PUBLICATION SNAPSHOT #1 · PUBLICATION SNAPSHOT #1 Prof. Andrea Sartore-Bianchi Niguarda Cancer...
Transcript of PUBLICATION SNAPSHOT #1 · PUBLICATION SNAPSHOT #1 Prof. Andrea Sartore-Bianchi Niguarda Cancer...
PUBLICATION SNAPSHOT #1
Prof. Andrea Sartore-BianchiNiguarda Cancer Center and University of Milano (La Statale)
Milano, Italy
2
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
3
BACKGROUND
4
• 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
5
CLINICAL DEVELOPMENT PROGRAM WITH LAROTRECTINIB
6
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
9
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
40
30
20
15
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
-100-110
Appendix
Cancer of unknown primary Cholangiocarcinoma
Pancreas
Thyroid
GIST
Colon
IFS
BreastBone sarcoma
Melanoma
Other soft tissue sarcoma
Congenital mesoblastic nephroma
Lung
Salivary gland
50
Individual patients
Max
imu
m c
han
ge in
tu
mo
ur
size
(%
)
*
†
Ŧ
†
†
† † †
† † ††
†
Ŧ Ŧ
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)
10
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
36
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
11
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
12
CLINICAL DEVELOPMENT PROGRAM WITH ENTRECTINIB IN ADULTS
13
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
16
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
5040
30
20
15
0
-10-20-30
-40
-50
-60-70
-80-90
-100Individual patients
Max
imu
m c
han
ge in
tu
mo
ur
size
(%
)*
EFFICACY RESULTS – RESPONSE AND DURATION OF RESPONSE
17
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
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
Follow us on Twitter
@ntrkconnectinfo
Follow the NTRK CONNECTgroup on LinkedIn
Watch us on theVimeo Channel
NTRK CONNECT
REACH NTRK CONNECT VIA TWITTER, LINKEDIN, VIMEO & EMAILOR VISIT THE GROUP’S WEBSITE
http://www.ntrkconnect.info
21
Dr. Antoine Lacombe Pharm D, MBA
+41 79 529 42 79
NTRK CONNECTBodenackerstrasse 174103 Bottmingen SWITZERLAND
Heading to the heart of Independent Medical Education Since 2012
Dr. Froukje Sosef MD
+31 6 2324 3636