EX-99.5 6 ex-99d5.htm EX-99.5

Exhibit 99.5

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Clinical Activity and Tolerability of BLU-667, a Highly Potent and Selective RET Inhibitor, in Patients with Advanced RET-Fusion+ Non-small Cell Lung Cancer Justin F. Gainor1, Dae Ho Lee2, Giuseppe Curigliano3, Robert C. Doebele4, Dong-Wan Kim5, Christina S. Baik6, Daniel Shao-Weng Tan7, Gilberto Lopes8, Shirish M. Gadgeel9, Philippe Alexandre Cassier10, Matthew H. Taylor11, Stephen V. Liu12, Benjamin Besse13, Michael Thomas14, Viola Weijia Zhu15, Hui Zhang16, Corinne Clifford16, Michael R. Palmer16, Christopher D. Turner16, Vivek Subbiah17 1Massachusetts General Hospital, Boston, MA; 2University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, Republic of (South); 3University of Milano, European Institute of Oncology, Division of Early Drug Development, Milan, Italy; 4University of Colorado Cancer Center, Aurora, CO; 5Seoul National University Hospital, Seoul, Korea, Republic of (South); 6Fred Hutchinson Cancer Research Center, Seattle, WA; 7National Cancer Center, Singapore, Singapore; 8Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL; 9University of Michigan/Rogel Cancer Center, Ann Arbor, MI; 10Centre Léon-Bérard, Lyon, France; 11Oregon Health & Science University, Portland, OR; 12Georgetown University Medical Center, Washington, DC; 13Paris-Sud University, Orsay and Gustave Roussy, Villejuif, France; 14Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany; 15Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA; 16Blueprint Medicines Inc, Cambridge, MA; 17The University of Texas MD Anderson Cancer Center, Houston, TX Justin F. Gainor 1 PRESENTATION DATE: June 3, 2019


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Disclosures 2 Justin F. Gainor, MD • Honoraria: Pfizer, Novartis, Theravance, Merck, Incyte, Roche • Consulting or advisory role: Bristol-Myers Squibb, Ariad/Takeda, Genentech/Roche, Loxo, Blueprint Medicines, Amgen, Agios, Regeneron, Oncorus • Research funding: Novartis, Genentech, Takeda • Institutional Research funding: Tesaro, Moderna, Blueprint Medicines, Bristol-Myers Squibb, Jounce, Array Biopharma, Adaptimmune, Novartis, Alexo, Merck • Travel: Novartis, Pfizer, Takeda, Genentech/Roche • Employment: Ironwood Pharmaceuticals (Spouse) BLU-667 is an investigational agent discovered by and currently in development by Blueprint Medicines Corporation (Blueprint Medicines) Justin F. Gainor


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RET Alterations: Diverse Oncogenic Drivers Lacking Targeted Therapeutic Approach Justin F. Gainor 3 • Chemotherapy: nonspecific, low response rates, significant toxicity NSCLC patients with RET fusions have not significantly benefited from existing therapy Non-small cell lung cancer: ~1-2% RET fusions1,2 Advanced medullary thyroid cancer: ~90% RET mutations3 Papillary thyroid cancer: ~20% RET fusions4 Multiple other tumor types including esophageal, breast, melanoma, colorectal, and leukemia: <1% RET-altered5,6 NSCLC, non-small cell lung cancer; ORR, overall response rate; PFS, progression-free survival. 1. Lipson, et al. Nat Med 2012; 2. Takeuchi, et al. Nat Med 2012; 3. Romei, et al. Oncotarget 2018; 4. Santoro, et al. J Clin Invest 1992; 5. Kato, et al. Clin Cancer Res 2017; 6. Ballerini, et al. Leukemia 2012; 7. Mazieres, et al. JCO 2018; 8. Drillon, et al. Lancet 2017; 9. Yoh, et al. Lancet Respir Med 2017 • Checkpoint inhibition: Preliminary evidence for lack of benefit in RET-altered NSCLC7 • Multikinase inhibitors: ↓ activity, ↑ off-target toxicity8,9 No selective RET inhibitors are approved


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BLU-667 Potently and Selectively Inhibits RET Alterations and Resistance Mutants Justin F. Gainor 4 aKinome illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com) (CSTI). The foregoing website is maintained by CSTI, and Blueprint Medicines is not responsible for its content. BLU-667 is an investigational agent discovered and currently in development by Blueprint Medicines Corporation (Blueprint Medicines). 1. Subbiah, et al. Cancer Discovery 2018; 2. Blueprint internal data BLU-667: High kinome selectivity for RETa BLU-667 vs. pharmacologically relevant kinases: • 90-fold more selective for RET than VEGFR2 • 20-fold more selective for RET than JAK1 BLU-667 Cellular activity in KIF5B-RET2 KIF5B-RET KIF5B-RET V804L KIF5B-RET V804M KIF5B-RET V804E BLU-667 10.1 nM (1x) 8.1 nM (0.8x) 14.1 nM (1.4x) 8.1 nM (0.8x) KIF5B-RET Cabozantinib-resistant KIF5B-RET(V804L) In vivo models of implanted, engineered Ba/F3 cells1 Vehicle QD Cabozantinib 60 mg/kg QD BLU-667 3 mg/kg BID BLU-667 10 mg/kg BID BLU-667 30 mg/kg BID


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ARROW: BLU-667 Dose-Escalation and Expansion Study ARROW is registered with clinicaltrials.gov (NCT03037385) Part 1: Dose-Escalation (N=62; Complete)1 Phase 2 dose determined (400 mg QD) Justin F. Gainor 5 BID, twice daily dosing; ECOG PS, Eastern Cooperative Oncology Group performance status; MTC, medullary thyroid cancer; QD, once daily dosing; RECIST, response evaluation criteria in solid tumors; SOC, standard of care. 1. Subbiah, et al. Cancer Res 2018. RET-altered advanced solid tumors BLU-667: 30-600 mg by daily oral administration (QD or BID) RET fusion+ NSCLC, prior platinum (n=80) RET fusion+ NSCLC, platinum naïve (n=40) MTC, prior cabozantinib or vandetanib (n=60) MTC, no prior cabozantinib or vandetanib (n=40) Other RET fusion+ tumors (n=40) RET-altered, prior selective RET inhibitor (n=20) Other RET-mutated tumors (n=20) Part 2: Expansion Cohorts (Ongoing) BLU-667 400 mg QD • Unresectable, advanced solid tumor • RET alteration status by local tumor testing • No additional driver mutation • ECOG PS 0-1 • Asymptomatic brain metastases allowed • Progressive disease or intolerant to SOC therapy, or not a candidate Primary objectives: Overall response rate (RECIST 1.1) Safety


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Baseline Characteristics RET Fusion+ Advanced NSCLC Patients ECOG PS, Eastern Cooperative Oncology Group Performance Status. aSmoking history is unknown for one patient. bIncludes RET fusion+ by fluorescence in situ hybridization (FISH); RET fusion partner to be determined via central analysis. Data cut-off date: 28 Apr 2019. Justin F. Gainor 6 RET Fusion Partner KIF5B 66% CCDC6 13% Other (DOCK1, EML4) 2% Fusion partner unknownb 19% RET-Fusion+ Advanced NSCLC 400 mg QD Starting Dose Characteristic All (N=120) Prior Platinum (N=91) Age (years), median (range) 60 (28-87) 60 (28-85) Male, n (%) 59 (49) 45 (49) ECOG PS, n (%) 0 46 (38) 33 (36) 1-2 74 (62) 58 (64) Brain metastases, n (%) 48 (40) 36 (40) Prior systemic regimens, median (range) 2 (0-11) 2 (1-11) Any prior anticancer treatment 101 (84) 91 (100) Chemotherapy, n (%) 92 (77) 91(100) PD-1 or PD-L1 inhibitor, n (%) 47 (39) 41 (45) Chemotherapy + PD-(L)1 combination, n (%) 41 (34) 41 (45) Multikinase inhibitor, n (%) 21 (18) 20 (22) Smoking historya Current/Prior 41 (34) 33 (36) Never 78 (65) 57 (63) Histology Adenocarcinoma 114 (95) 87 (96) Other 6 (5) 4 (4)


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BLU-667 is Well Tolerated by Patients with RET Fusion+ Advanced NSCLC RET Fusion+ Advanced NSCLC 400 mg QD Starting Dose (N=120) Adverse Events Treatment-Emergent (≥15% overall) Treatment-Related All Grade ≥3 All Grade ≥3 Constipation 30% 2% 17% 2% Neutropeniaa 26% 13% 26% 13% AST increased 24% 5% 20% 2% Fatigue 21% 3% 13% 3% Hypertension 20% 13% 13% 10% Anemia 18% 7% 11% 4% Diarrhea 18% 2% 9% - Pyrexia 18% - 2% - ALT increased 17% 3% 13% 2% Cough 17% - 3% - Dry mouth 17% - 12% - Justin F. Gainor Among 120 pts with advanced NSCLC receiving BLU-667 starting dose of 400 mg QD: • Treatment-related toxicity is generally low-grade and reversible • 7% discontinued BLU-667 due to treatment-related toxicity* - Pneumonitis, respiratory distress/ hypoxemia, mucositis/colitis, myelosuppression, gait disturbance, anemia Additional grade ≥3 treatment related AEs (≥2%): increased CPK (3%), leukopeniab (3%). 7 aCombined term including decreased neutrophils and neutropenia. bCombined term including leukopenia and white blood cell count decreased. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase. Data cut-off date: 28 Apr 2019. * Across the entire study (n=276), rate of discontinuation due to treatment-related toxicity is 4%.


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BLU-667 Demonstrates Substantial Antitumor Activity in RET Fusion+ Advanced NSCLC 8 CI, confidence interval; CR, complete response; DCR, disease control rate (best response of SD or better); ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Patients enrolled by 14 Nov 18, data cut-off 28 Apr 19. Response-evaluable population includes patients with measurable disease at baseline and ≥1 evaluable post-treatment disease assessment, and excludes 4 patients who previously received >1 cycle of a selective RET inhibitor. -100 -80 -60 -40 -20 0 20 40 Maximum % Reduction from Baseline Sum of Diameters of Target Lesions BLU-667 Starting Dose 400 mg QD Platinum-naive Prior Platinum Justin F. Gainor * All responses are confirmed on two consecutive assessments as per RECIST 1.1. ● 5/7 (71%) treatment-naïve patients had confirmed PR Best Response All (N=48) Prior Platinum (N=35) ORR (95% CI) 58% (43–72) 60% (42–76) CR* PR* SD PD 1 27 18 2 1 20 14 - DCR (95% CI) 96% (86–99) 100% (90–100)


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0 2 4 6 8 10 12 14 16 Treatment Duration (Months) BLU-667 Induces Rapid and Durable Responses in RET Fusion+ Advanced NSCLC 9 Justin F. Gainor Patients enrolled by 14 Nov 18, data cut-off 28 Apr 19. Treatment ongoing Treatment after PD Post-treatment follow-up CR PR PD - Most responses occur at the first scan (week 8) - 82% of responding patients remain on treatment as of the data cut-off - Median duration of response not yet reached - Patients have been on treatment up to 24 months (including dose-escalation and regardless of starting dose) Duration of Treatment and Response: BLU-667 Starting Dose 400 mg QD


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BLU-667 is Active Regardless of Prior Checkpoint Treatment Justin F. Gainor -100 -80 -60 -40 -20 0 20 40 Maximum Reduction - Sum of Diameter Change from Baseline, % BLU-667 Starting Dose 400 mg QD 10 Patients enrolled by 14 Nov 18, data cut-off 28 Apr 19. -100 -80 -60 -40 -20 0 20 40 Maximum % Reduction from Baseline Sum of Diameters of Target Lesions BLU-667 Starting Dose 400 mg QD Prior PD-1 or PD-L1 inhibitor PD-1 and PD-L1 inhibitor naïve


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BLU-667 is Active Across RET Fusion Genotypes Justin F. Gainor -100 -80 -60 -40 -20 0 20 40 Maximum % Reduction from Baseline Sum of Diameters of Target Lesions BLU-667 Starting Dose 400 mg QD CCDC6 KIF5B Other/unknown 11 Patients enrolled by 14 Nov 18, data cut-off 28 Apr 19.


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BLU-667 is Active Regardless of CNS Involvement Justin F. Gainor -100 -80 -60 -40 -20 0 20 40 Maximum % Reduction from Baseline Sum of Diameters of Target Lesions BLU-667 Starting Dose 400 mg QD CNS involvement No CNS involvement 12 CNS, central nervous system Patients enrolled by 14 Nov 18, data cut-off 28 Apr 19.


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BLU-667 is Active Against Intracranial Metastases • 7 of 9 (78%) patients had shrinkage of measurable brain metastases • No patients at 400 mg QD starting dose had progression due to new CNS involvement Justin F. Gainor 13 aData shown for 9 patients with brain lesion(s) identified as RECIST 1.1 target lesions at baseline. Data cut-off date: 28 Apr 2019. 0 2 4 6 8 -100 -75 -50 -25 0 25 50 Months on Study C h a n g e i n S u m o f D i a m e t e r o f T a r g e t B r a i n L e s i o n s , % Shrinkage of Brain Metastasesa RET fusion partner: Unknown CCDC6 KIF5B


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• 52-year-old woman, RET fusion+ NSCLC, prior platinum and checkpoint inhibitor • Near-complete resolution of previously untreated target brain metastasis after two months of BLU-667 400 mg QD • Continues to receive treatment with ongoing confirmed PR (70% shrinkage) at 6 months • 59-year-old man, RET fusion+ NSCLC, prior platinum and checkpoint inhibitor • Complete resolution of previously untreated nontarget brain metastasis after two months of BLU-667 400 mg QD • Continues to receive treatment with ongoing confirmed PR (67% shrinkage) at 6 months BLU-667 is Active Against Intracranial Metastases Images courtesy Dr. P Cassier Centre Leon Berard, Lyon, FR Images courtesy of Dr. Stephen Liu, Georgetown University, Washington, D.C. Justin F. Gainor 14 Data cut-off 28 Apr 19. Baseline Cycle 3, Day 1 Baseline Cycle 3, Day 1


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Rapid and Robust Clearance of RET Variant ctDNA with BLU-667 Among patients receiving a BLU-667 starting dose of 400 mg QD: • 18/20 (90%) with detectable RET fusion ctDNA at baseline had complete clearance within the first cycle • Clearance of genomic driver variants ctDNA has been associated with improved cancer outcomes1–3 -100 -50 0 % c t D N A R e d u c t i o n ( C 2 D 1 f r o m B a s e l i n e ) Best response PD SD PR RET Fusion+ Advanced NSCLC, BLU-667 starting dose 400 mg QD Justin F. Gainor 15 ctDNA: circulating tumor DNA. Data cut-off date: 28 Apr 2019. 1. Cabel, et al. Ann Oncol 2017; 2. Mok, et al. Clin Cancer Res 2015; 3. Drilon, et al. Nat Rev Clin Oncol 2018; Awad, et al. J Thorac Oncol 2018.


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BLU-667 has Activity in Other RET Fusion+ Malignancies • PR in 2/2 patients with metastatic pancreatic cancer - 67 yo male, CCDC6-RET fusion, continues with confirmed PR (53% shrinkage) at 6 months – 31 yo male, TRIM33-RET and JMJD1C-RET fusions, continues treatment after PR (41% shrinkage) at first response assessment • PR in a patient with intrahepatic bile duct carcinoma – 51 yo female, NCOA4-RET fusion, continues with confirmed PR (67% shrinkage) at 15 months • ORR 83% (5/6)* in RET-fusion PTC (Abstract 6018 presented June 1, 2019) • Safety profile similar to what was seen in RET fusion+ NSCLC 16 Justin F. Gainor * Confirmation of response is pending for two patients. Data cut-off date: 28 Apr 2019.


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Conclusions • BLU-667 demonstrates broad and durable antitumor activity in patients with RET fusion+ advanced NSCLC - 60% ORR and 100% DCR in patients previously treated with platinum chemotherapy, and 58% ORR in all RET fusion+ patients - Responses observed regardless of treatment history, RET fusion partner or CNS involvement - Active against intracranial metastases - Well tolerated at 400 mg QD with most AEs grade 1/2 • BLU-667 has FDA breakthrough therapy designation in RET fusion+ NSCLC that progressed following platinum based chemotherapy • Data support expansion of ARROW trial in treatment-naïve NSCLC patients and continued enrollment of other RET-altered solid tumor groups 17 Justin F. Gainor RP2D, recommended phase 2 dose. Data are preliminary and based on a data cut-off date of April 28, 2019.


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Acknowledgments • Participating patients and families • BLU-667-1101 Investigators and research coordinators • Colleagues at Blueprint Medicines Corporation 18 Justin F. Gainor - The University of Texas MD Anderson Cancer Center, Houston, TX, United States - Oregon Health & Science University, Portland, OR, United States - Massachusetts General Hospital Cancer Center, Boston, MA, United States - University of Pennsylvania, Philadelphia, PA, United States - University of California Irvine Medical Center, Irvine, CA, United States - University of Miami, Miami, FL, United States - Georgetown University Medical Center, Washington, District of Columbia, United States - University of Washington, Seattle, WA, United States - University of Michigan, Ann Arbor, MI, United States - Cornell University, New York, NY, United States - University of Colorado, Aurora, CO, United States - Washington University School of Medicine, St. Louis, MO, United States - Mayo Clinic, Rochester, MN, United States - Mayo Clinic, Jacksonville, FL, United States - Mayo Clinic, Phoenix, AZ, United States - Texas Oncology, Dallas, TX, United States - Thoraxklinik Heidelberg, Heidelberg, Germany - Universitatsklinikum Essen, Essen, Germany - Pius-Hospital Oldenberg, Oldenberg, Germany - Vall d’Hebron University Hospital, Barcelona, Spain - Hospital Universitario 12 de Octubre, Madrid, Spain - Hospital Universitario Ramon y Cajal, Madrid, Spain - Hospital Clinic Barcelona, Barcelona, Spain - Hospital Duran I Reynals, Barcelona, Spain - Centre Leon Berard, Lyon, France - Gustave Roussy, Villejuif, France - Institut Claudius Regaud, Toulouse, France - CHU de Rennes, Rennes, France - CHRU de Lille, Lille, France - Institut Bergonie, Bordeaux, France - University College of London NHS Foundation Trust, London, UK - Guy’s Hospital St. Thomas NHS Foundation Trust, London, UK - The Christie NHS Foundation Trust, Manchester, UK - University of Milano, Istituto Europeo di Oncologia, Milan, Italy - Grande Ospedale Metropolitano Niguarda, Milan, Italy - University Medical Center Gronigen, Gronigen, Netherlands - National Cancer Centre Singapore, Singapore, Singapore - Seoul National University Hospital, Seoul, Republic of Korea - Asan Medical Center, Seoul, Republic of Korea - Severance Hospital, Seoul, Republic of Korea - National Taiwan University Hospital, Taipei, Taiwan