PUBLICATION SNAPSHOT #1

Prof. Andrea Sartore-BianchiNiguarda Cancer Center and University of Milano (La Statale)

Milano, Italy

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Please note:

Views expressed within this presentation are the personal opinions of theauthor. They do not necessarily represent the views of the author’s academicinstitution or the rest of NTRK Connect group.

This content is supported by an Independent Educational Grant from Bayer.

Disclosures:

Prof. Andrea Sartore-Bianchi has received honoraria from the following:Amgen, Bayer, Sanofi and Servier.

DISCLAIMER

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BACKGROUND

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• Tissue-agnostic therapy is a treatment strategy that uses one drug to target various tumour types as long as they include the same genomic alteration

• NTRK (Neurotrophic Tyrosine Receptor Kinase) gene fusions are targetable genetic alterations that drive tumourigenesis

• NTRK gene fusions are found in various adult and paediatric cancers and can occur either at a high frequency in some rare cancers (high-prevalence tumours) or at a low frequency in more common cancer types (low-prevalence tumours)

• Two TRK inhibitors are currently approved for use in clinical practice (Larotrectinibapproved on November 2018 and entrectinib on August 2019 in the US)*

→ Efficacy and safety of both products in patients with TRK fusion-positive solid tumours have been explored in pooled analyses of the corresponding clinical trials

TRK, tropomyosin receptor kinase*: Larotrectinib is also approved in Canada, Brazil, European Union, Hong-Kong, Saudi Arabia and Israel; Entrectinib is also approved in Japan

LAROTRECTINIB IN PATIENTS WITH TRK FUSION-POSITIVE SOLID

TUMOURS: A POOLED ANALYSIS OF THREE PHASE 1/2 CLINICAL TRIALS

Hong DS, et al. Lancet Oncol. 2020;21:531-40

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CLINICAL DEVELOPMENT PROGRAM WITH LAROTRECTINIB

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TRK, tropomyosin receptor kinase1Drilon A, et al. N Engl J Med 2018;378:731-39; 2Hong DS, et al. Lancet Oncol 2020;21:531-40

3Based on clinicaltrials.gov (last visit 24 April 2020)

Adult in Phase 1Advanced solid tumours

NCT02122913

Paediatric in Phase 1/2 Advanced solid tumours

SCOUT: NCT02637687

Adult/adolescent in Phase 2Advanced solid tumours

NAVIGATE: NCT02576431

Data cutoff: 19 February 20192

8 12 35

Total of 55 patients with TRK fusion solid tumour

Data analysed in the publication

Patients:

Patients:

Total of 159 patients with TRK fusion solid tumour

12 50 97

Data cutoff: 17 July 20171 Data used to grant Marketing authorization approval

Active not recruiting3 Recruiting3 Recruiting3

At the time of the first prespecified analysis for larotrectinib (data cutoff 17 July 2017)1:

• The median duration of response and progression-free survival had not been reached

• Furthermore in the primary analysis set, the 55 patients represented 17 unique cancer types leading therefore to a low representation of several common cancer types including lung, melanoma, colon, and breast cancer making interpretation of efficacy challenging in these tumour types

• Finally, long-term safety was unknown

To address these limitations, the paper by Hong et al. reports efficacy and longer-term safety of larotrectinib in a larger pooled population of patients2:

159 patients including the 55 previously reported

OBJECTIVE OF THE PAPER

71Drilon A, et al. N Engl J Med 2018;378:731-39; 2Hong DS, et al. Lancet Oncol 2020;21:531-40

DISEASE CHARACTERISTICS IN TRK FUSION CANCER PATIENTS AT BASELINE (N=159)

8NTRK, neurotrophic tyrosine receptor kinase

Tumour type N (%)

Soft tissue sarcomaInfantile fibrosarcoma Gastrointestinal stromal tumour Other

29 (18%)4 (3%)

36 (23%)

Thyroid 26 (16%)

Salivary gland 21 (13%)

Lung 12 (8%)

Colon 8 (5%)

Melanoma 7 (4%)

Breast 5 (3%)

NTRK gene fusions N (%)

NTRK1 64 (40%)

NTRK2 4 (3%)

NTRK3 88 (55%)

Not confirmed 3 (2%)

Tumour type (Cont’d) N (%)

Bone sarcoma 2 (1%)

Cholangiocarcinoma 2 (1%)

Pancreas 2 (1%)

Appendix 1 (<1%)

Congenital mesoblastic nephroma

1 (<1%)

Hepatocellular 1 (<1%)

Prostate 1 (<1%)

Unknown primary 1 (<1%)

Various solid tumour types are representedAll NTRK gene fusions are represented in this population

121/153 evaluable patients (79%, CI 95%: 72-85)

EFFICACY RESULTS – PROGRESSION-FREE SURVIVAL & WATERFALL PLOT - RESPONSES BY TUMOUR TYPE

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CI, confidence interval; GIST=gastrointestinal stromal tumour. IFS=infantile fibrosarcoma; IQR, ; interquartile range; NE, not estimable*Maximum change in tumour size of 93% tumour growth. †Patients with brain metastases. ‡Patients with a pathological complete response.Source: Hong DS, et al. Lancet Oncol 2020;21:531-40

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Appendix

Cancer of unknown primary Cholangiocarcinoma

Pancreas

Thyroid

GIST

Colon

IFS

BreastBone sarcoma

Melanoma

Other soft tissue sarcoma

Congenital mesoblastic nephroma

Lung

Salivary gland

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Individual patients

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Tumour type

Objective responses with larotrectinib are seen in multiple tumour types and in most of the patients :

With 47 events (30%) in 159 patients, the median progression-free survival was28.3 months (95% CI 22.1–NE) with a median follow-up of 11.1 months (IQR 5.5–22.1)

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EFFICACY RESULTS – PROPORTION OF PATIENTS WITH RESPONSE & DoR BY TUMOUR TYPE

Patients n

Patients with response n (%, 95% CI)

Median DoR, months*Median (95% CI)

Overall 153 121 (79%, 72–85) 35.2 (22.8–NE)

Soft tissue sarcoma- Infantile fibrosarcoma- Gastrointestinal stromal tumour - Other

284

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27 (96%, 82–100)4 (100%, 40–100)29 (81%, 64–92)

NE (NE–NE)26.3 (7.6–26.3)NE (10.1–NE)

Thyroid 24 19 (79%, 58–93) NE (14.8–NE)

Salivary gland 20 18 (90%, 68–99) 35.2 (13.3–NE)

Lung 12 9 (75%, 43–95) NE (NE–NE)

Colon 8 4 (50%, 16–84) 3.7 (3.7–NE)

Melanoma 7 3 (43%, 10–82) NE (3.7–NE)

Breast 4 3 (75%, 19–99) NE (NE–NE)

Bone sarcoma 2 1 (50%, 1–99) 7.7 (NE–NE)

Cholangiocarcinoma 2 1 (50%, 1–99) 7.3 (NE–NE)

Pancreas 2 1 (50%, 1–99) 3.5 (NE–NE)

Appendix 1 0 (NC) -

Congenital mesoblastic nephroma 1 1 (100%, 3–100) NE (NE–NE)

Hepatocellular 1 0 (NC) -

Unknown primary 1 1 (100%, 3–100) NE (NE–NE)

CI, confidence interval; DoR, duration of response; NC, not calculable; NE, not estimable, PFS; progression-free survival*In patients with confirmed responses (n=108). Note: Proportions are based on investigator assessment

SAFETY RESULTS – TREATMENT-RELATED ADVERSE EVENTS

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Data are n (%). n=260. The adverse events listed here are those that occurred at any grade in at least 15% of patients, or at grade 3 or worse in at least 3% of patients, regardless of attribution.

Larotrectinib has a manageable safety profileIncreased alanine aminotransferase, anaemia and decreased neutrophil count are the most common grade 3–4 treatment related adverse events (≥2%)

Adverse events, regardless of attribution Treatment-related adverse events

Grade 1-2 Grade 3 Grade 4 Grade 3 Grade 4

Fatigue 79 (30%) 6 (2%) 0 1 (<1%) 0

Alanine aminotransferase increased 64 (25%) 7 (3%) 2 (<1%) 7 (3%) 1 (<1%)

Cough 71 (27%) 1 (<1%) 0 0 0

Constipation 69 (27%) 1 (<1%) 0 0 0

Anaemia 44 (17%) 25 (10%) 0 6 (2%) 0

Aspartate aminotransferase increased 62 (24%) 6 (2%) 1 (<1%) 2 (<1%) 0

Dizziness 64 (25%) 2 (<1%) 0 1 (<1%) 0

Nausea 62 (24%) 2 (<1%) 0 2 (<1%) 0

Vomiting 62 (24%) 2 (<1%) 0 0 0

Diarrhoea 59 (23%) 3 (1%) 0 0 0

Pyrexia 50 (19%) 2 (<1%) 1 (<1%) 0 0

Dyspnoea 35 (13%) 6 (2%) 0 0 0

Myalgia 38 (15%) 3 (1%) 0 2 (<1%) 0

Peripheral oedema 40 (15%) 1 (<1%) 0 0 0

Headache 38 (15%) 1 (<1%) 0 1 (<1%) 0

Neutrophil count decreased 18 (7%) 12 (5%) 2 (<1%) 4 (2%) 1 (<1%)

Lymphocyte count decreased 22 (8%) 7 (3%) 2 (<1%) 2 (<1%) 0

Hypokalaemia 12 (5%) 8 (3%) 1 (<1%) 0 0

Hypophosphatemia 5 (2%) 9 (3%) 0 0 0

ENTRECTINIB IN PATIENTS WITH ADVANCED OR METASTATIC NTRK

FUSION-POSITIVE SOLID TUMOURS: INTEGRATED ANALYSIS OFTHREE PHASE 1–2 TRIALS

Doebele RC, et al. Lancet Oncol 2020;21:271-82

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CLINICAL DEVELOPMENT PROGRAM WITH ENTRECTINIB IN ADULTS

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TRK, tropomyosin receptor kinaseDoebele RC, et al. Lancet Oncol 2020;21:271-82

ALKA-372-001: Phase 1Solid tumours

EudraCT 2012-000148-88

STARTRK-1: Phase 1/2 Solid tumoursNCT02097810

STARTRK-2: Phase 2Solid tumoursNCT02568267

Total of 54 adults with advanced or metastatic TRK fusion solid tumour

Data cutoff: 31 May 2018

Data analysed in the publication

Active not recruiting Active not recruiting Recruiting

1 2 51Patients:

Evaluation of the efficacy and safety profile of entrectinib in patients harbouring metastatic or locally advanced or unresectable NTRK fusion-positive solid tumours in a pooled analysis from three clinical trials

OBJECTIVE OF THE PAPER

14NTRK, neurotrophic tyrosine receptor kinase

DISEASE CHARACTERISTICS IN TRK FUSION CANCER PATIENTS AT BASELINE(N=54)

15NSCLC, non-small-cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase

Tumour type N (%)

Sarcoma 13 (24%)

NSCLC 10 (19%)

Mammary analogue secretory carcinoma (salivary) 7 (13%)

Breast 6 (11%)

Thyroid 5 (9%)

Colorectal 4 (7%)

Most frequent NTRK gene fusions N (%)

NTRK1: TPM3-NTRK1 4 (7%)

NTRK1: TPR-NTRK1 4 (7%)

NTRK3: ETV6-NTRK3 25 (46%)

Tumour type (Cont’d) N (%)

Neuroendocrine 3 (6%)

Pancreatic 3 (6%)

GynaecologicalOvarianEndometrial

2 (4%)1 (2%)1 (2%)

Cholangiocarcinoma 1 (2%)

Various solid tumour types are representedNTRK1 and NTRK3 gene fusions positive patients are the most frequent gene fusions in this population

EFFICACY RESULTS – WATERFALL PLOT -RESPONSES BY TUMOUR TYPE

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Responses in 48 patients with NTRK fusion-positive solid tumours (six patients without matched pre-therapy or post-therapy scans were excluded). CI, confidence interval; CRC, colorectal cancer; MASC, mammary analogue secretory carcinoma; NSCLC, non-small-cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase*Greatest change from baseline in sum of largest diameter in target lesions (%)Sources: Demetri GD, et al. ESMO 2018 (Abstract #LBA17); Doebele RC, et al. Lancet Oncol 2020;21:271-82

Objective responses with entrectinib are seen in multiple tumour types and in most of the patients: 57%; 95% CI 43.2–70.8

Tumour type CRC NSCLC Sarcomas

Pancreatic Thyroid MASC

Neurondocrine tumours Cholangiocarcinoma

Breast Gynaecological

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EFFICACY RESULTS – RESPONSE AND DURATION OF RESPONSE

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NE, not estimable

Efficacy-evaluable population (n=54)

Proportion of patients achieving a response 31 (57%)

Best overall response

Complete response 4 (7%)

Partial response 27 (50%)

Stable disease 9 (17%)

Progressive disease 4 (7%)

Non-complete response or progressive disease 3 (6%)

Missing or unevaluable 7 (13%)

Median duration of response, months 10·4 (7·1–NE)

Median progression-free survival, months 11·2 (8·0–14·9)

SAFETY RESULTS – TREATMENT-RELATED ADVERSE EVENTS

18NTRK fusion-positive safety-evaluable population (n=68) AE, adverse event; NTRK, neurotrophic tyrosine receptor kinase

Grade 1–2 Grade 3 Grade 4

Dysgeusia 32 (47%) 0 0

Constipation 19 (28%) 0 0

Fatigue 19 (28%) 5 (7%) 0

Diarrhoea 18 (27%) 1 (2%) 0

Oedema peripheral 16 (24%) 1 (2%) 0

Dizziness 16 (24%) 1 (2%) 0

Blood creatinine increased 12 (18%) 1 (2%) 0

Paraesthesia 11 (16%) 0 0

Nausea 10 (15%) 0 0

Vomiting 9 (13%) 0 0

Arthralgia 8 (12%) 0 0

Myalgia 8 (12%) 0 0

Weight increased 8 (12%) 7 (10%) 0

AST increased 7 (10%) 0 1 (2%)

ALT increased 6 (9%) 0 1 (2%)

Muscular weakness 6 (9%) 1 (2%) 0Anaemia 5 (7%) 8 (12%) 0

Asthenia 5 (7%) 0 0

Peripheral sensory neuropathy 4 (6%) 1 (2%) 0

Neutrophil count decreased 4 (6%) 0 0

Rash 4 (6%) 0 0

Grade 1–2 Grade 3 Grade 4

Disturbance in attention 3 (4%) 0 0

Pain of skin 3 (4%) 0 0

Neutropenia 3 (4%) 2 (3%) 0

Localised oedema 2 (3%) 1 (2%) 0

Hyperaesthesia 2 (3%) 0 0

Ataxia 2 (3%) 0 0

Platelet count decreased 2 (3%) 0 0

Hyperuricaemia 2 (3%) 0 2 (3%)

Hypophosphatemia 2 (3%) 2 (3%) 0

Dehydration 2 (3%) 0 0

Diplopia 1 (2%) 1 (2%) 0

Hypotension 1 (2%) 1 (2%) 0

Pyrexia 1 (2%) 0 0

Lymphocyte count decreased 1 (2%) 0 0

Pruritus 1 (2%) 0 0

Hypoxia 1 (2%) 0 0

Fall 1 (2%) 0 0

Osteoarthritis 0 1 (2%) 0

Blood uric acid increased 0 0 1 (2%)Hypermagnesemia 0 1 (2%) 0

Cardiac failure 0 1 (2%) 0

Cardiac failure congestive 0 1 (2%) 0Entrectinib has a manageable safety profileAmong the most common grade 3–4 treatment related AEs (≥2%) in bold in the table: fatigue, weight increase and anaemia are the most frequent ones

TAKE-HOME MESSAGESAND/OR

IMPACT ON CLINICAL PRACTICES

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CONCLUSION:

• Larotrectinib and entrectinib are two tumour agnostic treatment optionsavailable to patients with NTRK fusion-positive solid tumours

• These oncogenic drivers are highly enriched in selected tumour types but also infrequently found in subsets of other cancers, including common tumours

DISCUSSION:

• NTRK gene fusions should therefore be included in comprehensive testing of cancer patients’ genome analyses for expanding treatment options in the context of precision oncology

NEXT DEVELOPMENTS:

• Patients with or without CNS metastasis could benefit from either treatment but further investigations are needed

• Acquired-resistance mechanism to the TRK inhibitor emergence shows the importance of developing next-generation TRK inhibitors

CONCLUSIONS – DISCUSSIONS

20CNS, central nervous system; NTRK, neurotrophic tyrosine receptor kinase; TRK, tropomyosin receptor kinase

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