LIBRETTO-001: A phase 1 study of LOXO-292, a …

1 LIBRETTO-001: A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancersAlexander Drilon,1 Vivek Subbiah,2 Geoffrey R. Oxnard,3 Todd M. Bauer,4 VamsidharVelcheti,5 Nehal J. Lakhani,6 Benjamin Besse,7 Keunchil Park,8 Jyoti D. Patel,9 Maria E. Cabanillas,2 Melissa L. Johnson,4 Karen L. Reckamp,10 Valentina Boni,11 Herbert H. F. Loong,12 Martin Schlumberger,7 Ben Solomon,13 Scott Cruickshank,14S. Michael Rothenberg,14 Manisha H. Shah,15and Lori J. Wirth161 Memorial Sloan Kettering Cancer Center, New York, NY; 2MD Anderson Cancer Center, Houston, TX; 3 Dana-Farber Cancer Institute, Boston, MA; 4 Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN; 5 Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; 6 START Midwest, Grand Rapids, MI; 7 Institut Gustave Roussy, Villejuif, France; 8 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; 9 University of Chicago, Chicago, IL; 10 City of Hope Comprehensive Cancer Center, Duarte, CA; 11 START Madrid CIOCC Hospital UniversitarioSanchinarro, Madrid, Spain.

2 12 The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong; 13 Peter MacCallum Cancer Centre, East Melbourne, Australia; 14 Loxo Oncology, Stamford, CT; 15 The Ohio State University Comprehensive Cancer Center, Columbus, OH; 16 Massachusetts General Hospital Cancer Center, Boston, MADr. Alexander Drilon2 RET is activatedby two major mechanisms in cancerKIF5B(most common in lung cancer)CCDC6or NCOA4(most common in thyroid cancer)Dr. Alexander DrilonDrilonet al. Nat Rev Clin Oncol 2018;15:151 67; Kato et al. Clin Cancer Res 2017;23:1988 97; Pietrantonioet al. Ann Oncol 2018;Mar 10; Suet al. PLoSOne 2016;11(11)RETfusionsNon-small cell lung cancer (2%)Papillary and otherthyroid cancers (10 20%)Pancreatic cancer (<1%)Salivary gland cancer (<1%)Spitz tumors (<1%)Colorectal cancer (<1%)Ovarian cancer (<1%)Myeloproliferative disorders (<1%)Many others (<1%)KinaseDimerizationPPPPPPPPM edullary thyroid cancersporadic (>60%)hereditary (>90%)RETmutationsCommon mutation: RET M918 TPPPPPPPPPPPPA ctivation by ligand-independent dimerizationDirect kinaseactivationCovalent disulfide bonds in cysteine-rich regionKinase domain mutationLOXO-292 is a potent and selective RET inhibitorSubbiah et al.

3 Ann Oncol 2018 (accepted manuscript/available online); Cabo = cabozantinib; PDX = patient-derived xenograft; NSCLC = non-small cell lung cancer; CRCA = colorectal cancer; MTC = medullary thyroid cancer; BID = twice-daily; QD = once-daily3 RETO rthotopic brain modelCCDC6-RET orthotopic brain PDXX enograft modelsMultiple fusions/mutations/histologiesKinomeselec tivityHighly selective for RETKIF5B-RET (PDX-NSCLC)CCDC6-RET (PDX-CRCA)CCDC6-RET-V804M (PDX-CRCA)KIF5B-RET (NIH-3T3)KIF5B-RET-V804M (NIH-3T3)RET C634W (TT cell line-MTC)CCDC6-RET (LC-2/ad cell line-NSCLC)Tumor modelsTreatment10000 LOXO-292 CaboVehicle500100050-50-100 Change in tumor size (%)Day100500020601004080 VehicleLOXO-292 30 mg/kg BID Day 52 3 mg/kg BIDP onatinib 20 mg/kg QD Day 52 2 mg/kg QDTreatmentsSurvival (%)Dr.

4 Alexander DrilonEligibility Age 12 years ECOG 0 2 Patients with locally advanced or metastatic solid tumors refractory or intolerant to standard therapy Any number of prior therapies RETalteration not required initially ( triggered by adequate PK)Key endpoints Determine MTD or recommended dose Safety/tolerability PK Overall response rate (RECIST ) Duration of responseLIBRETTO-001: phaseI dose escalation design43 + 3 design28-day cyclesIntra-patient dose escalation allowedAdditional enrollment permitted at doses deemed safeDr. Alexander Drilon20 mg QD20 mg BID40 mg BID60 mg BID80 mg BID120 mg BID160 mg BID240 mg BIDn=6n=12n=4n=18n=10n=16n=10n=6QD = once-daily; BID = twice-dailyPK = pharmacokinetics; MTD = maximum tolerated doseApril 2, 2018 data cut-off date5 LIBRETTO-001: patient demographics and molecular featuresKIF5B47%CCDC625%NCOA410%CLIP12%E RC12%RUFY32%TFG2%PRKAR1A2%KTN12%Unknown3 6%RETfusion partner (n=49)RETmutation (n=29)M918T62%V804M7%A883F4%C620F/R/S4%D 631Y4%C630R/Y4%E632_L633 del3%D631_L633 del3%C618Y3%D378_G385>E3%898 del3%Dr.

5 Alexander DrilonNSCLC = non-small-cell lung cancer; MTC = medullary thyroid cancer1. Cabozantinib, vandetanib, or other MKI; 2. Only found in RETfusion-positive cancers; 3. FISH+April 2, 2018 data cut-off dateCharacteristicTotal (n=82)Female / Male, n (%)40 (49%) / 42 (51%)Median age (range), years61 (17 88)ECOG performance status, n (%)01221 (26%)58 (71%)3 (4%)Tumor type, n (%)RETfusion-positive NSCLCRET fusion-positive thyroid cancerRETfusion-positive pancreatic cancerRET-mutant MTCO ther38 (46%)9 (11%)2 (2%)29 (35%)4 (5%)Median prior systemic regimens (range)3 (1 9) 1 prior multikinaseinhibitor (MKI), n (%)101 254 (66%)28 (34%)30 (37%)24 (29%)Prior chemotherapy regimen, n (%)38 (46%)Prior immunotherapy regimen, n (%)20 (24%)Brain metastases, n (%)212 (15%)

6 LOXO-292 pharmacokinetics20 mg QD (Cohort 1, n=5)20 mg BID (Cohort 2, n=9)40 mg BID (Cohort 3, n=16)60 mg BID (Cohort 4, n=10)80 mg BID (Cohort 5, n=17)120 mg BID (Cohort 6, n=4)160 mg BID (Cohort 7, n=12)240 mg BID (Cohort 8, n=5)6 Horizontal lines represent the plasma level at which the unbound LOXO-292 concentration corresponds to IC50or IC90of the indicated target based on cellular assays10 20 40 80 160 320 640 LOXO-292 dose (mg/day)100000 Estimated AUC0 24of LOXO-292in plasma (ng*h/mL)100001000 AUC0 12with BID dosing was multiplied by 2 to estimate AUC0 24 Patient plasma exposures were dose-dependent and linearPatient plasma exposures exceeded IC90targetsDr.

7 Alexander Drilon10000 Concentration of LOXO-292in plasma (ng/mL)1000100100 2 4 6 8 10 12 RET M918 TRET wild typeRET M918 TRET wild typeTime (h) on Day 8 (steady state)IC90IC50 BID = twice-daily; QD = once-daily; AUC = area under the curveApril 2, 2018 data cut-off date7 LOXO-292 safety profileAll doses and patients, n=82 Treatment-emergent AEs ( 10% overall)Treatment-related AEsGrade 1 Grade 2 Grade 3 Grade 4 TotalGrade 3 Grade 4 TotalFatigue12%7% 20% 13%Diarrhea10%6% 16% 2%Constipation13%1% 15% 2%Dry mouth12% 12% 6%Nausea9%4% 12% 5%Dyspnea7%2%1% 11% Most treatment-emergent AEs were Grade 1 in severity Two treatment-related AEs grade 3: grade 3 tumor lysis syndrome (DLT), grade 3 increased ALT MTD not reachedDr.

8 Alexander DrilonAE = adverse event; DLT = dose limiting toxicity; ALT = alanine aminotransferase; MTD = maximum tolerated dose; Note: Total %s for any given AE may be different than the sum of the individual grades, due to roundingApril 2, 2018 data cut-off date8 Clinical activity of LOXO-292 in RET-altered cancersDr. Alexander DrilonRETfusion-positive cancersRET-mutant MTCNo known activating RETalterationAllNSCLCO ther1 Enrolled493811294 Eligible for response evaluation239309223 Overall Response Rate (95% CI)377%(61% 89%)77%(58% 90%)78%(40% 97%)45%(24% 68%)0%(0% 71%)Confirmed Overall Response Rate3,474%74%71%33%0%CR 1 uCR5 1 PR252055 uPR55323 SD64292PD 21 Not evaluable633 1 1.

9 Patients eligible for response evaluation include thyroid cancer (n=7), pancreatic cancer (n=2). 2. Excludes patients recently enrolled that remain on treatment, but have not hada first post-baseline response assessment. 3. Response status per RECIST Overall response rate = CR+uCR+PR+uPR. Overall response rate, Confirmed overallresponse rate: all RETfusion-positive (30/39, 25/34), RETfusion-positive NSCLC (23/30, 20/27), RETfusion-positive other (7/9, 5/7), RET-mutant MTC (10/22, 6/18). 4. Excludes patients with unconfirmed CR/PR pending confirmation at time of data cut-off. 5. Unconfirmed responses in patients that remain on treatment awaiting a confirmatory response assessment.

10 6. Patients that discontinued treatment prior to a first post-baseline response = non-small-cell lung cancer; MTC = medullary thyroid cancer; CR = complete response; PR = partial response; SD = stable disease; PD = progressive diseaseApril 2, 2018 data cut-off date9 RET fusion-positive cancersDr. Alexander Drilon10 Efficacy of LOXO-292 in RET fusion-positive cancersDr. Alexander Drilon 100 NSCLC = non-small cell lung cancerNote: Three patients not displayed due to treatment discontinuation prior to first post-baseline response assessment; *Denotes patient with 0% maximum change in tumor sizeApril 2, 2018 data cut-off date4020 NSCLCT hyroidPancreaticTumor type0 20 40 60 80 Maximum change in tumor size (%)*11 Efficacy of LOXO-292 regardless of RETfusion partnerDr.