Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC)

Transcription

1 Enrecinib in paiens wih locally advanced or measaic ROS1 fusion-posiive non-small cell lung cancer (NSCLC) Myung-Ju Ahn 1, Byoung Chul Cho 2, Salvaore Siena 3, Alexander Drilon 4, Filippo De Braud 5, Mahew G. Krebs 6, Thomas John 7, Chris Karapeis 8, Ann D. Johnson 9, Edna Chow-Maneval 9, Praik S. Mulani 9, Rober C. Doebele 10 1 Samsung Medical Cener, Seoul, Korea; 2 Yonsei Universiy College of Medicine, Seoul, Korea; 3 Niguarda Cancer Cener, Grande Ospedale Meropoliano Niguarda, Milan, Ialy; 4 Memorial Sloan Keering Cancer Cener, New York, USA; 5 Fondazione IRCCS Isiuo Nazionale Tumori, Milan, Ialy; 6 The Universiy of Mancheser and The Chrisie NHS Foundaion Trus, Mancheser, UK; 7 Olivia Newon-John Cancer Cenre, Ausin Healh, Melbourne, Ausralia; 8 Flinders Medical Cenre, Bedford Park, Ausralia; 9 Ignya, San Diego, USA; 10 Universiy of Colorado, Aurora, USA Absrac 8564

2 Disclosures Honoraria: AsraZeneca, BMS, Boehringer Ingelheim, MSD, Novaris Consulan or advisor: AsraZeneca, BMS, Boehringer Ingelheim, MSD, Novaris

3 Enrecinib CNS-Acive, Poen and Selecive ROS1 and TRK Inhibior Targe ROS1 TRKA TRKB TRKC IC 50 (nm) a x more poen han crizoinib agains ROS1 Mos poen pan-trk inhibior in clinical developmen; demonsraed clinical aciviy in muliple umor hisologies Designed o cross he blood-brain barrier, wih demonsraed clinical aciviy in primary brain umors and secondary CNS measases a Based on biochemical assay

4 Background ROS1 fusions occur in ~2% of NSCLC paiens CNS aciviy is an imporan aribue for novel firs-line argeed herapies in ROS1+ NSCLC ~ 20 o 40% of paiens have known CNS measases a presenaion CNS is a common sie of relapse in paiens progressing on crizoinib Mehods Enrecinib in ROS1 Fusion-Posiive NSCLC 32 ROS1 fusion-posiive, ROS1 inhibior-naïve NSCLC paiens enrolled across STARTRK-2 (Phase 2), STARTRK-1 (Phase 1), and ALKA (Phase 1) sudies as of 31 Dec 2016 Overall, 203 paiens have been reaed a he RP2D (600 mg, PO, once-daily) across hese 3 sudies (muliple biomarkers/hisologies) Daa cuoff dae: 13 Sepember 2017 NSCLC accouned for >90% of all ROS1+ solid umors enrolled in enrecinib sudies 6 oher umor ypes have been sudied: appendix, GBM, melanoma, pancreas, hyroid, sarcoma RP2D=Recommended Phase 2 Dose

5 Toal (N=32) Age, years Median (range) 52 (27, 71) Gender Female/Male, % 72/28 Race Asian/Non-Asian, % 38/62 ECOG Performance Saus 0-1/2, % 91/9 Smoking saus, n (%) Never smoker 23 (72) Former smoker 8 (25) Curren smoker 1 (3) Hisology, n (%) Adenocarcinoma 29 (91) Prior Sysemic Therapy*, n (%) 0-2/ 3 prior herapies, % 50/50 Chemoherapy 27 (84) Targeed herapy 7 (22) Immunoherapy 1 (3) CNS measases a baseline, n (%) 11 (34) * Paiens may have had muliple herapies Baseline Characerisics

6 CNS Measases a Baseline Toal (N=32) Invesigaor-Assessed, n (%) 11 (34) Prior Treamen, n (%) None 4 (36) Whole brain radiaion herapy (WBRT) 4 (36) WBRT + Sereoacic radiosurgery (SRS) 3 (27) Timing of Prior WBRT/SRS, n (%) n=7 <4 weeks 1 (14) 4 weeks o <6 monhs 5 (71) 6 monhs 1 (14)

7 Enrecinib Safey Summary Mos Common ( 10%) Treamen-Relaed Adverse Evens, n (%) Paiens reaed a he RP2D (N=203) All Grades Grade 3 Grade 4* 203 paiens have been reaed a he RP2D across 3 clinical sudies Mos adverse evens were Grade 1-2 and reversible Treamen-Relaed Adverse Evens (TRAEs): Leading o dose inerrupion: 32% Leading o dose reducion: 19% Serious Adverse Evens: 9% Leading o disconinuaion from sudy reamen: 3% Dysgeusia 78 (38) 1 (1) -- Faigue 59 (29) 6 (3) -- Consipaion 47 (23) 1 (1) -- Dizziness 46 (23) 1 (1) -- Weigh increased 39 (19) 10 (5) -- Diarrhea 35 (17) 1 (1) -- Nausea 33 (16) Pareshesia 32 (16) Myalgia 27 (13) 1 (1) -- Peripheral edema 25 (12) Anemia 23 (11) 9 (4) -- Blood creainine increased 22 (11) 1 (1) -- Vomiing 22 (11) Arhralgia 21 (10) 1 (1) -- *There were no Grade 4 evens occurring in >1% of paiens; no Grade 5 TRAEs were repored Daa cuoff dae: 13 Sepember 2017 RP2D=Recommended Phase 2 Dose

8 Bes Response o Enrecinib in ROS1 Fusion-Posiive, Inhibior-Naïve NSCLC 25 ou of 32 paiens had confirmed RECIST 1.1 responses by Invesigaor, for ORR of 78% 20 Maximum % Change from Baseline in Sum of Longes Diameers v SD PR -90 Daa cuoff dae: 13 Sepember v 0% change Three ou of 32 paiens had no pos-baseline scans and were non-evaluable

9 Bes Response o Enrecinib in ROS1 Fusion-Posiive, Inhibior-Naïve NSCLC 34% (11 ou of 32) of he paiens had CNS disease a baseline 20 Maximum % Change from Baseline in Sum of Longes Diameers v SD PR -90 Daa cuoff dae: 13 Sepember v 0% change CNS Measases a Baseline Three ou of 32 paiens had no pos-baseline scans and were non-evaluable

10 Bes Response o Enrecinib in ROS1 Fusion-Posiive, Inhibior-Naïve NSCLC 22 ou of 32 paiens had confirmed RECIST 1.1 responses by BICR, for ORR of 69% Maximum % Change from Baseline in Sum of Longes Diameers by BICR SD SD PR Daa cuoff dae: 13 Sepember 2017 BICR = blinded independen cenral review v 0% change CNS Measases a Baseline Five ou of 32 paiens had no pos-baseline scans (3) or were deemed non-measurable (2) by BICR

11 CNS Objecive Response Rae (by BICR) Inracranial Response (IC) Measurable Lesions (N=6) Measurable and Non-Measurable Lesions (N=7) CNS Responders 5/6 5/7 IC-ORR (95% CI) 83.3% (35.9, 99.6) 71.4% (29.0, 96.3) 53F, ROS1+ NSCLC, Asian, never smoker Baseline Cycle 2 May 2014: Lobecomy, adjuvan chemoherapy May 2015: Recurrence in muliple LNs in mediasinum/abdomen, pleura seeding and brain measasis. Sared pem+cis followed by mainenance pemerexed chemoherapy Dec 2014: CNS radiaion herapy (SRS) Jan 2016: Sared enrecinib Daa cuoff dae: 13 Sepember 2017 BICR = blinded independen cenral review

12 Time on Treamen wih Enrecinib (by BICR) 53% of Paiens Sill on Sudy CNS measases a baseline ongoing ime o response progression by RECIST v1.1 Daa cuoff dae: 13 Sepember 2017 BICR = blinded independen cenral review Time on Sudy (monhs)

13 Durabiliy of Enrecinib Treamen in ROS1+ NSCLC Paiens (by BICR) Median DOR of 28.6 monhs (95% CI: 6.8, 34.8) Median PFS of 29.6 monhs (95% CI: 7.7, 36.6) Durable Response Probabiliy Progression-Free Survival Probabiliy Median follow-up: 12.9 monhs (5.6, 30.2) Median follow-up: 8.5 monhs (5.4, 16.5) Daa cuoff dae: 13 Sepember 2017 BICR = blinded independen cenral review

14 Efficacy of Enrecinib in ROS1+ NSCLC Bes Response by BICR, n (%) Toal (N=32) Objecive Response Rae (BICR-ORR)* (95% CI) 68.8% (50.0, 83.9) Complee Response, n (%) 2 (6.3) Parial Response, n (%) 20 (62.5) Sable Disease, n (%) 4 (12.5) Inracranial BICR-ORR (paiens wih measurable disease) (95% CI) 83.3% (35.9, 99.6) Median Duraion of Response (BICR-mDOR) (95% CI) 28.6 monhs (6.8, 34.8) Median Progression-Free Survival (BICR-mPFS) (95% CI) 29.6 monhs (7.7, 36.6) * Invesigaor-Assessed ORR (95% CI) = 78.1% (60.0, 90.7) Daa cuoff dae: 13 Sepember 2017 BICR = blinded independen cenral review

15 Enrecinib demonsraes clinically meaningful and durable benefi in ROS1 NSCLC BICR-ORR of 69%, including 2 complee responses Invesigaor-assessed ORR of 78% Conclusions Median BICR-DOR of 29 monhs and median BICR-PFS of 30 monhs In addiion, enrecinib demonsraes srong CNS aciviy: inracranial BICR-ORR of 83% in paiens presening wih measurable CNS disease a baseline Enrecinib is well oleraed, including in he CNS, in >200 paiens reaed a he RP2D Mosly Grade 1-2 reversible reamen-relaed adverse evens 3% paiens reaed a he RP2D disconinued enrecinib due o reamen-relaed adverse evens The global Phase 2 sudy, STARTRK-2, remains open for enrollmen New Drug Applicaions for enrecinib in ROS1 NSCLC and TRK issue-agnosic anicipaed in 2018 Daa cuoff dae: 13 Sepember 2017 BICR = blinded independen cenral review RP2D = recommended Phase 2 dose

16 We hank he paiens, heir families and caregivers, and paricipaing clinical sies Ausralia Olivia Newon-John Cancer Research Insiue Flinders Medical Cenre Ialy Niguarda Cancer Cener, Grande Ospedale Meropoliano Niguarda Fondazione IRCCS, Isiuo Nazionale Tumori Singapore Naional Cancer Cenre Souh Korea Asan Medical Cener Samsung Medical Cener Seoul Naional Universiy Hospial Yonsei Universiy College of Medicine Unied Saes Ciy of Hope Cancer Cener Massachuses General Hospial Mayo Clinic Arizona Memorial Sloan Keering Cancer Cener Universiy Cancer & Blood Cener Universiy of Colorado, Aurora Universiy of Minnesoa Unied Kingdom Sarah Cannon Research Insiue UK The Chrisie Research NHS Foundaion Trus