 patients with TC (not shown) had non-measurable disease at baseline INV, Investigator response assessment Acknowledgments TRK fusion TC and SGC enrolled to 3 separate clinical trials Larotrectinib responses occur early and are durable (INV) n We thank the patients and their families, many of whom traveled long distances to participate in these studies n These studies are funded by Loxo Oncology, Inc • TRK fusion status determined by local CLIA-certified Adult phase I (or similarly accredited) laboratories • Age ≥18 years • Histology determined by local lab • Advanced solid tumors n=4 • Dosing – 18 patients received the dose SCOUT: pediatric phase I/II 19 patients with equivalent of 100 mg BID on a • Age ≤21 years TRK fusion continuous 28-day schedule • Advanced solid tumors n=2 TC and SGC * – One patient received 150 mg BID * Thyroid on the same schedule Salivary gland NAVIGATE: adult/adolescent Treatment ongoing phase II ‘basket’ trial • Response assessed by investigators Time to first response • Age ≥12 years n=13 and by independent radiology review Treatment after progression • Advanced solid tumors according to RECIST v1.1 • TRK fusion positive • 17 patients had measurable disease 0 3 6 9 12 15 18 21 24 27 (5 with TC and 12 with SGC) Median time Data cut-off: July 17, 2017 to response Overall treatment duration (months) 1.84 months BID, twice daily; CLIA, clinical laboratory improvement amendments; RECIST, Response Evaluation Criteria In Solid Tumors *Patient enrolled with non-measurable disease, assessed as non-CR/non-PD INV, Investigator response assessment