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Introduction

The family of tropomyosin receptor kinases (TRK), 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 maintenance25

Fusion events between the kinase domain of the NTRK1, 2, and 3 genes and various partners result in NTRK gene fusions (Figure 1)1,2

Activity of larotrectinib, a highly selective inhibitor of tropomyosin receptor kinase, in TRK fusion breast cancersFunda Meric-Bernstam,1 Neerav Shukla,2 Nir Peled,3,4 Yosef Landman,3 Adedayo A. Onitilo,5 Sandra Montez,1 Nora C Ku,6 David M. Hyman,2 Alexander Drilon,2 David S. Hong1

1The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 2Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA; 3Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; 4Soroka Cancer Institute, Ben Gurion University, Beer Sheva, Israel; 5Marshfield Clinic Weston Center, Weston, Wisconsin, USA; 6Loxo Oncology, Inc., South San Francisco, California, USA

San Antonio Breast Cancer Symposium - December 4-8, 2018

Table 2: Patient summary

Patient Subtype Regimen NTRK gene fusion

ER/PR/HER2 status

Best response Protocol

1Invasive ductal

carcinoma (NOS)

Larotrectinib TPM3-NTRK1ER+/PR+/

HER2- PDNAVIGATE

phase 2

2Invasive ductal with secretory

features Larotrectinib ETV6-NTRK3

ER-/PR-/ HER2- PR

Compassionate use

3 Secretory Larotrectinib ETV6-NTRK3ER-/PR-/ HER2- PR

Compassionate use

4Invasive ductal with secretory

features Larotrectinib ETV6-NTRK3

ER+/PR+/HER2+ PR

Compassionate use

5* Secretory Larotrectinib + letrozoleETV6-NTRK3

ER+/PR-/HER2- PR

Compassionate use

*Synchronous TRK fusion-negative ER+ invasive lobular breast cancer NOS, not otherwise specified; PD, progressive disease

References

1. Farago AF et al. JCO Precis Oncol. 2018. doi: 10. 1200/PO.18.00037

2. Vaishnavi A et al. Cancer Discov. 2015;5:25343. Drilon A et al. N Engl J Med. 2018;(378:7317394. Lassen UN et al. Ann Oncol. 2018;29(suppl8)5. Huang EJ et al. Annu Rev Biochem. 2003;72:6096426. Landman Y et al. Clin Breast Cancer. 2018;18(3):

e267e2707. Laetsch TW et al. Lancet Oncol. 2018;19:705714.

doi.org/10.1016/S14702045(18)30119-08. Amatu A et al. ESMO Open. 2016;1:e0000239. Skalova A et al. Am J Surg Pathol. 2010;34:599608

10. Tognon C et al. Cancer Cell. 2002;2:36737611. Li D et al. Modern Pathol. 2012;25:56757512. Hyman DM et al. J Clin Oncol. 2017;35(suppl):

abstr LBA250113. FDA. Larotrectinib Prescribing Information. Available

from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211710s000lbl.pdf. Accessed November 26, 2018

14. Landman Y et al. Clin Breast Cancer. 2018;18: e267e270

15. Shukla et al. JCO Precis Oncol. 2017. doi: 10.1200/PO.17.00034

AcknowledgmentsWe thank the patients and their families, many of whom travelled 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 Pharmaceuticals and Loxo Oncology, Inc.

DisclosuresThese studies were funded by Loxo Oncology, Inc. and Bayer AG.

34-year-old female diagnosed with invasive ductal carcinoma with metastasis to liver, lungs, bone, and brain (Table 2)

TPM3-NTRK1 gene fusion detected by FoundationOne; other findings included AKT1 E17K, ATM R337H, CCND1 amplification, and ZNF703 amplification

The patient had received 11 prior lines of systemic therapy over 4 years. Best response to prior therapy was not reported

Baseline symptoms were right arm lymphedema, bilateral pedal edema, left facial palsy, fatigue, hot flashes, pain, dry mouth, erythematous rash, pruritus, and abdominal pain

The starting dose of larotrectinib was 100 mg BID Radiographic progressive disease was detected by day 29, cycle 1 in both target and non-target lesions in the liver and lung

Treatment-emergent adverse events (TEAEs) were grade 1 nausea, vomiting, blurred vision, hoarseness, and grade 2 dyspnea. There were no grade 3 or 4 TEAEs

Patient 1: TPM3-NTRK1 invasive ductal carcinoma of the breast

Figure 5: PET CT scans at baseline and during treatment 62-year-old female with multifocal invasive ductal carcinoma with secretory features (Table 2) ETV6-NTRK3 gene fusion was detected by FoundationOne Prior treatment involved multiple lines of chemotherapy (including docetaxel + cyclophosphamide; anastrozole; eribulin + filgrastim), mastectomy and radiation therapy over an 18-month period

The patient presented with a left axillary mass (10.5 x 12.8 cm) and left lower lobe metastasis (2.8 x 2.3 cm) (Figure 5)

Starting dose of larotrectinib was 100 mg BID At 4 months of treatment, scant residual left lower lobe mass (Figure 5) and regressed hypodensity in the liver were observed. No new lesions were detected elsewhere

At 6 months, left lower lobe, axilla, and liver lesions were stable or improved and no new lesions were detected

At 11 months, the left lower lobe lesion had resolved completely, and a left axillary mass was detected (3.0 x 1.9 cm)

The patient received treatment for 11 months, which is ongoing TEAEs were mild neuropathy and anemia (hemoglobin >10 g/dL); the patient did not report any fatigue or dyspnea

Baseline 11 months

Conclusions

This case study series provides evidence that larotrectinib is effective in the treatment of breast cancer with secretory features harboring NTRK gene fusions

Larotrectinib therapy was well tolerated and was associated with minimal toxicity Larotrectinib is the first TRK inhibitor approved by the FDA (approval date: November 26, 2018). MAA was submitted to European Medicines Agency in August, 2018

Genomic profiling with assays capable of identifying NTRK gene fusions should be strongly considered in patients with breast cancer, and should be routinely performed for patients with secretory breast cancer features

Patient case studies

Patient 4: ETV6-NTRK3 invasive ductal carcinoma of the breast with secretory features

Baseline Cycle 17, day 27

Figure 6: PET CT scans at baseline and at cycle 17, day 27

Baseline imaging showed a 3.5 cm right axillary mass measurable/target lesion, which decreased to 1.1 cm by cycle 6 (as observed on scan C17/D27). Bone metastasis and left axillary lymph nodes captured as non-measurable/non-target lesions

46-year-old female diagnosed with secretory breast cancer at 6 years of age, which was locally resected. Development of a right axillary mass was identified at 17 years of age, confirmed as recurrent secretory carcinoma; the patient underwent surgery prior to 6 cycles of adjuvant chemotherapy (Table 2)

After 27 years, recurrent secretory carcinoma developed in the right axilla; tumor was (ER+/PR-/ HER2-) and ETV6-NTRK fusion-positive by FISH. A new left breast lesion was identified, histologically consistent with lobular carcinoma (ER+/PR+/HER2-, NTRK fusion-negative) and confirmed metastatic to the bone and left axillary lymph nodes

Prior treatment included 2 months of palbociclib and letrozole, resulting in improved left axillary disease (lobular histology) and worsening of right axillary disease (secretory histology)

Larotrectinib was started at 100 mg BID to treat right axillary secretory carcinoma in combination with letrozole 2.5 mg daily to treat left-sided lobular carcinoma

A PR was reported, with continuation of combination therapy and no notable toxicity At 4 weeks of therapy, the patient experienced grade 1 dizziness and myalgia and grade 1 anemia, which was considered possibly related to treatment

Patient 5: ETV6-NTRK3 secretory breast cancer

Baseline Day 54

Patient 3: ETV6-NTRK3 secretory breast cancer

Modified from Shukla et al.15

Figure 4: Clinical response in chest wall mass. Images of the bulky left chest mass at baseline (before initiation of larotrectinib treatment) and at day 54 of therapy

14-year-old female diagnosed with secretory breast carcinoma (Table 2)15

ETV6-NTRK3 fusion, a clonal TERT promoter mutation, and subclonal biallelic inactivation of CDKN2 were detected by MSK-IMPACT

Prior treatment (starting at 8 years of age) included multiple lines of chemotherapy (including fluorouracil + doxorubicin + cyclophosphamide; carboplatin + docetaxel; vinorelbine + gemcitabine; ifosfamide + doxorubicin + dacarbazine + mesna; and carboplatin + paclitaxel) and surgeries

Baseline symptoms were significant pain at the chest wall and a 10.4 x 8.5 cm fungating chest mass with numerous satellite lesions throughout the chest wall (Figure 4)

Starting dose of larotrectinib was 100 mg BID. Larotrectinib treatment produced a marked improvement in tumor-related pain within 3 days of treatment, and significant reduction in tumor size was achieved within 1 week of treatment, with near-complete resolution after 2 months (Figure 4). Computed tomography imaging revealed near-complete resolution of pulmonary metastases15

After 9 months of larotrectinib treatment, progressive disease was noted. Repeat molecular analysis revealed a NTRK3 G623R (solvent front) mutation. The patient is currently being treated with LOXO-195 under a compassionate use protocol

TEAEs were grade 1 and grade 2 dizziness; there were no grade 3 or 4 TEAEs

Patient 2: ETV6-NTRK3 invasive ductal carcinoma of the breast with secretory features

37-year-old female diagnosed with ductal breast carcinoma with prominent secretory features (Table 2)14

ETV6-NTRK3 fusion was detected by FoundationOne Prior treatment involved mastectomy and palliative radiation, but the patient declined chemotherapy on several occasions despite evidence of metastases

At baseline, the patient had ECOG PS 3, extensive involvement of the lungs and pleura with bilateral pleural effusions and severe dyspnea requiring supplemental O2, and peritoneal infiltration with ascites. Scattered bone metastases were identified. CA-125 was 2521 U/mL (normal 80% reduction in tumor size (Figure 3; 6-week scan; RECIST v1.1 criteria) with resolution of bilateral pleural effusion

At 8 weeks of treatment, clinical improvement continued, with normalization of CA-125 marker levels to 19 U/mL. The dose was reduced to 75 mg BID due to grade 1 dizziness. There were no grade 3 or 4 TEAEs. The response to treatment continued for 6 months

Disease progression occurred at 6.11 months. Repeat sequencing identified a G623R solvent front mutation in NTRK3

5040302010

0102030405060708090

100

Max

imum

cha

nge

in tu

mor

siz

e (%

)

BreastInfantile fibrosarcomaSoft tissue sarcomaThyroid

Salivary glandMelanomaAppendixLung

Gastrointestinal stromal tumorColonPancreasCholangiocarcinoma

Congenital mesoblastic nephromaUnknown primaryBone sarcoma

93.2

*

# #

ORR(95% CI)Best response

PRCR

Integrated (n=109)81%

(7288%)

63%17%

Includes nine unconfirmed PRs pending confirmation; does not include 13 patients continuing on study and awaiting initial response assessment; *Patient had TRKC solvent front resistance mutation (G623R) at baseline due to prior therapy; #Surgical CR; RECIST v.1.1 Note: Two patients not shown here. These patients discontinued treatment prior to any post-baseline tumor measurements. CR, complete response; ORR, objective response rate; PR, partial response Data cut-off July 30, 2018; per investigator assessment

Figure 2: Efficacy of larotrectinib in expanded dataset (n=109)4

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 cancers1,6,7

NTRK gene fusions have been identified in >20 tumor types.2 They have been implicated in ~1% of all solid tumors and are nearly pathognomonic among certain rare cancers, including infantile fibrosarcoma, mammary analogue secretory carcinoma, and secretory breast carcinoma1,3,810

Secretory breast carcinoma is a rare form of breast cancer (

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