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Activity of Larotrectinib, a Highly Selective Inhibitor of Tropomyosin

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Activity of Larotrectinib, a Highly Selective Inhibitor of Tropomyosin Activity of larotrectinib, a highly selective inhibitor of tropomyosin receptor kinase, in TRK fusion breast cancers Funda 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;6 Loxo Oncology, Inc., South San Francisco, California, USA San Antonio Breast Cancer Symposium® - December 4-8, 2018 Introduction Table 1: Adverse events with larotrectinib seen in ≥15% of patients Patient case studies Patient 3: ETV6-NTRK3 secretory breast cancer Patient 5: ETV6-NTRK3 secretory breast cancer (n=207)4 ■■ The family of tropomyosin receptor kinases (TRK), TRKA, B, and C are encoded by three distinct genes, NTRK1, 2, and 31 Treatment-emergent AEs (%) Treatment-related AEs (%) Patient 1: TPM3-NTRK1 invasive ductal carcinoma of the breast Baseline Day 54 Baseline Cycle 17, day 27 ■■ After embryogenesis, TRK proteins are primarily restricted to the nervous system and function during Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 3 Grade 4 Total normal neuronal development and maintenance2–5 ■■ 34-year-old female diagnosed with invasive ductal carcinoma with metastasis to liver, lungs, bone, Fatigue 18 15 3 – 36 <1 – 18 ■■ and brain (Table 2) Fusion events between the kinase domain of the NTRK1, 2, and 3 genes and various partners result in Dizziness 1,2 25 3 1 – 29 <1 – 21 NTRK gene fusions (Figure 1) ■■ TPM3-NTRK1 gene fusion detected by FoundationOne; other findings included AKT1 E17K, ATM Nausea 24 3 1 – 29 1 – 15 R337H, CCND1 amplification, and ZNF703 amplification Constipation Figure 1: TRK fusions are rare but recurrent oncogenic drivers4 22 5 <1 – 27 – – 12 ■■ The patient had received 11 prior lines of systemic therapy over 4 years. Best response to prior Anemia 10 7 10 – 27 2 – 11 therapy was not reported NTRK1/2/3 ALT increased 17 5 3 <1 26 2 <1 21 ■■ Baseline symptoms were right arm lymphedema, bilateral pedal edema, left facial palsy, fatigue, romoter 5 ʹ partner LBD Kinase domain AST increased hot flashes, pain, dry mouth, erythematous rash, pruritus, and abdominal pain 18 5 3 – 26 1 – 19 Modified from Shukla et al.15 ■■ Cough 23 3 <1 – 26 – – 1 The starting dose of larotrectinib was 100 mg BID ■■ Figure 6: PET CT scans at baseline and at cycle 17, day 27 Diarrhea 16 6 1 – 23 – – 5 Radiographic progressive disease was detected by day 29, cycle 1 in both target and non-target Figure 4: Clinical response in chest wall mass. Images of the bulky left chest mass at Vomiting lesions in the liver and lung baseline (before initiation of larotrectinib treatment) and at day 54 of therapy 5ʹ partner 17 6 <1 – 23 – – 10 Baseline imaging showed a 3.5 cm right axillary mass measurable/target lesion, which decreased TRK kinase domain AAAA ■■ Treatment-emergent adverse events (TEAEs) were grade 1 nausea, vomiting, blurred vision, Pyrexia 12 5 <1 <1 18 – – 1 ■■ 14-year-old female diagnosed with secretory breast carcinoma (Table 2)15 to 1.1 cm by cycle 6 (as observed on scan C17/D27). Bone metastasis and left axillary lymph nodes hoarseness, and grade 2 dyspnea. There were no grade 3 or 4 TEAEs P P ■■ captured as non-measurable/non-target lesions Tyr Tyr Dyspnea ETV6-NTRK3 fusion, a clonal TERT promoter mutation, and subclonal biallelic inactivation of ERK 10 6 2 – 18 – – 1 Headache 13 4 – – 16 – – 4 CDKN2 were detected by MSK-IMPACT ■■ 46-year-old female diagnosed with secretory breast cancer at 6 years of age, which was Amino terminal TRK kinase domain dimerization domain ■■ Myalgia 12 3 1 – 16 <1 – 7 Prior treatment (starting at 8 years of age) included multiple lines of chemotherapy (including locally resected. Development of a right axillary mass was identified at 17 years of age, TRK kinase domain fluorouracil + doxorubicin + cyclophosphamide; carboplatin + docetaxel; vinorelbine + gemcitabine; confirmed as recurrent secretory carcinoma; the patient underwent surgery prior to 6 cycles of Peripheral edema 12 4 – – 15 – – 7 Patient 2: ETV6-NTRK3 invasive ductal carcinoma of the breast with ifosfamide + doxorubicin + dacarbazine + mesna; and carboplatin + paclitaxel) and surgeries adjuvant chemotherapy (Table 2) Tyr Tyr AKT AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase secretory features ■■ Baseline symptoms were significant pain at the chest wall and a 10.4 x 8.5 cm fungating chest ■■ + - P P AEs observed in ≥15% of patients in the safety database (n=207). The relatedness of treatment to After 27 years, recurrent secretory carcinoma developed in the right axilla; tumor was (ER /PR / LBD, ligand binding domain AEs was determined by the investigators. Eleven (9%) of 122 patients with TRK fusion cancer required Baseline 6 weeks mass with numerous satellite lesions throughout the chest wall (Figure 4) HER2-) and ETV6-NTRK fusion-positive by FISH. A new left breast lesion was identified, ■■ + + - ■■ Recurrent chromosomal rearrangements that involve each NTRK gene have been identified and dose reductions; all maintained tumor regression on reduced dose. One (<1%) of 122 patients with TRK Starting dose of larotrectinib was 100 mg BID. Larotrectinib treatment produced a marked histologically consistent with lobular carcinoma (ER /PR /HER2 , NTRK fusion-negative) and fusion cancer discontinued. Data cut-off July 30, 20184 shown to be oncogenic drivers across a wide variety of adult and pediatric cancers1,6,7 improvement in tumor-related pain within 3 days of treatment, and significant reduction in tumor size confirmed metastatic to the bone and left axillary lymph nodes ■■ ■■ NTRK gene fusions have been identified in >20 tumor types.2 They have been implicated in ~1% was achieved within 1 week of treatment, with near-complete resolution after 2 months (Figure 4). Prior treatment included 2 months of palbociclib and letrozole, resulting in improved left axillary Methods 15 of all solid tumors and are nearly pathognomonic among certain rare cancers, including infantile Computed tomography imaging revealed near-complete resolution of pulmonary metastases disease (lobular histology) and worsening of right axillary disease (secretory histology) ■■ fibrosarcoma, mammary analogue secretory carcinoma, and secretory breast carcinoma1,3,8–10 After 9 months of larotrectinib treatment, progressive disease was noted. Repeat molecular ■■ Larotrectinib was started at 100 mg BID to treat right axillary secretory carcinoma in combination ■■ Five patients with previously treated breast cancer with an NTRK gene fusion, detected by ■■ Secretory breast carcinoma is a rare form of breast cancer (<1%) known to occur in children and analysis revealed a NTRK3 G623R (solvent front) mutation. The patient is currently being treated with letrozole 2.5 mg daily to treat left-sided lobular carcinoma molecular profiling from Clinical Laboratory Improvement Amendments-certified laboratories, adults of both sexes, that expresses basal-like markers (CK5/6 and EGFR), is frequently triple negative with LOXO-195 under a compassionate use protocol ■■ A PR was reported, with continuation of combination therapy and no notable toxicity – – – – 11 were identified; three were detected by FoundationOne, one by Memorial Sloan Kettering Cancer ■■ (ER , PR , and HER2 [ERBB2 ]), and usually presents with a balanced t(12;15) translocation creating TEAEs were grade 1 and grade 2 dizziness; there were no grade 3 or 4 TEAEs ■■ At 4 weeks of therapy, the patient experienced grade 1 dizziness and myalgia and grade 1 anemia, 10 Center (MSK-IMPACT), and one by FISH an ETV6-NTRK3 gene fusion, although other fusions involving an NTRK gene have been identified which was considered possibly related to treatment ■■ Eligibility criteria for the NAVIGATE study required patients to have locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–3, adequate Larotrectinib major organ function, and no prior TRK inhibitor therapy ■■ All patients initially received larotrectinib at 100 mg twice-daily (BID) orally on a continuous 28-day ■■ Larotrectinib is the first highly selective oral TRK inhibitor approved by the Food and Drug Administration Patient 4: ETV6-NTRK3 invasive ductal carcinoma of the breast with Conclusions NTRK schedule, as monotherapy, until disease progression or a lack of clinical benefit (FDA) for the treatment of adult and pediatric patients with advanced solid tumors harboring ■■ secretory features gene fusion3,12,13 Tumor response was assessed by investigators or the treating physician using RECIST v1.1 ■■ This case study series provides evidence that larotrectinib is effective in the treatment of breast ■■ Safety data were recorded until 28 days after the last dose of larotrectinib and adverse events (AEs) – Larotrectinib demonstrated robust tumor-agnostic efficacy in an expanded dataset of 109 patients cancer with secretory features harboring NTRK gene fusions with TRK fusion cancers in multiple tumor types enrolled across three clinical trials (Figure 2)4 were graded according to the Common Terminology Criteria for Adverse Events v4.03 Baseline 11 months ■■ Larotrectinib therapy was well tolerated and was associated
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