8-K

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: December 18, 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 December 18, 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 as reported by study investigators at the 2016 European Society for Medical Oncology Asia Congress in Singapore.  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.

On December 19, 2016, Loxo Oncology issued a press release announcing program updates and an investor conference call.  A copy of the press release is furnished as Exhibit 99.3 to this report and incorporated herein by reference.  A copy of the slides presented during the investor conference call are furnished as Exhibit 99.4 to this report and incorporated herein by reference.

The information furnished with this report, including Exhibit 99.1, Exhibit 99.2, Exhibit 99.3 and Exhibit 99.4, 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 December 18, 2016.
99.2	Slides presented by study investigators on December 18, 2016.
99.3	Press release dated December 19, 2016.
99.4	Slides presented by Loxo Oncology on December 19, 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: December 19, 2016	By:	/s/ Jennifer Burstein
	Name:	Jennifer Burstein
	Title:	Vice President of Finance and principal financial officer

3

EX-99.1

Exhibit 99.1

Loxo Oncology TRK Inhibitor Larotrectinib (LOXO-101) Shows Durable Anti-Tumor Activity Across TRK Fusion Cancers in ESMO Asia Phase 1 Update

— Six of Seven TRK Fusion Patients Achieve Confirmed RECIST Partial Responses and All Remain in Response —

— All TRK Fusion Patients Remain on Study With Median Follow-Up of 15 Cycles —

— Company to Host Investor Conference Call and Webcast on Monday, December 19, 2016 at 8:00 a.m. EST —

STAMFORD, Conn., December 18, 2016 — Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, today announced updated results from its adult Phase 1 open-label, dose-escalation trial of larotrectinib (LOXO-101), a selective inhibitor of tropomyosin receptor kinase (TRK). The data were presented today at the 2016 European Society for Medical Oncology (ESMO) Asia Congress in Singapore.  Data from this ongoing Phase 1 trial were last reported at the American Association for Cancer Research (AACR) Annual Meeting in April 2016.

As of a November 10, 2016 data cutoff, 59 patients with refractory solid tumors had been enrolled and treated with single agent larotrectinib, including eight patients with cancers harboring TRK fusions. Seven patients with TRK fusion cancers were on study sufficiently long for an efficacy assessment, while an eighth TRK fusion patient had been recently enrolled and was not yet evaluated for response. Six of the seven efficacy evaluable patients achieved a confirmed partial response, as defined by standard RECIST criteria. The seventh patient, as previously reported, demonstrated clear radiographic tumor regressions, including in the central nervous system, and remains on study, but had not met the threshold required for a RECIST response. All responders remained in response, with one patient in cycle 22, one patient in cycle 19, one patient in cycle 18, two patients in cycle 15 and one patient in cycle 11. Each cycle is 28 days, or approximately one month.

Larotrectinib has been well tolerated at doses that include and exceed the recommended Phase 2 dose of 100 mg BID. A maximum tolerated dose (MTD) has not been defined. The majority of adverse events reported by the investigators have been mild to moderate.

“The depth of responses and durability data with larotrectinib in patients with TRK fusion cancers are among the most promising that we see in oncology Phase 1 clinical trials,” said Todd Bauer, M.D., associate director, drug development and principal investigator, Sarah Cannon Research Institute and presenter of the larotrectinib oral presentation. “We believe our patients would benefit from the addition of larotrectinib to the armamentarium of matched targeted therapies for our patients, as our continued utilization of molecular testing in clinical practice will naturally lead to the identification of patients with TRK fusions.”

“We continue to be very pleased with the efficacy and safety data we are seeing across the larotrectinib program,” said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. “We look forward to further evaluating larotrectinib in adults with TRK fusion cancers in our Phase 2 NAVIGATE study and in pediatric patients in the SCOUT Phase 1/2 study, and sharing those data publicly over time.”

Larotrectinib (LOXO-101) Phase 1 Results

Larotrectinib is currently being evaluated in an ongoing dose-escalation Phase 1 trial in patients with solid tumors refractory to standard therapy. As of November 10, 2016, 59 patients with advanced cancer had been treated at six dose levels: 50 mg QD, 100 mg QD, 100 mg BID, 150 mg BID, 200 mg QD and 200 mg BID. The median age of these patients is 59 (ranging from 19-82) and the median number of prior treatments is three (ranging from 0-24).

Safety Analysis

Larotrectinib has been well tolerated in the 59 patients treated, including 34 patients at a dose of 100mg BID. Adverse events reported regardless of attribution to study drug are generally consistent with those previously presented. The most common adverse events, largely Grade 1 and 2, include fatigue (37 percent), dizziness (29 percent), anemia (25 percent) and dyspnea (25 percent). No individual Grade 3 or 4 adverse events occurred in more than three patients treated at 100mg BID or more than five patients in the entire study population. The frequency of toxicities did not correlate with dose level. The MTD has not yet been defined.

Efficacy Analysis

As of November 10, 2016, eight patients with cancers harboring TRK fusions had been enrolled, representing a broad range of tumor types, namely mammary analogue secretory cancer of the salivary glands (MASC, n=3), gastrointestinal stromal tumor (n=2), soft tissue sarcoma, thyroid carcinoma and non-small cell lung cancer. Seven patients with TRK fusion cancers were on study sufficiently long for an efficacy assessment, while an eighth TRK fusion patient had been recently enrolled and was not yet evaluated for response. Six of the seven efficacy evaluable patients achieved a confirmed partial response, as defined by standard RECIST criteria. A seventh patient, as previously reported, demonstrated clear radiographic tumor regressions, including in the central nervous system, and remains on study, but had not met the threshold required for a RECIST response. All responders remained in response, with one patient in cycle 22, one patient in cycle 19, one patient in cycle 18, two patients in cycle 15 and one patient in cycle 11. Each cycle is 28 days, or approximately one month.

On Monday, December 19, 2016, Loxo Oncology plans to file a Form 8-K with the U.S. Securities and Exchange Commission (SEC) containing the larotrectinib materials presented at the ESMO Asia meeting. These materials will also be posted to the Loxo Oncology website.

Conference Call and Webcast Information

Loxo Oncology will host a conference call and live webcast with slides and Q&A on Monday, December 19, 2016 at 8:00 a.m. ET to discuss the larotrectinib data and provide a comprehensive program and pipeline update. The company will issue a press release prior to the start of the call. The company anticipates that the conference call and webcast will last 60-90 minutes. To participate in the conference call, please dial (877) 930-8065 (domestic) or (253) 336-8041 (international) and refer to conference ID 16640119. 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 Larotrectinib (LOXO-101)

Larotrectinib (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, larotrectinib has demonstrated encouraging preliminary efficacy. Larotrectinib is also being evaluated in the NAVIGATE global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions, and the SCOUT Phase 1/2 trial in pediatric patients, including patients with advanced cancer, TRK gene fusions and infantile fibrosarcoma. Larotrectinib has been granted Breakthrough Therapy Designation by the U.S. FDA. For additional information about the larotrectinib 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 or visit www.loxooncologytrials.com.

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, the potential therapeutic benefits and economic value of our lead product candidate or other product candidates, and timing of future filings. Further information on potential risk factors that could affect our business and its financial results are detailed in our most recent Quarterly Report on Form 10-Q, 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

EX-99.2

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, Afshin Dowlati2, Howard A. Burris, III3, James J. Lee4, Marcia S. Brose5, Anna F. Farago6, Todd M. Bauer3, Matthew Taylor7, Alice T. Shaw6, Steve Smith8, Nisha Nanda8, Scott Cruickshank8, Michael C. Cox8, Robert C. Doebele9 1MD Anderson Cancer Center, Houston, TX 2University Hospitals Case Medical Center, Cleveland, OH 3Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN 4University of Pittsburgh Medical Center, Pittsburgh, PA 5University of Pennsylvania, Philadelphia, PA 6Massachusetts General Hospital, Boston, MA 7Oregon Health & Science University, Portland, OR 8Loxo Oncology, South San Francisco, CA 9University of Colorado, Aurora, CO

DISCLOSURE SLIDE Travel and accommodations expenses supported by Loxo Oncology I am an investigator on numerous Phase 1 studies of molecularly targeted agents, including other NTRK-targeting compounds

TRK fusions are found across human cancer 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

First and only selective TRK inhibitor Highly potent against TRKA, TRKB, TRKC (5-11 nM IC50) Highly selective: limited inhibition of other kinases and >1,000x selective over non-kinase off targets Highly soluble and bioavailable Moderately protein-bound Two clinical formulations: capsule and liquid Larotrectinib (loxo-101) TRK TRK

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 Study design Data cutoff 10-Nov-2016 50mg QD n=4 100mg QD n=5 RP2D 100mg BID n=34 200mg QD n=5 150mg BID n=7 200mg BID n=4

Baseline characteristics Characteristics Subjects (N= 59) Median age (range), years 59.0 (19 – 82) Sex Male / Female 34 (58%) / 25 (42%) Race White / Black / Other 49 (83%) / 7 (12%) / 3 (5%) Tumor Type* Non-small cell lung 9 (15%) Soft tissue sarcoma 8 (14%) Colon 5 (8%) Salivary gland 5 (8%) Breast 4 (7%) Pancreatic 4 (7%) ECOG Status 0 / 1 / 2 / 3 / Unknown 16 (27%) / 39 (66%) / 1 (2%) / 1 (2%) / 2 (3%) Prior systemic anticancer therapy, n (%) 58 (98%) Median number of regimens (range) 3 (0-24) TRK-fusion positive Mammary analogue secretory carcinoma (ETV6-NTRK3) 3 GIST (ETV6-NTRK3) 2 Soft tissue sarcoma (LMNA-NTRK1) 1 Thyroid (ETV6-NTRK3) 1 NSCLC (TPR-NTRK1) 1 Total 8 *Includes n=3 each of thymic and thyroid. Includes n=2 each of GIST, gastric, hepatocellular, and head/neck. Includes n=1 each of anal, appendix, unknown, cholangiocarcinoma, gallbladder, glioma, melanoma, mesothelioma, small cell lung cancer, and uterine.

Larotrectinib Phase 1 Interim Treatment-Emergent adverse events Regardless of attribution to study drug Dose 100 mg BID (n=34) Total (n=59) Adverse Events (AEs)* Gr 3/4 All Gr Gr 3/4 All Gr n (%) n (%) n (%) n (%) Fatigue 2 (6%) 10 (29%) 4 (7%) 22 (37%) Dizziness 1 (3%) 10 (29%) 1 (2%) 17 (29%) Anemia 3 (9%) 10 (29%) 5 (8%) 15 (25%) Dyspnea 2 (6%) 7 (21%) 3 (5%) 15 (25%) Nausea 0 8 (24%) 0 13 (22%) Cough 0 6 (18%) 0 12 (20%) Constipation 0 5 (15%) 1 (2%) 11 (19%) Arthralgia 0 8 (24%) 1 (2%) 10 (17%) Increased AST 1 (3%) 7 (21%) 4 (7%) 10 (17%) Decreased appetite 1 (3%) 5 (15%) 2 (3%) 10 (17%) Pyrexia 0 7 (21%) 1 (2%) 10 (17%) Vomiting 0 6 (18%) 0 10 (17%) Diarrhea 0 5 (15%) 0 9 (15%) Lymphocyte count decreased 2 (6%) 5 (15%) 2 (3%) 6 (10%) Pneumonia 2 (6%) 3 (9%) 2 (3%) 4 (7%) *Treatment-emergent adverse events (reported by > 15% of total subjects) or any Grade 3-4 events that occurred in at least 2 patients at 100 mg BID.

Summary of best response for patients with trk fusions Data as of 10-Nov-2016 N=7* CR 0 PR 6 SD 1 PD 0 Off-study prior to first response assessment 0 Overall Response Rate 86% (6/7) * Excludes 1 recently enrolled patient, on study for less than 8 weeks as of November 10, 2016. Note: Of the other 51 patients, a total of 7 (14%) continue to receive larotrectinib, ranging from 2 to 22 cycles. A total of 44 (86%) discontinued treatment. 32 patients discontinued within the first 2 cycles, and 12 patients discontinued after more than 2 cycles (range 3-11 cycles). CR = complete response (confirmed) PR = partial response (confirmed) SD = stable disease PD = progressive disease RECIST v1.1

Best Response to larotrectinib and duration of therapy for Patients with TRK Fusions Time to response (PR)* Treatment continuing Stable disease GIST MASC NSCLC Thyroid MASC MASC GIST Soft tissue sarcoma Time on Treatment (months) 0 6 12 18 24 30 36 Data cutoff November 10, 2016. * PR=partial response. Response is based on the investigator’s assessment using RECIST 1.1. 100mg BID 150mg BID 100mg BID 100mg BID 100mg BID 100mg QD 100mg BID NSCLC TPR-NTRK1 MASC ETV6-NTRK3 MASC ETV6-NTRK3 MASC ETV6-NTRK3 GIST ETV6-NTRK3 Soft Tissue Sarcoma LMNA-NTRK1 Thyroid ETV6-NTRK3 -100% -80% -60% -40% -20% 0% 20% 40% 60% 80% 100% Best Change from Baseline (%) Stable disease Confirmed partial response - 30%

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 22 First trk fusion treated with larotrectinib LMNA-NTRK1 fusion soft tissue sarcoma Study baseline Study cycle 3 day 1 Study cycle 13 day 1 Doebele et al. Cancer Discov. 2015 Oct;5(10):1049-57.

Larotrectinib is a purpose-built, oral, selective and potent TRK inhibitor Larotrectinib is well tolerated, with few adverse events likely related to drug Larotrectinib appears broadly active against TRK fusion cancers in this Phase 1 study Confirmed RECIST responses observed in 6 of 7 evaluable patients, with tumor regression in all 7 Encouraging durability signal: All TRK fusion patients remain on study with most past one year Larotrectinib Phase 2 basket trial currently enrolling patients with TRK gene fusions conclusions

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: Active in US, EU, and Asia (South Korea, Singapore, Japan) Patient assistance for trial travel and logistics Navigate trial Larotrectinib Phase 2 Basket Study

Larotrectinib patients and their families and caregivers Co-investigators and study support staffs This trial sponsored and supported by Loxo Oncology Larotrectinib invented by Array BioPharma acknowledgements

EX-99.3

Exhibit 99.3

Loxo Oncology Outlines Plans for Accelerated Path to U.S. FDA Approval for Larotrectinib (LOXO-101) and Provides Comprehensive Pipeline Update

—LarotrectinibApproximately85%EnrolledtoGoal;CompletionofEnrollmentforPrimaryEfficacyAnalysisExpectedEarly2017—

— NDA Submission for Larotrectinib Expected Late 2017 or Early 2018 —

— Company to Host Investor Conference Call and Webcast Today at 8:00 a.m. EST —

STAMFORD, Conn., December 19, 2016 — Loxo Oncology, Inc. (Nasdaq:LOXO), a biopharmaceutical company innovating the development of highly selective medicines for patients with genetically defined cancers, today announced a comprehensive program update for larotrectinib (LOXO-101), a selective inhibitor of tropomyosin receptor kinase (TRK), and its pipeline drug candidates, LOXO-292 and LOXO-195.

“Since initiating our NAVIGATE Phase 2 trial in October 2015, we have been hard at work identifying TRK fusion patients and engaging with regulators to pursue a rapid path to market for larotrectinib,” said Josh Bilenker, M.D., chief executive officer of Loxo Oncology. “Based on current enrollment and written regulatory correspondence, we are able to provide this exciting update for larotrectinib, and begin planning for a potential commercial launch.  We look forward to sharing top-line data for the NDA dataset in concert with worldwide regulatory filings.  We are also excited to bring LOXO-292 and LOXO-195 forward into potential proof-of-concept studies in 2017.”

The larotrectinib, LOXO-292, and LOXO-195 updates are summarized as follows:

Larotrectinib (LOXO-101): TRK Inhibitor

·Loxo Oncology’s larotrectinib program is currently approximately 85% enrolled to goal, and the company plans to complete enrollment for the primary efficacy analysis in early 2017.

·The efficacy and safety database sizes for larotrectinib will be within precedents set by prior targeted therapy drug approvals in oncology.

·The larotrectinib clinical trials will remain open to continue long-term follow-up of enrolled patients and provide a mechanism for continued drug access to newly identified patients through trial enrollment during regulatory interactions.

·The company expects to be in a position to report top-line data for the NDA dataset in the second half of 2017 and expects to submit a New Drug Application (NDA) in late 2017 or early 2018 and a European Marketing Authorisation Application (MAA) in 2018.

·Loxo Oncology intends to submit for approval “for the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments.”

·The Company plans to present clinical data from the SCOUT Phase 1/2 trial in pediatric patients in mid-2017.

·U.S. Food and Drug Administration (FDA) has granted rare pediatric disease designation to larotrectinib for the treatment of infantile fibrosarcoma, a rare pediatric cancer. The designation provides the opportunity for Loxo Oncology to apply for participation in the FDA’s Rare Pediatric Disease Priority Review Voucher Program.

LOXO-292: Highly Selective RET Inhibitor

·Initiate Phase 1 study: Early 2017

·Initial Phase 1 clinical data: Potentially by year end 2017

LOXO-195: Next-Generation TRK Inhibitor for Potential Acquired Resistance

·Initiate Phase 1 study: Mid-2017

·Initial Phase 1 clinical data: Potentially by year end 2017

Conference Call and Webcast Information

Loxo Oncology will host a conference call and live webcast with slides and Q&A on Monday, December 19, 2016 at 8:00 a.m. ET to discuss the larotrectinib ESMO Asia data and provide a comprehensive program and pipeline update. The company anticipates that the conference call and webcast will last 60-90 minutes. To participate in the conference call, please dial (877) 930-8065 (domestic) or (253) 336-8041 (international) and refer to conference ID 16640119. 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 Larotrectinib (LOXO-101)

Larotrectinib (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, larotrectinib has demonstrated encouraging preliminary efficacy. Larotrectinib is also being evaluated in the NAVIGATE global Phase 2 multi-center basket trial in patients with solid tumors that harbor TRK gene fusions, and the SCOUT Phase 1/2 trial in pediatric patients, including patients with advanced cancer, TRK gene fusions and infantile fibrosarcoma. Larotrectinib has been granted Breakthrough Therapy Designation and Rare Pediatric Disease Designation by the U.S. FDA. For additional information about the larotrectinib 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 or visit www.loxooncologytrials.com.

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 or regulatory approvals, the potential therapeutic benefits and economic value of our lead product candidate or other product candidates, and timing of future filings. Further information on potential risk factors that could affect our business and its financial results are detailed in our most recent Quarterly Report on Form 10-Q, 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

EX-99.4

Exhibit 99.4

Corporate Update December 19, 2016 1

Forward Looking Statements This presentation and the accompanying oral presentation contain “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. Examples of forward-looking statements include, among others, statements we make regarding our future financial performance, business plans and objectives, timing and success of our clinical trials, our ability to obtain regulatory approval or the timing of regulatory filings, the potential therapeutic benefits and economic value of our lead product candidate and second generation product candidate, potential growth opportunities, financing plans, competitive position, industry environment and potential market opportunities. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results and financial condition may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results and financial condition to differ materially from those indicated in the forward-looking statements include, among others, the following: those related to our future financial performance, our ability to develop and maintain partnerships, our ability to identify and develop new products in a timely manner, the outcome, cost and timing of our product development activities and clinical trials, market size and acceptance of our targeted small molecule therapeutics and diagnostics, our ability to maintain, protect and enhance our brand and intellectual property, our ability to continue to stay in compliance with applicable laws and regulations, our ability to scale our business and make key hires and such other factors as discussed under the section titled “Risk Factors” and elsewhere in a registration statement (including a prospectus) that we filed with the Securities and Exchange Commission (“SEC”) as well as our other filings and the documents incorporated by reference therein, with the SEC. Any forward-looking statement made by us in this presentation and the accompanying oral presentation is based only on information currently available to us and speaks only as of the date on which it is made. 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. Certain information in this slide deck on larotrectinib is derived from the presentation made at the 2016 ESMO Asia Congress by Dr. Bauer, an independent third-party investigator. 2

Agenda for Today’s Call Introduction Review updated larotrectinib (LOXO-101) adult Phase 1 data presented at ESMO Asia Outline larotrectinib development timelines and commercial opportunity LOXO-195 overview and program rationale LOXO-292 overview and program rationale Guidance on corporate milestones 3

Loxo Oncology: Foundational Theses Targeted therapies remain an essential category for new drug development in oncology Address low mutational burden/ IO-refractory, oncogene addicted cancers Leverage clinical and pathology trends towards comprehensive tumor profiling Potency, specificity and well-behaved pharmacology define the best-in-class drugs Should carry through to response rate, duration of response, safety Acquired resistance (when responding tumors progress) may be drugged through second generation profiles and extend durable disease control for patients 4

A Space in Evolution: “Accidental” Kinase Inhibitors Yield to Purpose-Built Drugs 5 Historical Approach Modern Approach CEP-701 / lestaurtinib TRK LOXO-101 / larotrectinib LOXO-292 CEP-32496 / RXDX-105 RXDX-101 / entrectinib Ibrance® / palbociclib Jakafi® / ruxolitinib Iclusig® / ponatinib

Loxo Oncology: History of Focused Execution 6 2013 Company founded 2014 LOXO-101 IND filed Initial public offering 2015 First TRK fusion patient enrolled First data reported in patients with TRK fusion cancers Initiated NAVIGATE Phase 2 study Initiated SCOUT pediatric Phase 1/2 study 2016 LOXO-101 breakthrough therapy designation AACR/ ESMO Asia Phase 1 durability updates TRK fusion enrollment ahead of plan 2017 Potentially submit LOXO-101 NDA LOXO-195 IND LOXO-292 IND

larotrectinib 7

Larotrectinib: Ongoing Clinical Trials Adult Phase 1 Data disclosed at EORTC 2015, AACR 2016, and ESMO Asia 2016 N=7 TRK fusion patients evaluable as of ESMO Asia 2016 presentation Enrollment ongoing Pediatric Phase 1/2 (SCOUT) First patient enrolled published as a case report in Spring 2016 Enrollment ongoing Adult/adolescent Phase 2 (NAVIGATE) Only enrolling patients with TRK fusion cancers, across tumor types First patient enrolled in October 2015; enrollment ongoing 8

Best Response to Larotrectinib and Duration of Therapy for Patients with TRK Fusions 9 Data shown from Phase 1 trial, as presented at ESMO Asia 2016 by Dr. Todd Bauer Data cutoff November 10, 2016. * PR=partial response. Response is based on the investigator’s assessment using RECIST 1.1. Duration of response continues in all patients at 11-22 months, and counting -100% -80% -60% -40% -20% 0% 20% 40% 60% 80% 100% Best Change from Baseline (%) Stable disease Confirmed partial response - 30% Time to response (PR)* Treatment continuing Stable disease GIST MASC NSCLC Thyroid MASC MASC GIST Soft tissue sarcoma Time on Treatment (months) 0 6 12 18 24 30 36 100mg BID 150mg BID 100mg BID 100mg BID 100mg BID 100mg QD 100mg BID NSCLC TPR - NTRK1 MASC ETV6 - NTRK3 MASC ETV6 - NTRK3 MASC ETV6 - NTRK3 GIST ETV6 - NTRK3 Soft Tissue Sarcoma LMNA - NTRK1 Thyroid ETV6 - NTRK3

Larotrectinib Well-Positioned for Infantile Fibrosarcoma (IFS) IFS presents unique opportunity for LOXO-101 Different commercially-facing product (i.e. liquid) Clinical impact may be very high (i.e. limb salvage) Market opportunity Estimated ~100 cases/year in the US1 Tumor type identified by histology instead of fusion status Currently enrolling in pediatric Phase 1/2 SCOUT trial; clinical data expected mid-2017 Loxo Oncology granted rare pediatric disease designation for larotrectinib in infantile fibrosarcoma 10 1 Loxo Oncology proprietary market research, conducted by Decision Resources. Image from Bhatnagar, J. Neonatal Surg 2012; 1: 5. Larotrectinib liquid formulation

Larotrectinib: Emerging Regulatory Clarity Breakthrough therapy designation (BTD) granted in July 2016 BTD indication: “For the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments” Company has engaged in longitudinal conversations with U.S. and ex-U.S. regulators; today’s update based on written meeting minutes 11

Larotrectinib: Emerging Regulatory Clarity Breakthrough therapy designation (BTD) granted in July 2016 BTD indication: “For the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments” Company has engaged in longitudinal conversations with U.S. and ex-U.S. regulators; today’s update based on written meeting minutes 12 Potential for larotrectinib to be the first cancer drug approved with a genetic, tumor-agnostic indication

Larotrectinib Regulatory Feedback Trial design and endpoints Ongoing Phase 2 NAVIGATE trial will form the basis of an NDA Primary endpoint: RECIST v1.1 overall response rate (ORR) based on independent radiology review Durability and safety will be key components of the risk-benefit determination upon NDA review Size of approval database Efficacy and safety database sizes for larotrectinib will be within precedents set by prior targeted cancer drug approvals 13

Larotrectinib Enrollment Update Currently ~85% enrolled to goal for primary efficacy analysis population of NDA submission Expect full enrollment early 2017 Enrolling worldwide US, EU, S Korea, Singapore, Japan Streamlined site selection Dozens of patients with TRK fusions enrolled across >10 different tumor types Clinical trials will remain open and continue to enroll beyond target goal Patients require long-term follow-up Data will support submissions Mechanism for continued drug access to newly identified patients through trial enrollment during regulatory interactions 14

Standard NDA/MAA Elements Clinical Last patient in Patient follow-up Independent radiology review Clinical study report CMC scale-up and stability testing Dictates the expiration date of the commercial product Long-term toxicology Clinical pharmacology studies Drug-drug interactions Food effect ADME Companion diagnostics development 15 – NDA submission expected in late 2017 or early 2018 – – MAA submission expected in 2018 –

Larotrectinib in Perspective Precedent Oncology Drug Timelines Years from IND to NDA Afatinib 9.0 Alemtuzumab 8.1 Axitinib 9.6 Belinostat 9.2 Bevacizumab 6.2 Bortezomib 4.5 Bosutinib 7.6 Brentuximab vedotin 4.7 Cabozantinib 7.0 Carfilzomib 6.4 Ceritinib 3.3 Cetuximab 9.0 Crizotinib 5.3 Dabrafenib 3.1 Dasatinib 2.8 Denosumab 11.7 Erlotinib 7.1 Ibritumomab 8.0 Ibrutinib 4.9 Imatinib 2.8 Ipilimumab 10.0 Lapatinib 5.9 Lenalidomide 5.0 Nilotinib 2.5 16 Years from IND to NDA Obinutuzumab 4.3 Ofatumumab 4.8 Osimertinib 2.0 Panitumumab 5.2 Pazopanib 6.3 Pertuzumab 10.7 Pomalidomide 9.5 Ponatinib 4.9 Ramucirumab 9.2 Regorafenib 5.9 Ruxolitinib 4.2 Siltuximab 9.8 Sorafenib 5.2 Sunitinib 4.4 Tositumomab 11.1 Trametinib 4.4 Trastuzumab 6.2 Trastuzumab emtansine 6.8 Vandetanib 10.5 Vemurafenib 4.7 Vismodegib 5.0 Vorinostat 5.0 Ziv-aflibercept 10.4 Acquired resistance approvals (avg 4.1 years) Small molecule, single-arm approvals (avg 5.1 years) Table adapted from Jardim et al, Oncotarget, 7:33.

Larotrectinib in Perspective Precedent Oncology Drug Timelines Years from IND to NDA Afatinib 9.0 Alemtuzumab 8.1 Axitinib 9.6 Belinostat 9.2 Bevacizumab 6.2 Bortezomib 4.5 Bosutinib 7.6 Brentuximab vedotin 4.7 Cabozantinib 7.0 Carfilzomib 6.4 Ceritinib 3.3 Cetuximab 9.0 Crizotinib 5.3 Dabrafenib 3.1 Dasatinib 2.8 Denosumab 11.7 Erlotinib 7.1 Ibritumomab 8.0 Ibrutinib 4.9 Imatinib 2.8 Ipilimumab 10.0 Lapatinib 5.9 Lenalidomide 5.0 Nilotinib 2.5 17 Years from IND to NDA Obinutuzumab 4.3 Ofatumumab 4.8 Osimertinib 2.0 Panitumumab 5.2 Pazopanib 6.3 Pertuzumab 10.7 Pomalidomide 9.5 Ponatinib 4.9 Ramucirumab 9.2 Regorafenib 5.9 Ruxolitinib 4.2 Siltuximab 9.8 Sorafenib 5.2 Sunitinib 4.4 Tositumomab 11.1 Trametinib 4.4 Trastuzumab 6.2 Trastuzumab emtansine 6.8 Vandetanib 10.5 Vemurafenib 4.7 Vismodegib 5.0 Vorinostat 5.0 Ziv-aflibercept 10.4 Acquired resistance approvals (avg 4.1 years) Small molecule, single-arm approvals (avg 5.1 years) Table adapted from Jardim et al, Oncotarget, 7:33. Larotrectinib: IND to potential NDA in <4 years, among the most rapid clinical development programs in recent oncology history

Larotrectinib: Commercial Opportunity Loxo Oncology has commissioned proprietary work to better understand the frequency of TRK+ cancers i.e. tumor banks and third party lab relationships Proprietary datasets suggest 1,500-5,000 late-line eligible patients per year in US Similar estimates for EU5 and Japan, proportional to cancer incidence/mortality in those regions Potential to move into earlier lines of therapy over time Widespread adoption of sensitive diagnostic testing is key to patient identification TRK market opportunity compares favorably with other actionable US oncology markets1: Advanced basal cell carcinoma: ~3,000 patients Advanced systemic mastocytosis: 600-1,600 patients2 ALK+ NSCLC: ~5,500 patients Hodgkin’s lymphoma: ~1,000 patients IDH1/2-mutant AML: ~2,000 patients Unresectable/metastatic PDGFR-mutant GIST: <500 patients 18 1 Figures reflect estimated late-line patients per year or estimated deaths per year. 2 New diagnoses.

Crizotinib for ALK: A Diagnostics Case Study August 2011: Initial FDA approval with Abbott FISH diagnostic June 2015: FDA approval of Ventana IHC diagnostic November 2016: Submission of PMA for Thermo Fisher Oncomine Universal Dx Test (NGS) 19 FISH = Fluorescent in situ hybridization IHC = Immunohistochemistry NGS = Next-generation sequencing Enable diverse pathologists around the world to identify patients with as many suitable diagnostic tools as possible

ALK+ NSCLC: A Commercial Case Study 20 Source: Pfizer, Novartis, and Roche financial reports. Xalkori, Zykadia, and Alecensa package inserts. Note: Market potential for larotrectinib may differ from that indicated by historical revenues for ALK+ NSCLC. * Xalkori was also FDA-approved for ROS1+ NSCLC in March 2016. 7.4-11.3 Median duration of response (mo.) ALK+ NSCLC: ~5,500 late-line patients/yr in US vs. TRK+ cancers: 1,500-5,000 late-line patients/yr in US 7.1-7.4 7.5-11.2 $0 $100 $200 $300 $400 $500 $600 $700 2011 2012 2013 2014 2015 2016 YTD, 9m* Worldwide Revenues ($MM) Crizotinib Zykadia Alecensa

LOXO-195 21

Mutations that limit drug binding are the most common form of acquired resistance; often the oncogene-addicted tumor remains addicted to the same oncogene Early lines of evidence offer a molecular understanding of potential mechanisms of resistance to larotrectinib in TRK fusion patients: Preclinical modeling Precedent paralogous targets (e.g. ALK, ROS1) Clinical case reports1,2 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 larotrectinib Rationale for LOXO-195 Solvent front Activation loop 22 Larotrectinib bound to ATP-binding pocket of TrkA: Steric hindrance caused by G595R or G667C

LOXO-195: Development Opportunity Foreshadowed by Other Classes Clinically, addressing acquired resistance allows clinicians and patients to maximize total duration of disease control over multiple lines of therapy ALK+ NSCLC Primary response on crizotinib 30-50% develop various mutations conferring resistance Potential for re-response to 2nd-line ceritinib/alectinib EGFR+ NSCLC Primary response on erlotinib/gefitinib 50-60% develop T790M mutation conferring resistance Potential for re-response to 2nd-line osimertinib TRK+ tumors Primary response on larotrectinib Patients may develop various mutations conferring resistance Potential for re-response to 2nd-line LOXO-195 Downstream signaling nodes (e.g. MEK) may be clinically useful as single agents post-progression 23

LOXO-195: Selectivity 24 LOXO-195 LOXO-101 Entrectinib TRKB TRKB TRKA TRKB TRKA TRKA Blake et al. EORTC-NCI-AACR 2016. Abstract 442. Kinase LOXO-195 % control TRKA 0.5 TRKB 0 EGFR 100 KIT 100 Met 100 PDGFRalpha 100 PDGFRbeta 100 KDR (VEGFR2) 100

LOXO-195: Potency Against Diverse Resistance Mutations 25 Blake et al. EORTC-NCI-AACR 2016. Abstract 442. D TRKA 0.01 0.1 1 10 100 1000 10000 0 25 50 75 100 Drug Concentration (nM) p T R K ( % o f C o n t r o l ) ETV6-NTRK3 0.01 0.1 1 10 100 1000 10000 0 25 50 75 100 Drug Concentration (nM) p E R K ( % o f C o n t r o l ) D TRKA G595R 0.01 0.1 1 10 100 1000 10000 0 25 50 75 100 Drug Concentration (nM) p T R K ( % o f C o n t r o l ) ETV6-NTRK3 G623R 0.01 0.1 1 10 100 1000 10000 0 25 50 75 100 Drug Concentration (nM) p E R K ( % o f C o n t r o l ) D TRKA G667C 0.01 0.1 1 10 100 1000 10000 0 25 50 75 100 Drug Concentration (nM) p T R K ( % o f C o n t r o l ) ETV6-NTRK3 G696A 0.01 0.1 1 10 100 1000 10000 0 25 50 75 100 Drug Concentration (nM) p E R K ( % o f C o n t r o l ) LOXO-195 LOXO-101 Entrectinib LOXO-195 LOXO-101 Entrectinib

LOXO-195: In Vivo Tumor Regressions 26 Blake et al. EORTC-NCI-AACR 2016. Abstract 442. Vehicle 30 mg/kg BID LOXO-195 100 mg/kg BID LOXO-195 300 mg/kg BID LOXO-195 60 mg/kg QD LOXO-101 Vehicle 30 mg/kg BID LOXO-195 100 mg/kg BID LOXO-195 300 mg/kg BID LOXO-195 60 mg/kg QD LOXO-101 0 2 4 6 8 10 12 0 1000 2000 3000 NIH 3T3 D TRKA Day T u m o r V o l u m e ( m e a n ± S E M , m m 3 ) NIH 3T3 D TRKA G595R 0 2 4 6 8 10 12 0 1000 2000 3000 Day T u m o r V o l u m e ( m e a n ± S E M , m m 3 ) 0 2 4 6 8 10 12 0 1000 2000 3000 NIH 3T3 D TRKA G667C Day T u m o r V o l u m e ( m e a n ± S E M , m m 3 ) 0 2 4 6 8 10 12 0 10 20 30 NIH 3T3 D TRKA Day B o d y W e i g h t ( m e a n ± S E M , g ) 0 2 4 6 8 10 12 0 10 20 30 NIH 3T3 D TRKA G595R Day B o d y W e i g h t ( m e a n ± S E M , g ) 0 2 4 6 8 10 12 0 10 20 30 NIH 3T3 D TRKA G667C Day B o d y W e i g h t ( m e a n ± S E M , g )

LOXO-195 LOXO-195 preclinically active against all acquired resistance mutations identified to date LOXO-195 Phase 1 study expected to start by mid-2017 Operational synergy with larotrectinib program Expect single agent activity at biologically relevant doses Assuming availability of appropriate patients, potential for initial clinical data by YE 2017 Loxo Oncology is well-positioned to be the first oncology company ever to simultaneously develop a first-generation inhibitor and a second-generation inhibitor to address acquired resistance 27

LOXO-292 (RET) 28

RET (REarranged during Transfection) Adapted from Mulligan, Nature Reviews Cancer (2014) 14: 173-185; Besset, JBC 2000 275: 39159-39166 Wild-type RET Extracellular mutation C634R Intracellular mutation M918T Oncogenic fusion KIF5B-RET CCDC6-RET ~60% medullary thyroid cancer ~2% NSCLC, 10-20% papillary thyroid cancer 29 ~5,000 late-line eligible patients per year in US

M918T Clinically Validated in MTC EXAM Phase 3 Trial, cabozantinib vs. pbo Source: Schlumberger, ASCO 2015 ITT Population HR 0.15 p<0.0001 HR 0.67 p=0.1875 30

Multikinase Inhibitors Have Clinically Validated RET Fusions in NSCLC 31 Drug Publication N RECIST ORR1 Median PFS Issues Cabozantinib Initial data: ASCO 2015 Follow-up data: Lancet Oncol 2016 16 25 38% (6/16) 28% (7/25) 7m 5.5m Frequent AEs and dose reductions Lenvatinib ESMO 2016 25 16% (4/25) 7.3m Frequent dose reductions and D/Cs Vandetanib Lancet Respir 2016 Annals Oncology 2016 17 18 53% (9/17) 17% (3/18) 4.7m 4.5m Gr3/4 hypertension, diarrhea, rash, QTc prolongation CEP-32496/ RXDX-105 ASCO 2016, EORTC-NCI-AACR 2016 10 30% (3/10) NR Gr3 rash, diarrhea, continued dose-finding 1 Includes all RET fusion patients treated, regardless of prior therapy. Only includes confirmed responses.

Multikinase Liabilities On Display 32 Excerpt from commentary “ ”

hERG IC50 100 10 1 0.1 0.01 Vandetanib 300mg QD RET IC50 RET IC90 KDR IC50 EGFR IC90 EGFR IC50 KDR IC90 100 10 1 0.1 0.01 RET IC50 hERG IC50 MET IC50 RET IC90 KDR IC50 MET IC90 KDR IC90 Cabozantinib 140 mg QD 60 mg QD RET: Incomplete Target Coverage with Multikinase Inhibitors Human exposure (plasma ug/ml) 33 Source: Publicly-availably FDA review documents.

RET: Product Profile Goals Potent against RET fusions and mutations Superior RET inhibition in pharmacodynamic models Tumor regression in in vivo models Activity against predicted acquired resistance mutations, such as V804M and V804L Avoid off-targets such as VEGFR, Aurora kinase, FGFR, EGFR, MET Excellent drug-like properties High GI absorption, low clearance Once daily or BID dosing Low potential for drug-drug interactions 34

LOXO-292: KDR/VEGFR2 Selectivity 35 Vandetanib LOXO-292 1:10 1:100 1:1 RET:KDR 10 10 100 4000 100 40 40 4 1 RET cell IC50 (nM) 400 1000 1000 400 KDR/VEGFR2 cell IC50 (nM) Cabozantinib Vandetanib LOXO-292 Brandhuber et al. EORTC-NCI-AACR 2016. Abstract 441.

LOXO-292: Log-Scale Cell Line Selectivity 36 No RET alteration (n=83) RET alteration (n=4) Insensitive Sensitive Cabozantinib Vandetanib LOXO-292 10 100 1000 Cell Count EC50 (nM) Brandhuber et al. EORTC-NCI-AACR 2016. Abstract 441.

LOXO-292: Anticipating Resistance 37 Brandhuber et al. EORTC-NCI-AACR 2016. Abstract 441. RET Mutation WT V804M V804L A883F M918T S891A KIF5B-RET/RET M918T 0.01 0.1 1 10 100 1000 10000 0 25 50 75 100 Drug Concentration (nM) p R E T ( % o f C o n t r o l ) LOXO-292 KIF5B-RET Cabozantinib KIF5B-RET Vandetanib KIF5B-RET LOXO-292 RET M918T RET V804L/M 0.01 0.1 1 10 100 1000 10000 0 25 50 75 100 Drug Concentration (nM) p R E T ( % o f C o n t r o l ) Vandetanib V804M Cabozantinib V804L LOXO-292 V804L Vandetanib V804L Cabozantinib V804M LOXO-292 V804M

LOXO-292: In Vivo Tumor Regressions 38 Brandhuber et al. EORTC-NCI-AACR 2016. Abstract 441. 0 5 10 15 0 200 400 600 800 1000 NIH 3T3 KIF5B-RET Day T u m o r V o l u m e ( m e a n ± S E M , m m 3 ) 0 5 10 15 0 500 1000 1500 2000 2500 NIH 3T3 KIF5B-RET V804M Day T u m o r V o l u m e ( m e a n ± S E M , m m 3 ) 0 4 7 11 14 18 21 25 28 0 500 1000 PDX CCDC6-RET Day T u m o r V o l u m e ( m e a n ± S E M , m m 3 ) 0 2 6 9 13 16 20 23 26 28 0 500 1000 1500 2000 PDX CCDC6-RET V804M Day T u m o r V o l u m e ( m e a n ± S E M , m m 3 ) 0 5 10 15 20 0 500 1000 LC-2/ad Lung Cancer CCDC6-RET Day T u m o r V o l u m e ( m e a n ± S E M , m m 3 ) 0 5 10 15 20 0 500 1000 TT Medullary Thyroid Cancer RET C634W Day T u m o r V o l u m e ( m e a n ± S E M , m m 3 ) 0 2 6 9 13 16 20 23 26 28 20 21 22 23 24 Body Weight PDX CCDC6-RET V804M Day B o d y W e i g h t ( m e a n ± S E M , g ) 0 25 50 75 100 1000 10000 PK-PD Relationship Drug Plasma Concentration (ng/mL) p R E T i n T u m o r ( P e r c e n t o f C o n t r o l ) 10 mg/kg 30 mg/kg 100 mg/kg 60 mg/kg 0 Veh 10 mg/kg 30 mg/kg 10 mg/kg 30 mg/kg 3000 30000 Cabozantinib KIFB-RET LOXO-292 KIF5B-RET LOXO-292 close analog KIF5B-RET V804M Cabozantinib KIF5B-RET V804M LOXO-292 close analog KIF5B-RET Vehicle 3 mg/kg BID LOXO-292 10 mg/kg BID LOXO-292 30 mg/kg BID LOXO-292 40 mg/kg QD cabozantinib 20 mg/kg QD ponatinib

LOXO-292 Clinical Development LOXO-292 Phase 1 study expected to start in early 2017 Opportunity for patient enrichment in Phase 1 Growing target awareness Detection technology is relatively straightforward Expect single agent activity at biologically relevant doses Potential for initial clinical data by YE 2017 39

summary 40

Milestones and Capitalization 41 PROGRAM UPDATE ESTIMATED TIMEFRAME Larotrectinib (LOXO-101, TRK) Complete enrollment for primary efficacy analysis dataset Early 2017 Present Phase 1/2 pediatric clinical data Mid-2017 Announce top-line data for NDA dataset 2H 2017 Submit NDA with US FDA Late 2017 / Early 2018 LOXO-195 (TRK) Initiate Phase 1 study Mid-2017 Assuming availability of appropriate patients, potential for initial clinical data By Year End 2017 LOXO-292 (RET) Initiate Phase 1 study Early 2017 Potential for initial clinical data By Year End 2017 FINANCIAL* NASDAQ: LOXO Shares Outstanding*: 21.7M basic, 2.3M options ($12.94 weighted avg strike price) Cash, cash equivalents, and investments*: $156.5M (runway into mid-2018) * As of 3Q 2016 10-Q.

Loxo Oncology: History of Focused Execution 42 Cash runway through larotrectinib NDA submission and potential approval 2013 Company founded 2014 LOXO-101 IND filed Initial public offering 2015 First TRK fusion patient enrolled First data reported in patients with TRK fusion cancers Initiated NAVIGATE Phase 2 study Initiated SCOUT pediatric Phase 1/2 study 2016 LOXO-101 breakthrough therapy designation AACR/ ESMO Asia Phase 1 durability updates TRK fusion enrollment ahead of plan 2017 Potentially submit LOXO-101 NDA LOXO-195 IND LOXO-292 IND