UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

WASHINGTON, DC 20549

 

FORM 8-K

 

CURRENT REPORT PURSUANT TO

SECTION 13 OR 15(d) OF THE

SECURITIES EXCHANGE ACT OF 1934

 

Date of Report: April 17, 2016

(Date of earliest event reported)

 

LOXO ONCOLOGY, INC.

(Exact Name of Registrant as Specified in Its Charter)

 

Delaware

(State or Other Jurisdiction of Incorporation)

 

001-36562

 

46-2996673

(Commission File Number)

 

(IRS Employer Identification No.)

 

281 Tresser Blvd., 9th Floor
Stamford, CT

 

06901

(Address of Principal Executive Offices)

 

(Zip Code)

 

(203) 653-3880

(Registrant’s Telephone Number, Including Area Code)

 

Not Applicable

(Former name or former address, if changed since last report.)

 

Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):

 

o Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)

o Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)

o Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))

o Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))

 

 

 



 

Item 7.01 Regulation FD.

 

On April 17, 2016, Loxo Oncology, Inc. (“Loxo Oncology”) issued a press release announcing the presentation of updated clinical data for Loxo Oncology’s ongoing LOXO-101 Phase 1 trial by the study investigators at the American Association for Cancer Research Annual Meeting in New Orleans.  A copy of the press release is furnished as Exhibit 99.1 to this report and incorporated herein by reference.   A copy of the slides presented by the study investigators are furnished as Exhibit 99.2 to this report and incorporated herein by reference.

 

The information furnished with this report, including Exhibit 99.1 and Exhibit 99.2, shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (“Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference into any other filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such a filing.

 

Item 9.01 Financial Statements and Exhibits

 

(d) Exhibits.

 

Exhibit
Number

 

Description of Exhibit

 

 

 

99.1

 

Press release dated April 17, 2016.

 

 

 

99.2

 

Slides presented by study investigators on April 17, 2016.

 

2



 

SIGNATURES

 

Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.

 

 

 

Loxo Oncology, Inc.

 

 

 

Date: April 18, 2016

By:

/s/ Jennifer Burstein

 

 

Name:

Jennifer Burstein

 

 

Title:

Vice President of Finance and principal financial officer

 

3


Exhibit 99.1

 

 

Loxo Oncology TRK Inhibitor LOXO-101 Shows Durable Anti-Tumor Activity Across TRK Fusion Cancers in AACR Phase 1 Update

 

— Five of Six Evaluable Patients with TRK Fusion Cancers Achieve Confirmed RECIST Partial Responses; All Six Demonstrate Significant Tumor Regressions —

 

— All TRK Fusion Patients Remain on Study, With Longest Follow-up Beyond One Year —

 

— Company to Host Investor Conference Call and Webcast on Monday, April 18, 2016 at 8:00 a.m. EST —

 

STAMFORD, Conn., April 17, 2016 — Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, today announced new results from its Phase 1 open-label, dose-escalation trial of LOXO-101, a selective inhibitor of tropomyosin receptor kinase (TRK). A presentation at the 2016 American Association for Cancer Research (AACR) Annual Meeting in New Orleans on April 17, 2016 provided updated data from the Phase 1 trial, which was last reported at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in November 2015.

 

LOXO-101 Phase 1 study investigators reported that, as of the March 25, 2016 data cutoff date, 43 patients with solid tumors refractory to standard therapy had been enrolled and treated, including seven patients with cancers harboring TRK gene fusions. Data regarding the first three of these patients were initially reported at the AACR-NCI-EORTC conference in November 2015.

 

Six patients with TRK fusion cancers had been on study sufficiently long for their first efficacy assessment, and all six exhibited significant tumor regressions. A seventh patient with a TRK fusion cancer was enrolled more recently and thus had not yet been evaluated for response as of the data cutoff date, though the patient remains on study. Five of the six efficacy evaluable patients achieved a confirmed partial response, as defined by standard RECIST criteria. The sixth patient demonstrated clear radiographic tumor regressions, including in the central nervous system, but has not met the threshold required for a RECIST response. Tumor regressions have been observed in five different anatomically-defined cancers: sarcoma, gastrointestinal stromal tumor, mammary analogue secretory cancer of the salivary glands, thyroid cancer and non-small cell lung cancer. No TRK fusion patients have progressed, with one patient in cycle 14, two patients in cycle 10 and three patients in cycle 7, as of the data cutoff date. In addition, LOXO-101 has been highly active and well-tolerated at doses that include the recommended Phase 2 dose of 100 mg BID. The majority of adverse events reported by the investigators have been mild to moderate. A maximum tolerated dose (MTD) has not been defined.

 



 

“The responses, durability and safety data with LOXO-101 clearly suggest that this is an important drug candidate for patients with TRK fusion cancers,” said David Hong, M.D., deputy chair and associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center in Houston and presenter of the LOXO-101 oral presentation. “We are excited to continue to follow these Phase 1 patients and treat additional TRK fusion patients in the LOXO-101 Phase 2 trial. I hope these data encourage my colleagues to test for TRK fusions and refer patients to a LOXO-101 study.”

 

“The consistent efficacy of LOXO-101 in patients with TRK gene fusions, independent of tumor type, is very exciting,” said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. “The data update also provides an encouraging snapshot of response durability, particularly at the recommended Phase 2 dose of 100mg twice-daily. These data suggest that LOXO-101 can deeply inhibit its target at a well-tolerated dose and generate durable disease control in a diverse group of patients with TRK gene fusions.”

 

LOXO-101 Phase 1 Results

 

LOXO-101 is currently being evaluated in an ongoing dose-escalation Phase 1 trial in patients with solid tumors refractory to standard therapy. As of March 25, 2016, 43 patients with advanced cancer had been treated at five dose levels: 50 mg QD, 100 mg QD, 100 mg BID, 150 mg BID and 200 mg QD. The median age of these patients is 57 (ranging from 28-76) and the median number of prior treatments is three (ranging from 0-11).

 

Safety Analysis

 

LOXO-101 has been well tolerated in the 43 patients treated, including 24 patients at a dose of 100mg BID. Adverse events reported regardless of attribution to study drug are generally consistent with those previously presented.  Grade 1 and 2 adverse events include fatigue (33 percent), constipation (23 percent) and dizziness (23 percent). Grade 3 adverse events included fatigue, constipation, anemia, increased liver enzymes, dyspnea, abdominal pain, hypertension, hyperkalemia, delirium, pleural effusion, and syncope. No Grade 4 adverse events have been reported. The frequency of toxicities did not correlate with dose level. The maximum tolerated dose (MTD) has not yet been defined.

 

Efficacy Analysis

 

As of March 25, 2016, seven patients with cancers harboring TRK fusions have been enrolled, representing a broad range of tumor types: mammary analogue secretory cancer of the salivary glands (MASC, n=3), soft tissue sarcoma, gastrointestinal stromal tumor, thyroid carcinoma and non-small cell lung cancer. As of the March 25, 2016 data cutoff date, six patients had been evaluated for response, and five had achieved a confirmed objective response. All six patients experienced significant tumor regression, with response status summarized below:

 

·                  Soft tissue sarcoma, LMNA-NTRK1 fusion: Confirmed partial response, remains on study in cycle 14 at a dose of 100 mg BID

 



 

·                  Gastrointestinal stromal tumor, ETV6-NTRK3 fusion: Confirmed partial response, remains on study in cycle 10 at a dose of 150 mg BID

·                  MASC, ETV6-NTRK3 fusion: Confirmed partial response, remains on study in cycle 10 at 100 mg BID

·                  MASC, ETV6-NTRK3 fusion: Confirmed partial response, remains on study in cycle 7 at 100 mg QD; this patient started therapy on 100 mg BID and dose-reduced early in cycle 1 to 100 mg QD due to transient dizziness possibly related to drug

·                  Papillary thyroid cancer, ETV6-NTRK3 fusion: Confirmed partial response, remains on study in cycle 7 at 100 mg BID

·                  Non-small cell lung cancer, TPR-NTRK1 fusion: 18% tumor regression of bone-only RECIST evaluable disease (stable disease), remains on study in cycle 7 at 100mg BID

 

All six patients remain on study as of March 25, 2016. The seventh patient was recently enrolled and not yet evaluable for efficacy as of the data cutoff date, but also remains on study.

 

On Monday, April 18, 2016, Loxo Oncology plans to file a Form-8-K with the U.S. Securities and Exchange Commission (SEC) containing the LOXO-101 materials presented at the AACR meeting. These materials will also be posted to the Loxo Oncology website.

 

Upcoming Milestones for Loxo Oncology

 

Loxo Oncology continues to make significant progress across its pipeline. Upcoming milestones are expected to include:

 

·                  Continued enrollment of the LOXO-101 Phase 2 global, multi-center, single-arm, open-label basket trial in adult patients with solid tumors that harbor a TRK fusion, with an enrollment update expected in the second half of 2016.

·                  Initiation of a Phase 1 study of a selective RET inhibitor in late 2016 or early 2017.

·                  Initiation of a Phase 1 study of next-generation TRK inhibitor LOXO-195, addressing previously-treated patients with acquired resistance, in 2017.

 

Conference Call and Webcast Information

 

Loxo Oncology will host a conference call, live webcast with slides and Q&A on Monday, April 18, 2016 at 8:00 a.m. ET to discuss the LOXO-101 data and program updates. To participate in the conference call, please dial (877) 930-8065 (domestic) or (253) 336-8041 (international) and refer to conference ID 77038770. A live webcast of the presentation will be available at http://ir.loxooncology.com/. A replay of the webcast will be available shortly after the conclusion of the call and archived on the company’s website for 30 days following the call.

 

About LOXO-101

 

LOXO-101 is a potent, oral and selective investigational new drug in clinical development for the treatment of patients with cancers that harbor abnormalities involving the tropomyosin receptor kinases (TRKs). Growing research suggests that the

 



 

NTRK genes, which encode for TRKs, can become abnormally fused to other genes, resulting in growth signals that can lead to cancer in many sites of the body. In an ongoing Phase 1 clinical trial, LOXO-101 has demonstrated encouraging preliminary efficacy. LOXO-101 is also being evaluated in a global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions and a Phase 1 trial in pediatric patients. For additional information about the LOXO-101 clinical trials, please refer to www.clinicaltrials.gov. Interested patients and physicians can contact the Loxo Oncology Physician and Patient Clinical Trial Hotline at 1-855-NTRK-123.

 

About Loxo Oncology

 

Loxo Oncology is a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers. Our pipeline focuses on cancers that are uniquely dependent on single gene abnormalities, such that a single drug has the potential to treat the cancer with dramatic effect. We believe that the most selective, purpose-built medicines have the highest probability of maximally inhibiting the intended target, thereby delivering best-in-class disease control and safety. Our management team seeks out experienced industry partners, world-class scientific advisors and innovative clinical-regulatory approaches to deliver new cancer therapies to patients as quickly and efficiently as possible. For more information, please visit the company’s website at www.loxooncology.com.

 

Forward Looking Statements

 

This press release contains “forward-looking” statements within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: “anticipate,” “intend,” “plan,” “goal,” “seek,” “believe,” “project,” “estimate,” “expect,” “strategy,” “future,” “likely,” “may,” “should,” “will” and similar references to future periods. These statements are subject to numerous risks and uncertainties that could cause actual results to differ materially from what we expect. Examples of forward-looking statements include, among others, statements we make regarding the timing and success of our clinical trials, and the potential therapeutic benefits and economic value of our lead product candidate or other product candidates. Further information on potential risk factors that could affect our business and its financial results are detailed in our most recent Annual Report on Form 10-K, and other reports as filed from time to time with the Securities and Exchange Commission. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise.

 

###

 

Contacts for Loxo Oncology, Inc.

 

Company:
Jacob S. Van Naarden
Chief Business Officer

jake@loxooncology.com

 



 

Investors:

Peter Rahmer
The Trout Group, LLC
646-378-2973
prahmer@troutgroup.com

 

Media:

Dan Budwick
Pure Communications, Inc.
973-271-6085
dan@purecommunicationsinc.com

 


Exhibit 99.2

 

Clinical safety and activity from a Phase 1 study of LOXO-101, a selective TRKA/B/C inhibitor, in solid-tumor patients with NTRK gene fusions David S. Hong1, Anna F. Farago2, Marcia S. Brose3, Howard A. Burris, III4, Afshin Dowlati5, Todd M. Bauer4, Matthew Taylor6, Alice T. Shaw2, Adriana Estrada-Bernal7, Anh T. Le7, Nisha Nanda8, Michael C. Cox8, Robert C. Doebele7 April 17, 2016 1 2016 AACR Annual Meeting 1MD Anderson Cancer Center, Houston, TX 2Massachusetts General Hospital, Boston, MA 3University of Pennsylvania, Philadelphia, PA 4Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN 5University Hospitals Case Medical Center, Cleveland, OH 6Oregon Health & Science University, Portland, OR 7University of Colorado, Aurora, CO 8Loxo Oncology, South San Francisco, CA

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Disclosure Information AACR 2016 Author Disclosures David S. Hong Travel expenses supported by Loxo Oncology Anna F. Farago None Marcia S. Brose None Howard A. Burris, III None Afshin Dowlati None Todd M. Bauer None Matthew Taylor None Alice T. Shaw None Adriana Estrada-Bernal Research grant from Loxo Oncology Anh T. Le Research grant from Loxo Oncology Robert C. Doebele Research grant from Loxo Oncology Michael C. Cox Nisha Nanda Employees and shareholders of Loxo Oncology 2 I will discuss the following off label use and/or investigational use in my presentation: Results of the ongoing Phase 1 trial of LOXO-101

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Kinase Fusions Deserve Our Attention 3 GENETIC ALTERATION COMMERCIALLY AVAILABLE DRUGS ABL fusion dasatinib, imatinib, nilotinib, ponatinib ALK fusion alectinib, ceritinib, crizotinib BRAF mutation cobimetinib, dabrafenib, trametinib, vemurafenib BRAF fusion cobimetinib, trametinib cKIT mutation dasatinib, imatinib, nilotinib EGFR mutation afatinib, erlotinib, gefitinib, osimertinib HER2 amplification lapatinib, pertuzumab, trastuzumab, T-DM1 PDGFR fusion dasatinib, imatinib, nilotinib PDGFR mutation dasatinib, imatinib, nilotinib RET fusion cabozantinib ROS1 fusion crizotinib

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TRK Fusions are Oncogenic and Signal Through Canonical Downstream Pathways Normal TRK Proteins Family of neurotrophin receptors TrkA (NTRK1) Pain, thermoregulation TrkB (NTRK2) Movement, memory, mood, appetite, body weight TrkC (NTRK3) Proprioception TRK Fusions Ligand binding domain replaced by 5’ fusion partner; highly expressed by promoter of 5’ fusion gene Ligand-independent activation 4 NTRK1/2/3 ERK AKT ERK AKT TrkA/B/C

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TRK Fusions Found in Diverse Cancer Histologies 5 TRK Fusion Frequency <5% 5–25% >75% CNS Astrocytoma Brain low-grade glioma Glioblastoma GI Colorectal cancer Cholangiocarcinoma GIST Pancreatic cancer Head and neck Squamous cell carcinoma Lung Adenocarcinoma Large cell neuroendocrine Other Acute myeloid leukemia Breast invasive carcinoma Melanoma Sarcoma Congenital mesoblastic nephroma Papillary thyroid cancer Pontine glioma Spitz tumors Mammary analogue secretory carcinoma (MASC) of the salivary glands Secretory breast carcinoma Infantile fibrosarcoma

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Enriching for TRK Fusions 6 1 Bishop JA et al. Am J Surg Pathol. 2013 Jul;37(7):1053-7. 2 Prasad ML et al. Cancer. 2016 Jan 19. 3 Brenca M et al. J Pathol. 2016 Mar;238(4):543-9. 4 Haller F et al. J Pathol. 2016 Feb 11. Mammary analogue secretory carcinoma1 >50% of nonparotid acinic cell carcinomas may be MASC tumors harboring TRK fusions Papillary thyroid cancer2 7 of 28 younger patients (25%) tested TRK fusion positive Ages 6-18 yo 6 of 7 ages 13-18 GIST3 TRK fusions present in GIST tumors tested wild-type for KIT/PDGFR/BRAF/SDH Sarcoma4 TRK fusions may share myopericytic/haemangiopericytic pattern seen by routine histologic assessment

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LOXO-101: A Rationally Designed Selective TRK Inhibitor 7 Chartier M, Chénard T, Barker J, Najmanovich R. (2013) Kinome Render: a stand-alone and web-accessible tool to annotate the human protein kinome tree. PeerJ 1:e126 TRK TRK Highly selective: limited inhibition of other kinases and >1,000x selective over other off targets Highly potent against TRKA, TRKB, TRKC (5-11 nM IC50)

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LOXO-101 Phase 1 Study Design Ongoing dose escalation study Advanced or metastatic solid tumors ECOG 0/1, normal organ function QD or BID oral fixed, continuous dosing, 28-day cycles Outcome measures Safety and tolerability Pharmacokinetics measured at cycle 1, days 1 and 8 Efficacy assessments conducted every other cycle starting C3D1 8 Dose Cohort PATIENTS ENROLLED 50mg QD 4 100mg QD 5 100mg BID 24 200mg QD 5 150mg BID 5 TOTAL 43 Data cutoff March 25, 2016

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Baseline Characteristics characteristics Subjects (N= 43) Median age (range), years 57.0 (28 – 76) Sex Male / Female 25 (58%) / 18 (42%) Race White / Black / Other 34 (79%) / 6 (14%) / 3 (7%) Tumor Type* Head and neck 8 (19%) Lung 8 (19%) Breast 3 (7%) Colorectal 3 (7%) Pancreatic 3 (7%) ECOG Status 0 / 1 / 2 / Unknown 13 (30%) / 27 (63%) / 2 (5%) / 1 (2%) Prior systemic anticancer therapy, n (%) 41 (95%) Median number of regimens (range) 3 (0-11) 9 *Includes n=2 each of sarcoma, thymoma, and thyroid. Includes n=1 each of anal, angiosarcoma, appendiceal peritoneal carcinomatosis, gall bladder, gastric, GE junction, melanoma, retroperitoneal leiomyosarcoma, retroperitoneal atypical lipomatous, soft tissue carcinoma, and thymus. Includes n=1 unknown. TRK-fusion positive Mammary analogue secretory carcinoma (ETV6-NTRK3) 3 Soft tissue sarcoma (LMNA-NTRK1) 1 GIST (ETV6-NTRK3) 1 Thyroid (ETV6-NTRK3) 1 NSCLC (TPR-NTRK1) 1 Total 7

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Disposition 10 ALL PATIENTS TRK Fusion Patients TRK MUTATION/ AMPLIFICATION PATIENTS N=43 N=7 N=5 On study 13 (30%) 7 (100%) 2 (40%) Discontinued 30 (70%) 0 (0%) 3 (60%) Reasons for discontinuation Disease Progression 23 (53%) -- 3 (60%) Adverse Event 3 (7%)* -- -- Withdrawal of consent 2 (5%) -- -- Noncompliance 1 (2%) -- -- Other 1 (2%) -- -- *Patients discontinued for adverse events of syncope, pleural effusion, and enterocutaneous fistula.

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Linear PK profile following oral administration shows high plasma exposure and no accumulation Slow off-rate; T1/2 = 160 min LOXO-101 Exposure 11 The horizontal line representing TRKA IC90 refers to the total plasma concentration of LOXO-101 that is associated with an unbound concentration of LOXO-101 that is equal to its IC90 for inhibition of NGF-stimulated activity in a cellular assay. The IC90 values for TRKB and TRKC are not shown, but are similar to those of TRKA. Dotted lines in the right panel are inferred PK from the evening BID dose. LOXO-101 CMAX LOXO-101 EXPOSURE OVER TIME 0 6 12 18 24 1 10 100 1000 Time (h) C o n c e n t r a t i o n o f L O X O - 1 0 1 i n P l a s m a ( n g / m L ) TRKA IC 50 TRKA IC 90 50 mg QD (n=4) 100 mg QD (n=6) 100 mg BID (n=13) 150 mg BID (n= 4) 200 mg QD (n=3) 50 mg QD (n=4) 100 mg QD (n=5, 6) 100 mg BID (n=17,13) 150 mg BID (n=5, 4) 200 mg QD (n=4, 3) 0 1000 2000 3000 4000 Dose C m a x o f L O X O - 1 0 1 i n P l a s m a ( n g / m L ) Day 1 Day 8 TRKA IC 90

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LOXO-101 Phase 1 Interim Treatment-Emergent AEs, Regardless of Attribution to Study Drug Dose 100 mg BID (n=24) Total (n=43) Adverse Events (AEs)* Gr 3/4 All Gr Gr 3/4 All Gr n (%) n (%) n (%) n (%) Fatigue 0 5 (21%) 2 (5%) 14 (33%) Constipation 0 3 (13%) 1 (2%) 10 (23%) Dizziness 0 6 (25%) 0 10 (23%) Anemia 1 (4%) 4 (17%) 3 (7%) 8 (19%) Increased AST 1 (4%) 5 (21%) 4 (9%) 8 (19%) Cough 0 4 (17%) 0 8 (19%) Diarrhea 0 4 (17%) 0 8 (19%) Increased ALP 0 5 (21%) 1 (2%) 7 (16%) Dyspnea 1 (4%) 3 (13%) 1 (2%) 7 (16%) Nausea 0 4 (17%) 0 7 (16%) Abdominal pain 0 3 (13%) 1 (2%) 6 (14%) Increased ALT 1 (4%) 4 (17%) 2 (5%) 6 (14%) Anxiety 0 2 (8%) 0 5 (12%) Hypertension 0 4 (17%) 1 (2%) 5 (12%) Peripheral edema 0 2 (8%) 0 5 (12%) Pyrexia 0 2 (8%) 0 5 (12%) Vomiting 0 2 (8%) 0 5 (12%) Hyperkalemia 1 (4%) 1 (4%) 2 (5%) 3 (7%) Delirium 1 (4%) 1 (4%) 2 (5%) 2 (5%) Pleural effusion 1 (4%) 1 (4%) 2 (5%) 2 (5%) Syncope 0 0 2 (5%) 2 (5%) *Treatment-emergent adverse events (reported by > 10% of total subjects) or any Grade 3-4 events that occurred in at least 2 patients. 12

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LOXO-101 Summary of Best Response Data as of March 25, 2016 13 ALL PATIENTS* TRK Fusion Patients** TRK MUTATION/ AMPLIFICATION PATIENTS N=41 N=6 N=5 CR 0 0 0 PR 5 5 0 SD 7 1 3 PD 23 0 2 Off-study prior to first response assessment 6 0 0 Overall Response Rate 12% (5/41) 83% (5/6) 0% (0/5) * Excludes 2 recently enrolled patients, on study for less than 8 weeks as of March 25, 2016. ** Excludes 1 recently enrolled patient, on study for less than 8 weeks as of March 25, 2016. CR = complete response (confirmed) PR = partial response (confirmed) SD = stable disease PD = progressive disease RECIST v1.1

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Best Response to LOXO-101 for Patients with TRK Fusions 14 Note: Ongoing cycle number noted for each patient below each bar; 28-day cycles -100% -80% -60% -40% -20% 0% 20% 40% 60% 80% 100% Maximum Change in Tumor Size (%) Stable disease Confirmed partial response - 30% 7+ 7+ 10+ 10+ 7+ 14+

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PATIENT CASES – TRK FUSIONS 15

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Patient #1: LMNA-NTRK1 fusion soft tissue sarcoma 42 yo female with undifferentiated sarcoma progressed through epirubicin, ifosfamide, sorafenib, and doxorubicin 100mg BID Rapid resolution of dyspnea and hypoxemia Confirmed partial response Currently on study in cycle 14 Study baseline Study cycle 3 day 1 Study cycle 13 day 1 16

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Patient #2: ETV6-NTRK3 fusion GIST 55 yo male with GIST progressed through imatinib, sunitinib, sorafenib, nilotinib, and regorafenib 150mg BID Confirmed partial response Currently on study in cycle 10 17 CT PET Study baseline Study cycle 5 day 1 Study baseline Study cycle 3 day 1 Study cycle 9 day 1 Study cycle 9 day 1

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Study baseline Study cycle 3 day 1 Study cycle 9 day 1 Patient #3: ETV6-NTRK3 fusion mammary analogue secretory carcinoma of the salivary gland (MASC) 33 yo male progressed through docetaxel, carboplatin and 5FU 100mg BID Confirmed partial response Currently on study in cycle 10 18

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19 Patient #4: ETV6-NTRK3 fusion mammary analogue secretory carcinoma of the salivary gland (MASC) 66 yo male progressed through radiotherapy, dasatinib, GDC-0941+ erlotinib, and ABBV-399 100mg QD* Confirmed partial response Currently on study in cycle 7 Study baseline Study cycle 3 day 1 Study cycle 7 day 1 * Patient enrolled at 100mg BID and dose reduced to 100mg QD on C1D2 due to transient dizziness possibly related to drug

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Patient #5: ETV6-NTRK3 fusion papillary thyroid cancer 20 33 yo male progressed through RAI, pazopanib, trametinib 100mg BID Confirmed partial response Rapid improvement cervical lymphadenopathy Currently on study in cycle 7 Study baseline Study cycle 3 day 1 Study cycle 7 day 1

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Patient #6: TPR-NTRK1 non-small cell lung cancer 21 28 yo male progressed through cisplatin and etoposide 100mg BID 18% reduction; stable disease Patient’s only RECIST evaluable lesions are in the bone Non-target lesion regressions in lung and brain Resolution of cough and pain Currently on study in cycle 7 Study baseline Study cycle 3 day 1 Study cycle 7 day 1

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Best Response to LOXO-101 for Patients with TRK Fusions 22 Note: Ongoing cycle number noted for each patient below each bar; 28-day cycles -100% -80% -60% -40% -20% 0% 20% 40% 60% 80% 100% Maximum Change in Tumor Size (%) Stable disease Confirmed partial response - 30% 7+ 7+ 10+ 10+ 7+ 14+

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LOXO-101 Phase 2 Adult Basket Trial Solid tumors, including CNS tumors, with TRK fusion based on local or pre-existing testing Enrolling patients 12 yo; ECOG 0-3 Dose: 100mg BID Primary endpoint: Best ORR Global study (20-30 sites) Patient concierge service for enrollment, including single patient protocols Hotline: 855-NTRK-123 23

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TRK Fusions Present Assay Complexity Due to Varied Fusion Partners 24 KINASE DOMAIN NTRK1/2/3 NTRK1 NTRK2 NTRK3 Selection of fusion constructs shown. Graphic is not comprehensive for all TRK fusion constructs described in the literature. BCAN TPR CD74 CEL IRF2BP2 LMNA MPRIP NFASC SSBP2 TFG TPM3 AFAP1 AGBL4 NACC2 QKI SQSTM1 TRIM24 VCL BTBD1 ETV6

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Finding Fusions Requires Careful Assay Design NGS, Next-Generation Sequencing RT-PCR, Reverse Transcription Polymerase Chain Reaction FISH, Fluorescence In Situ Hybridization IHC, Immunohistochemistry 25 Assay designs present varied challenges for fusion detection

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Different Methods Lead to Variable Estimates of Fusion Frequency, Ex. ALK in NSCLC 26 DETECTION TECHNOLOGY ALK FUSION FREQUENCY IN LARGE NSCLC COHORTS REFERENCE DNA NGS (hybrid capture) 4.4% (n=1,070) Ali et al. ASCO 2014 Annual Meeting; Abstract 8049 RNA NGS (amplicon) 4.3% (n=115) Hovelson et al. Neoplasia. 2015 Apr; 17(4):385–399 RNA NGS (anchored multiplex PCR) 2.4% (n=741) Farago et al. ASCO 2015 Annual Meeting; Abstract 8095 RNA NGS (RNA-Seq / whole transcriptome) 1.0% (n=513) Stransky et al. Nat Commun 2014;5:4846. RT-PCR 2.7% (n=7,344) Li et al. J Thorac Oncol. 2014 Jan; 9(1):18-25 FISH 5.5% (n=1,500) Kwak et al. NEJM 2010; 363:1693-1703 IHC 6.5% (n=441) McLeer-Florin et al. J Thorac Oncol. 2012; 7:348–354 FISH + IHC 0.4% (n=227) Rodig et al. Clin Cancer Res. 2009 August 15; 15(16): 5216–5223 Note: Select publications/cohorts shown

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Point Estimates of TRK Fusion Frequency Are Similarly Varied 27 LUNG CANCER DETECTION TECHNOLOGY TRK FUSION FREQUENCY REFERENCE RNA NGS (anchored multiplex PCR) 2/1,378 (0.1%) Farago et al. J Thorac Oncol. 2015;10: 1670–1674. RNA NGS (RNA-Seq / whole transcriptome) 1/513 (0.2%) Stransky et al. Nat Commun 2014;5:4846. FISH 11/443 (2.5%) Varella-Garcia et al. WCLC 2015. Abstract 37.01. DNA NGS + FISH 3/91 (3.3%) Vaishnavi et al. Nat Med. 2013 Nov;19(11):1469-72. COLORECTAL CANCER DETECTION TECHNOLOGY TRK FUSION FREQUENCY REFERENCE RNA NGS (RNA-Seq / whole transcriptome) 2/286 (0.7%) Stransky et al. Nat Commun 2014;5:4846. IHC + PCR 1/66 (1.5%) Ardini et al. Mol Oncol 2014;pii:S1574-7891(14)00125–2. RNA NGS 3/147 (2.0%) Park et al. Oncotarget. 2015 Dec 22. doi: 10.18632/oncotarget.6724. RNA NGS 2/74 (2.7%) Lee et al. Oncotarget. 2015 Nov 17;6(36):39028-35.

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TRK fusions have been identified across multiple tumor types Trend toward younger patients Consider patients lacking other “common” mutations Lung: EGFR-negative, ALK-negative, ROS1-negative, KRAS-negative Colorectal: KRAS-negative, BRAF-negative GIST: KIT-negative, PDGFR-negative Thyroid: BRAF-negative Panel-based detection available through send-out labs, academic labs, or commercially available NGS kits RNA-based NGS best captures diversity of TRK fusions Key question to ask: how well does the selected approach “cover” TRK fusions? 28 Considerations for Patient Screening

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Universally encountered with targeted therapies As of this presentation, no LOXO-101 responder has progressed Most common: mutations that limit drug binding Gatekeeper: ABL-T315I, EGFR-T790M, ALK-L1196M Solvent front: ALK-G1202R, ROS1-G2032R Case reports: two patients with tumor progression after initial response to a different TRK inhibitor in the clinic1,2 Patient 1: NTRK1 G595R (solvent front) + Y667C Patient 2: NTRK3 G623R (solvent front) 29 Russo et al. Cancer Discovery. Published OnlineFirst on November 6, 2015; DOI: 10.1158/2159-8290. Drilon et al. Annals of Oncology. Advance Access published February 15, 2016 667C 595R LOXO-101 Acquired Resistance to Kinase Inhibitors Solvent front Activation loop

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LOXO-195: 2nd Generation TRK Inhibitor LOXO-101 “like” Highly potent: nanomolar in cell against TRKA, TRKB, TRKC Highly selective: >1,000x selective over other off targets Excellent drug properties: orally dosed, high exposure, low clearance Structural modeling: should be active against acquired resistance mutations Experimental assays confirm structural insights LOXO-195 active against all acquired resistance mutations identified to date Entering Phase 1 in 2017 30 TRK WT TRK G595R LOXO-101 LOXO-195 LOXO-101 LOXO-195

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Conclusions LOXO-101 is a purpose-built, oral, selective and potent TRK inhibitor PK analyses demonstrate very high Cmax (mean levels >IC90) and linear PK with no significant drug accumulation LOXO-101 is well tolerated, with most common adverse events including Grade 1/2 fatigue, constipation, and dizziness; MTD not yet defined LOXO-101 appears broadly active against TRK fusion cancers in this Phase 1 study Significant tumor regression observed in all 6 evaluable patients Confirmed RECIST responses observed in 5 of 6 evaluable patients All TRK fusion patients are currently on study without progression, with the longest patient over one year LOXO-101 Phase 2 basket trial currently enrolling for patients with TRK gene fusions 31

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Acknowledgements LOXO-101 patients and their families and caregivers Co-investigators and study support staffs This trial sponsored and supported by Loxo Oncology LOXO-101 and LOXO-195 invented by Array BioPharma 32

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