Abstract # 4536 Presentation # 444PD Safety and Preliminary Clinical Activity of Repotrectinib in Patients with Advanced ROS1/TRK Fusion-Positive Solid Tumors (TRIDENT-1 Study)

Alexander Drilon,1 Byoung Chul Cho,2 Dong-Wan Kim,3 Jeeyun Lee,4 Jessica J. Lin,5 Viola W. Zhu,6 D. Ross Camidge,8 Shanna Stopatschinskaja,7 J. Jean Cui,7 David M. Hyman,1 Sai-Hong Ignatius Ou,6 Alice T. Shaw,5 Robert C. Doebele8 1 Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA; 2 Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; 3 Seoul National University Hospital, Seoul, Republic of Korea; 4 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 5 Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 6 Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA ; 7 Turning Point Therapeutics Inc, San Diego, CA, USA; 8 University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.

INTRODUCTION RESULTS (as of 22 July 2019) RESULTS: EFFICACY RESULTS: EFFICACY PIVOTAL PHASE 2 PORTION OF TRIDENT-1

• ROS1 gene fusions (ROS1+) have been identified as oncogenic drivers in 1-2% of non-small cell lung cancer (NSCLC)1 and • Global registrational Phase 2 is ongoing, patients with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3 or ALK Table 4. Demographics and Disease Characteristic of ROS1+ Figure 2. Distribution of Prior ROS1+ TKIs Figure 5. Preliminary Efficacy of Repotrectinib by BICR in Patients with ROS1+ NSCLC Pretreated with 2 TKIs Figure 8. Preliminary Efficacy of Repotrectinib Observed in a TKI-Naïve Patient with Advanced NTRK+ Thyroid Cancer crizotinib is the current standard of care for the treatment of ROS1+ NSCLC. gene fusions will be assigned into 6 distinct expansion (EXP) cohorts (Figure 11). Advanced NSCLC Patients • Neurotrophic-tropomyosin receptor kinase (NTRK) gene fusions are also known oncogenic drivers of adult and pediatric tumors2. Case Study 2 Baseline Cycle 6 (-68%) • Recommended Phase 2 Dose (RP2D): Characteristics N=40 Overall Response • Larotrectinib has FDA approval for adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known Pretreated with 2 PRIOR TKIs Case Study 1 • 160 mg QD for the first 14 days, may increase to 160 mg BID based on patient tolerability. (N=7) acquired resistance mutation. Age, median (range) 57 (30, 79) (N=7) Baseline Cycle 6 (-100%) • Repotrectinib can be taken with or without food. • Entrectinib recently received FDA approval for adult patients with metastatic NSCLC whose tumors are ROS1+ and approval for Sex, females n (%) 26 (65) Confirmed ORR*, n/N (%) 2/7 (29%) adult and pediatric patients ≥ 12 years with advanced solid tumors harboring a NTRK gene fusion. Figure 11. Schema of TRIDENT-1 Phase 2 Portion Race, Asian n (%) 21 (53) 95% CI (%) 4 – 71 • Resistance has inevitably developed to the current ROS1 and TRK targeted therapies and solvent front mutations (SFMs) are 3 Median lines of prior systemic common resistance mechanisms to crizotinib, entrectinib and larotrectinib . 2 (1, 8) therapy (range) Clinical Benefit Rate, n/N (%) 5/7 (71%) ROS1+ Advanced NSCLC Exploratory NTRK+ Advanced Solid Tumors • Repotrectinib, a next-generation ROS1/TRK/ALK TKI, was designed with a compact macrocyclic structure to overcome resistance 3 Prior chemotherapy, n (%) 34 (85) Pivotal Cohorts Cohort Pivotal Cohorts mutations (Figure 1) with the potential to be a best in class ROS1 and TRK inhibitor. 95% CI (%) 29 – 96 (up to n=190) (up to n=26) (up to n=90) CNS metastases at baseline n (%) 20 (50) • Preclinical studies demonstrated that repotrectinib is >90-fold more potent than crizotinib against ROS1 and >100-fold more • 49-year-old Caucasian female potent than larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. Median # of prior ROS1 TKIs (range) 1 (0, 3) * 2 responders remain in response both at • In addition, repotrectinib has robust activity against all known ROS1/TRK resistance mutations, including the most common SFMs • Diagnosed with stage IV NSCLC in 2012 TKI naïve, n (%) 11 (28) 3.7+ months EXP-4 of ROS1 G2032R, TRKA G595R, and TRKC G623R/E (Table 1 & Table 2). EXP-5 EXP-6 • Received carboplatin+paclitaxel +bevacizumab EXP-1 EXP-2 EXP-3 ROS1 or ALK TKI pretreated, n (%) 29 (72) 2 Prior ROS1 TRK TKI-naïve TRK TKI- ROS1 TKI-naïve 1 Prior ROS1 TKI-naïve ROS1+ Figure 1. Modeling of ROS1 TKIs in the Complex with ROS1 G2032R and TRK TKIs in the Complex with TRKA G595R • Tested for ROS1 fusion positive NTRK+ pretreated 1 prior TKI 18 (45) ROS1+ TKI ROS1+ TKI ROS1+ or ALK+ advanced advanced advanced advanced advanced solid NTRK+ advanced • Received crizotinib for ~5 years solid tumors Crizotinib Entrectinib Lorlatinib Repotrectinib Crizotinib only 12 (67) NSCLC tumors solid tumors NSCLC NSCLC (non-NSCLC) (n=50) (n=40) Ceritinib or entrectinib 6 (33) • ROS1G2032R mutation detected in 2016 (n=50) (n=100) (n=40) (n=12-26) • 68-year-old Caucasian female ≥2 prior TKIs 11 (28) • Received lorlatinib for ~4 months • NTRK+ advanced thyroid cancer diagnosed in December 2017 2 prior TKIs 7 (64) • Started repotrectinib at 160 mg QD, increased • Received prior systemic therapy including levothyroxine and selumetinib to 160 mg BID and achieved PR in Cycle 2, 100% 3 prior TKIs 4 (36) • Started repotrectinib at 160 mg QD in February 2019 tumor regression in Cycle 6 and continuing on CONCLUSIONS • Of 11 patients who received ≥2 prior TKIs, lorlatinib was used in 10 patients, cabozantinib in 3 patients, ceritinib and entrectinib study treatment • Achieved a cPR with 65% tumor regression at Cycle 4 by BICR assessment Repotrectinib in 1 patient each (all after crizotinib). Larotrectinib Entrectinib • Maximum tumor regression 68% at the end of Cycle 6 by BICR and patient remains in cPR for 3.8+ months • TRIDENT-1 Phase 1 data support repotrectinib as a potential best-in-class ROS1 agent in advanced NSCLC • Preliminary clinical activity demonstrated in TKI-naïve and TKI pretreated patients with ROS1+ NSCLC Figure 6. Preliminary Clinical Activity of Repotrectinib Against ROS1 G2032R Solvent Front Mutation Figure 9. Preliminary Efficacy of Repotrectinib in a TKI-Pretreated Patient with Advanced NTRK+ MASC TRKA • TKI-naïve: TRKA TRKA G595R Case Study 3 G595R G595R RESULTS: EFFICACY • cORR 91% (10/11) Overall Response • The probability of DOR ≥ 18 months is 65% Figure 3. Preliminary Efficacy of Repotrectinib in TKI-Naïve ROS1+ NSCLC by BICR (N=7) • Solvent front mutations ROS1 G2032R and TRKA G595R sterically hinder the binding of crizotinib, entrectinib and lorlatinib to the • ROS1 G2032R mutations were identified in plasma • TKI-pretreated: ROS1 G2032R kinase domain and larotrectinib and entrectinib to the TRKA G595R kinase domain, respectively. TKI Naïve Overall Response Intracranial Response cfDNA or tumor tissue by NGS in 7 patients who • 1 prior TKI: cORR 39% (7/18) (N=11) (N=3) had prior crizotinib Table 1. ROS1 TKIs Inhibited ROS1 Fusion Ba/F3 Cell Proliferation IC50 (nM)* (N=11) • cORR 57% (4/7) in crizotinib-pretreated patients at 160 mg QD and above Solvent Front Mutation (SFM) Gatekeeper Mutation Confirmed ORR, n/N (%) 10/11 (91%) • All 7 patients experienced tumor regressions on • 2 prior TKIs: cORR 29% (2/7), including 1 cPR that had 100% tumor regression pending confirmation No Kinase Domain Mutation 95% CI (%) (59 ­­­–100) ROS1 G2032R (GKM) ROS1 L2026M repotrectinib • 1 additional patient (not included in the cORR) with uCR at first scan, pending confirmation CD74- SDC4- EZR- TPM3- CD74- SDC4- EZR- TPM3- EZR- TPM3- ORR at 160mg QD or above 6/7 (86%) ROS1 Inhibitor • Confirmed ORR: 3/7 (43%) • Repotrectinib is a next-generation ROS1/TRKA-C/ALK inhibitor designed to overcome TKI resistant mutations ROS1 ROS1 ROS1 ROS1 ROS1 ROS1 ROS1 ROS1 ROS1 ROS1 Duration of response (DOR) • All 7 ROS1+ NSCLC patients with the G2032R SFM experienced tumor regressions with a cORR of 43% (3/7) Repotrectinib <0.2 0.2 <0.1 <0.1 3.3 3 5 16.3 <0.2 <0.1 %DOR ≥ 18 months1 65% • 2/3 (67%) with 1 prior TKI treated at 160 mg QD and above • Preliminary clinical activity also demonstrated in NTRK+ TKI-naïve and TKI-pretreated patients with advanced solid Crizotinib 14.6 19.6 19.4 31.1 266.2 4661 660 500.6 95.6 236.2 Range 3.7+ – 23.3+ Intracranial ORR (IC-ORR)2, n/N (%) 3/3 (100%) tumors Lorlatinib 0.2 0.3 0.2 0.3 160.7 352.9 190.5 434.9 1.6 1.9 • 1 cPR with DOR 5.5+ months and on • Repotrectinib was well tolerated with a manageable safety profile Entrectinib 10.5 ND 1.5 9.4 1813 ND 2947 1093 13.3 40.7 95% CI (%) (29 – 100) treatment 7.6+ months Baseline Week 8 Baseline Week 4 Week 12 Ceritinib 42.8 59.8 33.1 105 1391 1883 885.8 543.7 12.6 66.5 Clinical benefit rate, n/N (%) 11/11 (100%) • 51-year-old Asian male diagnosed with ETV6-NTRK3+ mammary analogue secretory carcinoma with acquired TRKC G623E • Global registrational Phase 2 portion of the study is ongoing 95% CI (%) (72 – 100) • 1 cPR with DOR 4.4 months and on solvent front substitution Cabozantinib 0.5 3 0.4 4.5 11.3 169.4 39.5 60.7 3.4 12.6 treatment 21.2 months *Other than repotrectinib, data based on evaluation of comparable proxy chemical reagents purchased from comercial sources. Median follow-up time, months 20.1 • Prior TKI treatment: crizotinib, entrectinib and entrectinib+trametinib Range 5.3 – 24.9+ • 1/3 (33%) with 2 prior TKIs treated at 160 mg • Confirmed PR with repotrectinib treatment with DOR of 9.8 months and DOT 17.9 months Table 2. TRK TKIs Inhibited Ba/F3 Cell Proliferation IC (nM) REFERENCES 50 * QD and above • Resumed repotrectinib treatment in January 2019 under compassionate use, achieved an unconfirmed PR (per RECIST v1.1) • Median duration of response is not mature, 5 out of and remained on treatment for 7.2+ months as of August 13, 2019 1. Gainor JF et al., JCO Precis Oncol 2017 LMNA-TRKA ETV6-TRKB ETV6-TRKC • 1 cPR with DOR 3.7+ months and on 10 (50%)* responders by BICR were ongoing without 2. Okamura R et al., JCO Precis Oncol 2018 an event at the time of this analysis: 3.7+, 14.8+, 16.4+, treatment 5.6+ months SFM XDFG GKM SFM SFM SFM GKM 3. Drilon A et al., Cancer Discov 2018 TRK Inhibitor WT WT WT 17.6+, and 23.3+ months. G595 G667C F589L G639R G623R G623E F6171 • Duration of cPR in 3 patients with IC-ORR were 14.8+, RESULTS: SAFETY Repotrectinib <0.1 0.2 9.2 <0.2 <0.1 1.7 <0.2 1.0 0.6 <0.2 17.6+, and 23.1 months. • Most treatment emergent (TEAEs) and treatment-related adverse events (TRAEs) were Grade 1 or 2 in severity; there were no LOXO-195 4.6 15.1 94.9 26.5 1.4 20.8 4.0 23.9 36.1 40.9 1 Estimated using Kaplan-Meier method ACKNOWLEDGEMENTS 2 Grade 4 TRAEs (Table 5). Larotrectinib 18.9 2817 1863 597 28.2 2500 41.4 7500 1486 4000 For patients with CNS measurable disease at baseline Clinical Benefit Rate: CR + PR + SD ≥ 2 Cycles • TRAEs leading to dose discontinuation, dose interruption, or dose reduction occurred in 3 (3%), 5 (5%), and 11 (12%) patients, Entrectinib 0.4 711 186.7 <0.2 0.6 1577 0.8 1670 1500 54.9 respectively. • The patients and families for participation in the study *Other than repotrectinib, data based on evaluation of comparable proxy chemical reagents purchased from commercial sources. • The most commonly reported TEAE was low grade dizziness, and majority did not require dose interruptions or reductions. • Participating sites Figure 4. Preliminary Efficacy of Repotrectinib by BICR in Patients with ROS1+ NSCLC Pretreated with 1 TKI Figure 7. Preliminary Duration of Repotrectinib Treatment in N=40 ROS1+ NSCLC by BICR • No cases of dizziness have led to permanent treatment discontinuation. • No Grade 3 or Grade 4 ALT or AST elevations were reported. METHODS: STUDY DESIGN AND PATIENTS Pretreated with 1 PRIOR TKI Overall Response Intracranial Response • Intra-patient dose escalation was allowed (N=18) (N=4) • In the phase 1 study, eligible patients had locally advanced or metastatic solid tumors with ROS1, NTRK or ALK gene fusions (N=18) • Continuous treatment post radiographic PD was allowed Table 5. Safety Summary: Treatment-Emergent and Treatment-Related AEs CORRESPONDING AUTHOR (ROS1+, NTRK+, or ALK+), with or without asymptomatic central nervous system metastases. Confirmed ORR, n/N (%) 7/18 (39%) All Treated Patients (N=93) (17 – 64) • ROS1+, NTRK+, or ALK+ status was determined by local CLIA lab or equivalent. 95% CI (%) TEAEs (≥10% of patients) TRAEs Alexander Drilon: [email protected] ORR at 160mg QD or above 6/11 (55%) All Grades Grade 1 Grade 2 Grade 3 Grade 41 Grade 3 Grade 4 • Patients were allowed to receive prior systemic therapies (ie, chemotherapy/IO or TKI therapies). Adverse Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) • Crizotinib as ONLY prior TKI 4/7 (57%) Dizziness 54 (58.1) 43 (46.2) 8 (8.6) 3 (3.2) --- 3 (3.2) --- • As of the data cut-off date 22 July 2019, the safety population included 93 patients with ROS1+, NTRK+, or ALK+ advanced solid 1 tumors across 9 dose cohorts under fed and fasted conditions (Table 3). IC-ORR , n/N (%) 3/4 (75%) Dysgeusia 45 (48.4) 44 (47.3) 1 (1.1) ------95% CI (%) (19 – 99) DISCLOSURES • Preliminary efficacy results evaluated by BICR (Blinded Independent Central Review) in 40 ROS1+ NSCLC patients and 2 case Anaemia 28 (30.1) 7 (7.5) 10 (10.8) 11 (11.8) --- 3 (3.2) --- studies (1 NTRK+ advanced thyroid cancer and 1 NTRK+ advanced salivary gland cancer) are presented. Clinical benefit rate, n/N (%) 14/18 (78%) Constipation 28 (30.1) 17 (18.3) 11 (11.8) ------95% CI (%) (52 – 94) Fatigue 28 (30.1) 17 (18.3) 9 (9.7) 2 (2.2) ------This study was sponsored by Turning Point Therapetuics, Inc. Clinical trial information: NCT03093116 Table 3. Number of Patients per Dose Cohort Dyspnoea 27 (29.0) 9 (9.7) 12 (12.9) 5 (5.4) 1 (1.1) 1 (1.1) --- Median follow-up time, months2 7.3 SIO & VWZ: Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine – shareholder. Paraesthesia 27 (29.0) 26 (28.0) 1 (1.1) ------JJC & SS: Turning Point Therapeutics – employment/shareholder. 120 mg 160 mg 160 mg 0.6 – 19.3+ Nausea 21 (22.6) 14 (15.1) 5 (5.4) 2 (2.2) ------40 mg 80 mg 160 mg 200 mg 160 mg 200 mg 40 mg 18 of 40 patients (45%) remain on treatment Cough 18 (19.4) 12 (12.9) 6 (6.5) ------1 QD QD QD/BID TKI Naïve TKI Pretreated QD QD QD QD BID BID 2 QD w/ Food w/ Food w/ Food *2 of 7 patients remain in cPR both at 5.5+ months. (N=11) (N=29) Pyrexia 17 (18.3) 14 (15.1) 3 (3.2) ------# (%) of Patients 7 (64) 11 (38) Headache 15 (16.1) 13 (14.0) 1 (1.1) 1 (1.1) ------Safety population Remaining on Treatment 1 For patients with CNS measurable disease at baseline 25.7+ 23.0+ Vomiting 13 (14.0) 9 (9.7) 4 (4.3) ------(ROS1+, NTRK1-3+, ALK+ 13 12 23 10 12 2 3 6 12 93* 25.3+ 21.6+ 2 For all TKI-pretreated patients using reverse Kaplan-Meier Ataxia 12 (12.9) 8 (8.6) 4 (4.3) ------Copies of this poster obtained through the QR Code are for solid tumors) method 22.3+ 19.3+ Myalgia 11 (11.8) 8 (8.6) 3 (3.2) ------20.0+ 7.6+ personal use only and may not be reproduced without written Efficacy population Clinical Benefit Rate: CR + PR + SD ≥ 2 Cycles 19.8+ 7.4+ Upper respiratory tract infection 11 (11.8) 6 (6.5) 5 (5.4) ------permission from the authors of this poster. 5 5 10 2 6 0 2 4 6 40 Duration of Treatment 17.5+ 5.6+ (ROS1+ NSCLC) (month) Abdominal pain 10 (10.8) 8 (8.6) 2 (2.2) ------8.8+ 5.5+ 1 Muscular weakness 10 (10.8) 6 (6.5) 3 (3.2) 1 (1.1) ------2 ALK+ patients enrolled. 5.3+ 2 160 mg QD for one week followed by 160 mg BID; 6 safety patients not evaluable for response in ROS1+ NSCLC cohort include: 2 newly enrolled 5.2+ Pain in extremity 10 (10.8) 7 (7.5) 2 (2.2) 1 (1.1) ------ROS1+ NSCLC TKI-pretreated patients without post-baseline scans prior to the data cutoff date, 1 NTRK+ patient, 1 ROS1+ patient with gastric 3.6+ 1 Additional Grade 4 TEAEs: cerebrovascular accident, influenza, hyperkalemia, bacterial pneumonia, sepsis (n=1 each), respiratory failure (n=2); none were cancer, and 2 ROS1+ NSCLC patients (1 naïve and 1 pretreated) with no post-baseline scans. 2.0+ determined to be related to treatment. * N=93 patients: 31 were ALK+; 10 were NTRK+ including: 2 GBM, 2 thyroid carcinoma, 2 soft tissue sarcoma, 1 salivary gland carcinoma/MASC, Grade 5 TEAEs: respiratory failure (n=2), pneumonia, sepsis, sudden death (n=1 each); only the case of sudden death was determined to be possibly related 1 squamous NSCLC, 1 cholangiocarcinoma, and 1 biliary gland carcinoma; 52 were ROS1+ advanced tumors (of which 40 ROS1+ advanced NSCLC to treatment. were evaluable for efficacy by BICR).

Presented at: European Society for Medical Oncology (ESMO) 2019; 27 Sep–1 Oct 2019; Barcelona, Spain