Introduction

The family of tropomyosin kinase receptors, TRKA, B and C are encoded by three distinct genes, NTRK1, 2, and 31

After embryogenesis, TRK proteins are primarily restricted to the nervous system, and function during normal neuronal development and maintenance2-4

Fusion events with the kinase domain of NTRK1, 2, and 3 genes with various partners result in NTRK gene fusions, which are oncogenic drivers (Figure 1)1,2

Recurrent chromosomal rearrangements that involve each NTRK gene have been identified and shown to be oncogenic drivers across a wide variety of adult and pediatric cancers1,5,6

NTRK gene fusions have been identified in >20 tumor types;2 they have been implicated in up to 1% of all solid tumors, including non-small-cell lung cancer (NSCLC) and are nearly pathognomonic among certain rare cancers, including mammary analogue secretory carcinoma (MASC) and secretory breast carcinoma1,3,7,8,9

– In NSCLC, NTRK gene fusions have been reported to occur at an approximate frequency of 0.23%1

– Patients with NSCLC harboring NTRK gene fusions had no concurrent oncogenic alterations in KRAS, EGFR, ALK, ROS1, or other known drivers1

– NTRK gene fusions occur in patients with NSCLC regardless of gender, age, and smoking history1

– Fusions identified in patients with NSCLC predominantly involve either NTRK1 or NTRK31

Larotrectinib is the first highly selective oral TRK inhibitor in clinical development (Figure 2)3,10

– Larotrectinib demonstrated tumor-agnostic efficacy in 55 patients with TRK fusion cancers in 17 unique tumor types enrolled across 3 clinical trials3

– Larotrectinib was well tolerated in children and adults in the clinical trials3

– Larotrectinib demonstrated durable antitumor activity in the overall study population with an independent review (IR)-assessed objective response rate (ORR) of 75%, and an ORR of 80% according to investigator assessment, with 71% patients still responding to treatment at one year (Figure 3)3

Figure 1: TRK fusions are rare but recurrent oncogenic drivers

Rapid, robust and durable responses to larotrectinib in patients with TRK fusion non-small cell lung cancerFarago AF,1 Kummar S,2 Ibabekci S,3 Corsi-Travali S,3 Cruickshank S,3 Cox MC,3 Ku NC,3 Drilon A4

1Cancer Center, Massachusetts General Hospital, Boston, MA, USA; 2Stanford Cancer Institute, Stanford, CA, USA; 3Loxo Oncology, Inc., South San Francisco, CA, USA; 4Memorial Sloan Kettering Cancer Center, New York, NY, USA

Figure 2: Larotrectinib is a highly selective pan-TRK inhibitor

Objectives

The primary endpoint of the combined analysis across three clinical studies (NCT02122913, NCT02637687, and NCT02576431) is to determine the ORR of larotrectinib, by an independent review committee (IRC)

Secondary objectives included the determination of the safety of larotrectinib and ORR according to investigator assessment

Here, we report the details and follow-up of 4 patients with TRK fusion NSCLC as of February 19, 2018

ERK

AKT

Promoter 5ʹ partner

5ʹ partner

Tyr Tyr

LBD Kinase domain

TRK kinase domain

5ʹ partner

Tyr Tyr

TRK kinase domain 5ʹ partner

Tyr Tyr

TRK kinase domain

NTRK1/2/3

TKL

STE

CK1

AGC

CAMK

CMGC

TK

TRKA/B/C

Figure 3: Efficacy of larotrectinib in patients with non-small-cell lung cancer

50

40

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20

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–10

–20

–30

–40

–50

–60

–70

–80

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Max

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Lung

Other solid tumors

Data presented in this waterfall plot are investigator-assessedNote: One patient not shown here. Patient experienced clinical progression and no post-baseline tumor measurements were recordedModified from: Drilon et al. N Engl J Med. 2018; 378:731-39

Adverse events regardless of attribution Treatment-related adverse events

Grade 1 Grade 2 Grade 3 Grade 4 Any grade Grade 3 Grade 4Any

gradePercent of patients with event

Increased ALT or AST 31 4 7 0 42 5 0 38Fatigue 20 15 2 0 36 0 0 16Vomiting 24 9 0 0 33 0 0 11Dizziness 25 4 2 0 31 2 0 25Nausea 22 7 2 0 31 2 0 16Anemia 9 9 11 0 29 2 0 9Diarrhea 15 13 2 0 29 0 0 5Constipation 24 4 0 0 27 0 0 16Cough 22 4 0 0 25 0 0 2Increased body weight 11 5 7 0 24 0 0 11Dyspnea 9 9 0 0 18 0 0 2Headache 13 4 0 0 16 0 0 2Pyrexia 11 2 2 2 16 0 0 0Arthralgia 15 0 0 0 15 0 0 2Back pain 5 9 0 0 15 0 0 0Decreased neutrophil count 0 7 7 0 15 2 0 9

AST, aspartate aminotransferase; ALT, alanine aminotransferase; Modified from: Drilon et al. N Engl J Med. 2018; 378:731-39. The adverse events listed here are those that occurred in at least 15% patients, regardless of attribution. The relatedness of the treatment to adverse events was determined by the investigators.

Table 2: Safety profile of larotrectinib in overall study population (n=55) Patient 2: TPR-NTRK1 fusion non-small-cell lung cancer 28-year-old male diagnosed with Stage IV NSCLC, adenocarcinoma with neuroendocrine features, with brain and bone metastases

NTRK fusion gene detected by FoundationOne Prior treatment with cisplatin and etoposide, which was discontinued due to progressive disease (PD), followed by radiotherapy resulting in stable disease

Following initiation of larotrectinib at a starting dose of 100 mg twice-daily, the patient experienced a marked improvement in symptoms of cough and back pain by Study Day 29

Best overall response was partial response, with a duration of response of 8.21 months (Table 1) PD was identified as metastasis to the right femur. Treatment continued with an escalated dose (150 mg BID) for 5.22 months and discontinued after development of more widespread PD (Figure 4)

At disease progression, sequencing of plasma DNA using the Guardant360 platform revealed the presence of a G595R solvent front mutation and a G667S xDFG mutation in NTRK1, likely explaining the disease progression

All adverse events were grade 1 with no serious adverse events reported

Gene fusion MeasurablediseaseBest

responseDOR

(months)Ongoing

treatmentPatient 1 ETV6-NTRK3 No SD* >14.78* Yes

Patient 2 TPR-NTRK1 Yes PR 8.21 No**

Patient 3 IRF2BP2-NTRK1 No CR >20.27 Yes

Patient 4 SQSTM1-NTRK1 Yes PR >12.88 NoData presented are as per IRC of February 19, 2018*PR per investigator assessment**Identified solvent front acquired resistance mutation in the fusion gene at the time of progressionCR, complete response; DOR, duration of response; PR, partial response; SD, stable disease

Table 1: Efficacy of larotrectinib in patients with non-small-cell lung cancer

1. Farago AF et al. JCO Precis Oncol 2018:2;1-12.2. Vaishnavi A et al. Cancer Discov. 2015; 5:25-34.3. Drilon A et al. N Engl J Med. 2018; 22(378):731-39.4. Huang EJ et al. Annu Rev Biochem. 2003; 72:609-42.5. Landman et al. Clin Breast Cancer, 2018;

18(3):e267-e270.

6. Laetsch TW et al. Lancet Oncol. 2018;19(5):705-714.7. Amatu A et al. ESMO Open. 2016; 1:e000023.8. Skalova A et al. Am J Surg Pathol. 2010; 34:599-608.9. Tognon C et al. Cancer Cell. 2002; 2:367-76.

10. Hyman DM et al. J Clin Oncol. 2017; 35(suppl):abstr LBA2501.

AcknowledgmentsWe thank the patients and their families, many of whom traveled long distances to participate in these studies. Under the authors’ conceptual direction, medical writing assistance was provided by Alison Scott, PhD and Tina Tremaine, PhD, of Scion (London, UK), funded by Bayer Healthcare. These studies are funded by Loxo Oncology, Inc.

Baseline Cycle 3, Day 1 Cycle 7, Day 1

Figure 4: Durable response in TPR-NTRK1 fusion non-small-cell lung cancer

Patient 3: IRF2BP2-NTRK1 fusion non-small cell lung cancer 31-year-old female diagnosed with Stage IV NSCLC adenocarcinoma, with metastases to the left side of the neck, axillae, and the right internal mammary node

NTRK fusion gene detected by FoundationOne History of Hodgkin lymphoma treated with ABVD chemotherapy and subsequent radiation to the abdomen and supraclavicular fossa

At baseline, the patient presented with peripheral neuropathy, neck pain, and mucositis with no response to all prior systemic treatments including cisplatin, pemetrexed, and docetaxel

In response to larotrectinib 100 mg BID, a complete response was confirmed at Study Day 56, with complete resolution of all baseline symptoms (Figure 5)

The duration of response by RECIST was >20.27 months, and the patient remains on treatment (Table 1) Adverse events were primarily grade 1, with no serious adverse events reported

Patient 1: ETV6-NTRK3 fusion in adenocarcinoma of the lung 76-year-old male diagnosed with Stage IV lung adenocarcinoma, with metastases to the liver and bone NTRK fusion gene detected by FoundationOne Prior treatment included a pneumonectomy in combination with radiotherapy and unspecified chemotherapy. After localized and systemic relapse, he received systemic treatment with carboplatin, pemetrexed, gemcitabine, and nivolumab, with best response of SD

Baseline symptoms were cough, dyspnea, and fatigue The starting dose of larotrectinib was 100 mg twice daily, by cycle 2 there was notable improvement in anorexia and the ECOG PS improved from ECOG 2 to ECOG 1

A partial response was assessed by the investigator with a duration of response (DOR) >14.78 months and the patient remains on treatment (Table 1)

Treatment-emergent adverse events (TEAEs) were all grade 1. There were no grade 2, 3, or 4 TEAEs reported

Conclusions Targeted TRK inhibition with larotrectinib produced rapid symptom resolution, a high RECIST response rate, and durable disease control in patients with NSCLC harboring NTRK gene fusions

Larotrectinib was well tolerated in patients with NSCLC with no progressive central nervous system events observed; this safety profile suggests that long-term treatment is feasible

The results from these cases provide specific support for the tumor-agnostic efficacy observed in the pooled analysis3

Data from these patients, and the overall clinical trial program, provide strong evidence for the inclusion of routine testing for NTRK gene fusions in patients with lung cancer

References

Methods

For the primary analysis, 55 patients (aged 4 months to 76 years) with TRK fusion cancer detected by molecular profiling, were enrolled across 3 clinical trials (NCT02122913, NCT02637687, and NCT02576431)

Eligibility criteria for enrollment of patients into clinical studies required locally advanced or metastatic solid tumor, ECOG score of 0–3, adequate major organ function and no prior TRK-inhibitor therapy

Patients received larotrectinib at 100 mg twice-daily (BID) orally, until disease progression occurred or a lack of clinical benefit

Tumor response was assessed by investigators and by independent radiology review at baseline and every 8 weeks for 1 year, and every 12 weeks thereafter until disease progression, according to RECIST v 1.1. First protocol assessment was required at the end of cycle 2

All response data in this poster are presented based on independent radiology review (unless otherwise noted); the waterfall plot is based on investigator assessment

Safety data were recorded until 28 days after the last dose of larotrectinib and adverse events were graded according to the Common Terminology Criteria for Adverse Events v 4.0

From the 55 patients in the primary analysis set, 4 adult patients with previously treated lung adenocarcinoma with an NTRK gene fusion, detected by molecular profiling from CLIA-certified laboratories, were identified

Results

Durable responses (ranging from 8.21 to >20.27 months) were seen in 3 of 4 patients with NSCLC harboring NTRK gene fusions treated with larotrectinib (Table 1)

In the overall population of 55 patients with TRK fusion cancers, the majority of adverse events (93%) were grade 1 or 2, with few grade 3 or 4 events reported (Table 2). Adverse events leading to dose reduction occurred in only 15% of patients

Larotrectinib was well tolerated in patients with NSCLC, with the occurrence of primarily grade 1 adverse events reported, except for one grade 2 adverse event (decreased neutrophil count) noted across patients

Baseline 2 Months

Figure 5: Durable response in IRF2BP2-NTRK1 fusion non-small-cell lung cancer

Durable response in ETV6-NTRK3 fusion non-small-cell lung cancer

Baseline Cycle 4

Figure 6: Durable response in SQSTM1-NTRK1 fusion non-small-cell lung cancer

Patient 4: SQSTM1-NTRK1 fusion non-small-cell lung cancer 45-year-old female diagnosed with Stage IV NSCLC adenocarcinoma, with metastases in the liver and mediastinum and symptoms of hypertrophic osteoarthropathy (HOA)

NTRK fusion gene detected by Paradigm Cancer Diagnostics She had received previous platinums (cis- and carbo-) and pemetrexed with a confirmed best response to treatment of SD

Baseline symptoms included arthralgia due to HOA, cough causing sleep disturbance, and fatigue The patient experienced a rapid response to larotrectinib 100 mg twice daily, demonstrated by an improvement in HOA symptoms, cough and fatigue by cycle 1 (Study Day 8) and complete absence of cough by cycle 3. A partial response was noted by Study Day 54

The duration of response by investigator assessment was >12.88 months. She subsequently withdrew consent in order to pursue alternative non-traditional therapies

Adverse events were primarily grade 1, with one grade 2 event reported.

DisclosuresA.F.F. received research support from Bayer and Loxo Oncology and provided consulting to Bayer and Loxo Oncology. A.D. has provided consulting to Loxo Oncology. M.C.C., N.C.K., S.C-T., S.C. and S.I. are employees of Loxo Oncology. S.K. has no conflicts of interest to disclose.

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