Activity of larotrectinib, a highly selective inhibitor of ... · ascites. Scattered bone...
1
Introduction ■ ■ The family of tropomyosin receptor kinases (TRK), TRKA, B, and C are encoded by three distinct genes, NTRK1, 2, and 3 1 ■ ■ After embryogenesis, TRK proteins are primarily restricted to the nervous system and function during normal neuronal development and maintenance 2–5 ■ ■ 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 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. Hong 1 1 The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; 2 Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA; 3 Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel; 4 Soroka Cancer Institute, Ben Gurion University, Beer Sheva, Israel; 5 Marshfield Clinic Weston Center, Weston, Wisconsin, USA; 6 Loxo 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 1 Invasive ductal carcinoma (NOS) Larotrectinib TPM3- NTRK1 ER + /PR + / HER2 - PD NAVIGATE phase 2 2 Invasive ductal with secretory features Larotrectinib ETV6- NTRK3 ER - /PR - / HER2 - PR Compassionate use 3 Secretory Larotrectinib ETV6- NTRK3 ER - /PR - / HER2 - PR Compassionate use 4 Invasive ductal with secretory features Larotrectinib ETV6- NTRK3 ER + /PR + / HER2 + PR Compassionate use 5* Secretory Larotrectinib + letrozole ETV6- 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;5:25−34 3. Drilon A et al. N Engl J Med. 2018;(378:731−739 4. Lassen UN et al. Ann Oncol. 2018;29(suppl8) 5. Huang EJ et al. Annu Rev Biochem. 2003;72:609−642 6. Landman Y et al. Clin Breast Cancer. 2018;18(3): e267−e270 7. Laetsch TW et al. Lancet Oncol. 2018;19:705–714. doi.org/10.1016/S1470–2045(18)30119-0 8. Amatu A et al. ESMO Open. 2016;1:e000023 9. Skalova A et al. Am J Surg Pathol. 2010;34:599−608 10. Tognon C et al. Cancer Cell. 2002;2:367−376 11. Li D et al. Modern Pathol. 2012;25:567−575 12. Hyman DM et al. J Clin Oncol. 2017;35(suppl): abstr LBA2501 13. 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: e267−e270 15. Shukla et al. JCO Precis Oncol. 2017. doi: 10.1200/ PO.17.00034 Acknowledgments We 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. Disclosures These 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 metastases 15 ■ ■ 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 O 2 , and peritoneal infiltration with ascites. Scattered bone metastases were identified. CA-125 was 2521 U/mL (normal <35 U/mL) at initiation of therapy ■ ■ Starting dose of larotrectinib was 100 mg BID. Within days of treatment there was a marked improvement in dyspnea and the patient required less O 2 . There was significant and rapid improvement to ECOG PS 1 after 2 weeks ■ ■ At 6 weeks, O 2 was no longer required, and only minor exertional dyspnea was reported. Positron emission tomography scan revealed >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 50 40 30 20 10 0 –10 –20 –30 –40 –50 –60 –70 –80 –90 –100 Maximum change in tumor size (%) Breast Infantile fibrosarcoma Soft tissue sarcoma Thyroid Salivary gland Melanoma Appendix Lung Gastrointestinal stromal tumor Colon Pancreas Cholangiocarcinoma Congenital mesoblastic nephroma Unknown primary Bone sarcoma 93.2 * ## ORR (95% CI) † Best response † PR CR Integrated ‡ (n=109) 81% (72–88%) 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 cancers 1,6,7 ■ ■ 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 carcinoma 1,3,8–10 ■ ■ Secretory breast carcinoma is a rare form of breast cancer (<1%) known to occur in children and adults of both sexes, that expresses basal-like markers (CK5/6 and EGFR), is frequently triple negative (ER – , PR – , and HER2 – [ERBB2 – ]), 11 and usually presents with a balanced t(12;15) translocation creating an ETV6-NTRK3 gene fusion, although other fusions involving an NTRK gene have been identified 10 Larotrectinib ■ ■ Larotrectinib is the first highly selective oral TRK inhibitor approved by the Food and Drug Administration (FDA) for the treatment of adult and pediatric patients with advanced solid tumors harboring NTRK gene fusion 3,12,13 – Larotrectinib demonstrated robust tumor-agnostic efficacy in an expanded dataset of 109 patients with TRK fusion cancers in multiple tumor types enrolled across three clinical trials (Figure 2) 4 – Larotrectinib demonstrated durable antitumor activity with an investigator-assessed objective response rate (ORR) of 81% (Figure 2), and 73% of patients still responding to treatment at 1 year 4 – In the primary dataset, at a median follow-up of 17.5 months, the median duration of response was still not reached 4 – Larotrectinib was well tolerated in children and adults 3 (Table 1) Baseline 6 weeks Modified from Landman et al. 14 Figure 3: PET CT scans at baseline and after 6 weeks PET, positron emission tomography; CT, computed tomography Arrows identify location of tumors in the baseline scan and absence of tumors in the 6 week scan ERK AKT Promoter 5ʹ partner 5ʹ partner LBD Tyr Tyr P P Kinase domain TRK kinase domain AAAA Amino terminal dimerization domain TRK kinase domain TRK kinase domain NTRK1/2/3 Tyr Tyr P P Figure 1: TRK fusions are rare but recurrent oncogenic drivers 4 LBD, ligand binding domain Treatment-emergent AEs (%) Treatment-related AEs (%) Grade 1 Grade 2 Grade 3 Grade 4 Total Grade 3 Grade 4 Total Fatigue 18 15 3 – 36 <1 – 18 Dizziness 25 3 1 – 29 <1 – 21 Nausea 24 3 1 – 29 1 – 15 Constipation 22 5 <1 – 27 – – 12 Anemia 10 7 10 – 27 2 – 11 ALT increased 17 5 3 <1 26 2 <1 21 AST increased 18 5 3 – 26 1 – 19 Cough 23 3 <1 – 26 – – 1 Diarrhea 16 6 1 – 23 – – 5 Vomiting 17 6 <1 – 23 – – 10 Pyrexia 12 5 <1 <1 18 – – 1 Dyspnea 10 6 2 – 18 – – 1 Headache 13 4 – – 16 – – 4 Myalgia 12 3 1 – 16 <1 – 7 Peripheral edema 12 4 – – 15 – – 7 AEs, adverse events; ALT, alanine aminotransferase; AST, aspartate aminotransferase AEs observed in ≥15% of patients in the safety database (n=207). The relatedness of treatment to AEs was determined by the investigators. Eleven (9%) of 122 patients with TRK fusion cancer required dose reductions; all maintained tumor regression on reduced dose. One (<1%) of 122 patients with TRK fusion cancer discontinued. Data cut-off July 30, 2018 4 Table 1: Adverse events with larotrectinib seen in ≥15% of patients (n=207) 4 ■ ■ Here, we report the details and follow-up of five patients with TRK fusion breast cancer who were treated with larotrectinib as of data cut-off, July 2018. One patient was enrolled in the NAVIGATE global phase 2 study, and four patients were treated under single-patient compassionate-use protocols Methods ■ ■ Five patients with previously treated breast cancer with an NTRK gene fusion, detected by molecular profiling from Clinical Laboratory Improvement Amendments-certified laboratories, were identified; three were detected by FoundationOne, one by Memorial Sloan Kettering Cancer Center (MSK-IMPACT), and one by FISH ■ ■ 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 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 schedule, as monotherapy, until disease progression or a lack of clinical benefit ■ ■ Tumor response was assessed by investigators or the treating physician using RECIST v1.1 ■ ■ Safety data were recorded until 28 days after the last dose of larotrectinib and adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events v4.03 Results ■ ■ The five patients all had breast cancer with secretory characteristics, but had diverse ER/PR/HER2 status (Table 2) – Two patients had triple-negative disease – Four patients harbored ETV6-NTRK3 fusions ■ ■ Larotrectinib treatment yielded a response rate of 80% (4/5 partial response [PRs]). All responses occurred within the first 2 cycles of therapy and cancer-related symptoms resolved rapidly ■ ■ No treatment-related grade ≥3 AEs were reported and the safety profile was similar to that reported for the combined analysis (Table 1) 3,4 This presentation is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.
Transcript of Activity of larotrectinib, a highly selective inhibitor of ... · ascites. Scattered bone...
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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