new paradigms of precision oncology martin forster...restricted new paradigms of precision oncology...
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New Paradigms of Precision OncologyMartin ForsterAssociate Professor and Consultant in Medical Oncology UCL Cancer Institute / UCLH
PP-VIT-GB-0143 • June 2020 Prescribing information is available at the end of this presentation
This promotional webinar was organized and funded by Bayer
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Disclosures
• I have received an honorarium from Bayer for this webcast• I have no other conflicts of interest
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Branched evolution and tumour heterogeneity
Malignant Transformation: accumulation of mutations
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Large-scale molecular changes
The Philadelphia (Ph) Chromosome: t(9;22) translocation
CML – links to a single molecular abnormality
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* Progression was defined by any of the following events, whichever came first: death, accelerated-phase or blast-crisis CML, loss of response, or an increasing white-cell count. †p
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Comparing the efficacy of imatinib with IFN-ɑ/low-dose cytarabine in newly diagnosed chronic-phase CML
O’Brien et al. NEJM 2003;348(11):994–1004
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Discovering clonal oncogenic driver events
• Fusion proteins• Tumour mutations • Protein Overexpression• Synthetic lethality
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ALK rearrangements in NSCLC
1. Soda et al. Nature 2007;448:561–566; 2. Shaw et al. J Clin Oncol 2009;27:4247–4253;
3. Camidge et al. Clin Cancer Res 2010;16:5581–5590
• EML4 is the most common ALK fusion partner in NSCLC, allowing tumoral expression of the oncogenic fusion protein EML4-ALK1
• ALK rearrangements in NSCLC are more common in:2,3
• tumors with adenocarcinoma histology • tumors without other known oncogenic
drivers (i.e. EGFR and KRAS wild type)
• never or light smokers
Chart1
EGFR M+
EML4-ALK
Others
NSCLC
15
5
80
Sheet1
NSCLC
EGFR M+15
EML4-ALK5
Others80
To resize chart data range, drag lower right corner of range.
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Crizotinib: ‘Selective’ MET / ALK inhibitor
Modified from Tan et al. J Clin Oncol 2010;28:15S abstract 2596
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Crizotinib in EML4-ALK +ve NSCLC
Best % Change from Baseline in Target Lesions
Camidge et al. Lancet Oncol. 2012;13(10):1011–1019
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Non-squamous NSCLC, Targets and Therapy• The greatest unmet need is for a KRAS targeted drug…..
Tsao AS et al. J Thorac Oncol 2016
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Mutations unique to cancer also potentially good targets
• NOT all mutations are driver mutations• Estimated ~5 driver and ~40 passenger mutations in solid
cancers although highly variable
• Some successes……• EGFR mutation in lung cancer• cKIT in GIST• PTCH mutation in BCC• BRAF mutation in melanoma
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KRAS Mutation in Colorectal Cancer
Amado et al, Journal of Clinical Oncology 28(10):1626, 2008
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Chemotherapy + trastuzumab vs chemotherapy: Overall Survival
Slamon D et al. New England Journal of Medicine 344(11):783, 2001
Study comparing trastuzumab, a recombinant monoclonal antibody against HER2 in women with metastatic breast cancer that overexpressed HER2. n=469
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Biomarker challenges
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NTRK1 – first ‘tumour agnostic’ molecular driver
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Larotrectinib▼ is a potent, highly selective NTRK inhibitor
CNS, central nervous system; IC50, half inhibitory concentration; TRK, tyrosine receptor kinase.1. Drilon A et al. N Engl J Med 2018;378:731–739 (supp_app);
2. Laetsch TW and Hawkins DS. Expert Rev Anticancer Ther 2018;19:1–10.
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Larotrectinib integrated analysis
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Larotrectinib integrated analysis: Baseline characteristics (1/2)
Hong DS et al. Lancet Oncol 2020;21(4):531-540.*Clinical Trials NCT02122913, NCT02637687 and NCT02576431 Data cut-off: 19 February 2019
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Larotrectinib integrated analysis: Baseline characteristics (2/2)
1. Hong DS et al. Lancet Oncol 2020;21(4):531-5402. Hyman DM et al. Poster presented at ESMO 2019 445PD
Data cut-off: 19 February 2019*Patients may be counted in more than one row; **Directly demonstrated or inferred (8 of 88 patients) by ETV6 break-apart fluorescence in situ hybridisation in patients with infantile fibrosarcoma; †Molecular profiling test used not certified by CLIA (or other similar accrediting body)
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Larotrectinib integrated analysis: Tumour types
Hong DS et al. Lancet Oncol 2020;21(4):531-540.
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Larotrectinib integrated analysis: Response
Data cut-off: 19 February 2019
Hong DS et al. Lancet Oncol 2020;21(4):531-540.
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Larotrectinib integrated analysis: Maximum change in tumour size
Hong DS et al. Lancet Oncol 2020;21(4):531-540.
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Larotrectinib integrated analysis: Response by tumour type
Hong DS et al. Lancet Oncol 2020;21(4):531-540.*A response included a complete or partial response; **In patients with confirmed responses (n=108).CI, confidence interval; DOR, duration of response; NC, not calculable; NE, non-estimable
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Larotrectinib integrated analysis: Response in patients with and without brain metastases*
*Brain metastases at baseline; **Includes 13 patients with unconfirmed partial responses pending confirmation but does not include six patients continuing on study and awaiting an initial response assessment (one paediatric patient, five adult patients); †Due to clinical deterioration prior to an initial response assessment. Hong DS et al. Lancet Oncol 2020;21(4):531-540.
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Larotrectinib integrated analysis: Duration of response
Hong DS et al. Lancet Oncol 2020;21(4):531-540.Data cut-off: 19 February 2019Tick marks indicate censored patients. Two patients had complete responses pending confirmation following an earlier assessment of
partial response (i.e. classified overall as confirmed responses).*Among patients with a confirmed response; **Median follow up of 12.9 months (IQR 5.7–23.1)
Median DOR: 35.2 months
(95% CI:22.8–NE)**
n=108*
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Larotrectinib integrated analysis: Survival
Data cut-off: 19 February 2019
Hong DS et al. Lancet Oncol 2020;21(4):531-540.*Kaplan–Meier estimates
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Larotrectinib integrated analysis: Adverse events (1/2)
Data cut-off: 19 February 2019The AEs listed here are those that occurred at any grade in at least 15% of patients, or at Grade 3 or 4 in at least 3% of patients, regardless of attribution. AE, adverse event; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event. Hong DS et al. Lancet Oncol 2020;21(4):531-540.
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Larotrectinib integrated analysis: Adverse events (2/2)
Data cut-off: 19 February 2019The AEs listed here are those that occurred at any grade in at least 15% of patients, or at Grade 3 or 4 in at least 3% of patients, regardless of attribution. AE, adverse event; TEAE, treatment-emergent adverse event; TRAE, treatment-related adverse event. Hong DS et al. Lancet Oncol 2020;21(4):531-540.
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Larotrectinib integrated analysis: Adverse event summary
Hong DS et al. Lancet Oncol 2020;21(4):531-540.Data cut-off: 19 February 2019 n=260 (expanded safety profile)
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Larotrectinib integrated analysis: Summary
1. Hong DS et al. Lancet Oncol 2020;21(4):531-540; 2. Hong DS et al. Lancet Oncol 2020. doi: 10.1016/S1470-2045(19)30856-3_Supp_Appendix.Data cut-off: 19 February 2019
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VITRAKVI®▼(Larotrectinib) 20mg/mL oral solutionPrescribing Information(Refer to full Summary of Product Characteristics (SmPC) beforeprescribing)Presentation: One bottle of 100 mL oral solution. Each mL oforal solution contains larotrectinib sulfate equivalent to 20 mg oflarotrectinib. Indication(s): Larotrectinib as monotherapy isindicated for the treatment of adult and paediatric patients withsolid tumours that display a Neurotrophic Tyrosine ReceptorKinase (NTRK) gene fusion, - who have a disease that is locallyadvanced, metastatic or where surgical resection is likely toresult in severe morbidity, and - who have no satisfactorytreatment options. VITRAKVI® has been authorised under aconditional approval scheme. Posology & method ofadministration: The presence of an NTRK gene fusion in atumour specimen should be confirmed by a validated test priorto initiation of treatment with larotrectinib. For oral use. The oralsolution should be administered by mouth using an oral syringeof 1 mL or 5 mL volume or enterally by using a nasogastricfeeding tube. Do not mix with feeding formulas. Do not take withgrapefruit or grapefruit juice. Adults: 100 mg larotrectinib twicedaily, until disease progression or until unacceptable toxicityoccurs. Children & adolescents: Dosing is based on bodysurface area (BSA). The recommended dose in paediatricpatients is 100 mg/m2 larotrectinib twice daily with a maximumof 100 mg per dose until disease progression or untilunacceptable toxicity occurs. Hepatic impairment: The startingdose of larotrectinib should be reduced by 50% in patients withmoderate (Child-Pugh B) to severe (Child-Pugh C) hepaticimpairment. No dose adjustment is recommended for patientswith mild hepatic impairment (Child-Pugh A). Renalimpairment: No dose adjustment is required. Elderly: No doseadjustment is recommended. Co-administration with strongCYP3A4 inhibitors: Reduce larotrectinib dose by 50%, refer toSmPC. Contra-indications: Hypersensitivity to the active
substance or to any of the excipients. Warnings &precautions: Larotrectinib should only be used if there are notreatment options for which clinical benefit has beenestablished, or where such treatment options have beenexhausted (i.e., no satisfactory treatment options). Neurologicreactions including dizziness, gait disturbance and paraesthesiawere reported in patients receiving larotrectinib. Withholding,reducing, or discontinuing larotrectinib dosing should beconsidered, depending on the severity and persistence of thesesymptoms. ALT and AST increase have been observed,therefore liver function, including ALT and AST assessments,should be monitored before the first dose, and monthly for thefirst 3 months of treatment, then periodically during treatment,with more frequent testing in patients who developtransaminase elevations. Withhold or permanently discontinuelarotrectinib based on severity. If withheld, the larotrectinib doseshould be modified when resumed. Avoid co‐administration ofstrong or moderate CYP3A4/P‐gp inducers with larotrectinibdue to a risk of decreased exposure. Women of childbearingpotential must use highly effective contraception while takinglarotrectinib and for at least one month after stopping treatment.Males of reproductive potential with a non-pregnant womanpartner of child bearing potential should be advised to usehighly effective contraception during treatment with larotrectiniband for at least one month after the final dose. VITRAKVI®20 mg/mL oral solution contains excipients with known effects:sucrose, sorbitol, propylene glycol, methyl parahydroxy-benzoate. Essentially sodium free (
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National Genomics Medicine Service: An OverviewProfessor Rachel Butler, MBESW Genomic Laboratory Hub
PP-VIT-GB-0144 • June 2020
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or
search for MHRA Yellow Card in Google Play or Apple App Store. Adverse events should also be reported to Bayer plc.
Tel.: 0118 206 3500, Fax.: 0118 206 3703, Email: [email protected]
This webcast is organised and funded by Bayer plcPrescribing information is available and can be found at the end of this webcast.
http://www.mhra.gov.uk/yellowcardmailto:[email protected]
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DisclosuresSpeaker fees/Honoraria: Pfizer, AstraZeneca, Bayer, Roche, Takeda, Merck, MSK, Boehringer, Illumina and Qiagen
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Where does genetics/genomics help in cancer management?• Earlier diagnosis• Identifying patients/families at risk• Identifying sub-types of cancer • Informing on prognosis• Avoiding dangerous side effects from treatment• Guiding and selecting treatment for the individual• Increasing efficacy and understanding resistance
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Genomics for all: the NHS Genomic Medicine Service1
• The Genomic Medicine Service connects & consolidates infrastructure in the NHS, including the service elements first developed to support the 100,000 Genomes Project
• It brings together existing clinical genetics and cancer services with the new Genomic Laboratory Hubs and ex-GMCs to provide seamless delivery of service across the nation
Genomic MedicineService Alliance
1 Personal Speaker Communication. Adapted from NHS England Genomics Unit.
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Genomic Laboratory Hubs: Cancer service delivery
• Deliver services described in the National Genomic Test Directory (https://www.england.nhs.uk/publication/national-genomic-test-directories/)
• Core, local services delivered within clinically appropriate timescales by all GLHs
• High throughput, high quality, resilient, efficient and cost-effective
• All GLHs will provide the same service specification
• Majority of services delivered by a pan-solid tumour gene panel
• Detects single-nucleotide variants, copy number variants and gene fusions
• Future-proof (>beyond the NGTD)
(Note: The devolved nations are expected to take the same approach)
1 Personal Speaker Communication. Adapted from NHS England Genomics Unit.
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The national genomic test directory - the heart of the NHS GMS1
The National Test Directory defines all the genetic and genomic tests available through the NHS in England – setting out the appropriate test that should be delivered for each clinical indication.
1 Personal Speaker Communication. Adapted from NHS England Genomics Unit.
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Future-enabled to keep pace with technological advance1• The Directory will be updated through a clear and transparent process, with specified
timelines and governance.• The process for evaluating genomic tests has three key aims:
1.To systematically review all available genomic testing by condition to inform thedefinitive repertoire of tests
2.To standardise the testing available by defining the specific genes that need to betested for and by which technology the testing should be delivered
3.To support the ongoing evaluation of new tests and technologies to enable access to themost effective and affordable technologies now and in the future
• A committee of clinical and scientific experts from across the UK has now beenestablished to oversee and implement the evaluation process.
• The Cancer Directory is currently being updated ready for implementationin April 2020.
1 Personal Speaker Communication. Adapted from NHS England Genomics Unit.
COVID-delayed
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e.g. NSCLC Panel Content2
2 Personal Speaker Communication. Gene list developed by GLH Working Group.NSCLC – non-small cell lung cancer
Note: Draft gene lists at time of preparation.
Genes to direct treatment, includes genes expected to be approved
Genes for clinical trials / research
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GLH: Gene panel strategy3
3 Personal Speaker Communication. GTAB – genomic tumour advisory board
Sample receipt, assessment
and preparation (DNA / RNA extraction)
500-gene panel analysisTumour-agnosticDetects SNVs,
CNVs and gene fusions
Bioinformaticanalysis
Analysis by tumour type (for selected
genes)
Clinical reporting
MDT / GTABs
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Gene panel strategy: Tumour agnostic3
3 Personal Speaker Communication. CRC – colorectal cancer, H&N – head & neck
1. Data available for future lines of treatment2. Gene re-analysis can be requested
Sample receipt,
assessment and
preparation
500-gene panel
analysisBioinformatic
analysisClinical
reporting
Tumour types:LungCRCMelanomaNeuroPancreaticProstateOvarianBreastBladderThyroidH&NRenal
Haem ….
Genes selected according to tumour type
Licensed treatment (compassionate use)
NICE approved treatment
Clinical trial
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Benefits: NTRK – multiple childhood and adult cancers4
4 Hong et al. Lancet Oncology Jan 2020; 21:531-540 https://doi.org/10.1016/S1470-2045(19)30856-3
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Benefits: Tumour mutational burden and survival after immunotherapy5
5 Samstein et al. Nat Genetics Feb 2019; 51:202-206 https://doi.org/10.1038/s41588-018-0312-8
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Gene panel strategy: Pathway salvage3
3 Personal Speaker Communication
Salvage pathway Outcome
Insufficient tissue or poor quality DNA
Targeted mutation analysis
Prioritised SoC results* only
NGS failure (poor quality DNA)
Targeted mutation analysis
Prioritised SoC results* only
Urgent request Targeted mutation analysis
Prioritised SoC results* only
*Prioritised SoC tests will be agreed for each tumour type by all GLHs
Sample receipt,
assessment and
preparation
500-gene panel
analysisBioinformatic
analysisClinical
reporting
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Where are we now?• Solid tumour gene panel services were due to be available from 01/04/2020
‒ Now COVID-delayed• Cancer genomic services are being delivered but using existing technologies and
funding routes.• This is generally targeted mutation analysis / small gene panels
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VITRAKVI®▼(Larotrectinib) 20mg/mL oral solutionPrescribing Information(Refer to full Summary of Product Characteristics (SmPC) beforeprescribing)Presentation: One bottle of 100 mL oral solution. Each mL oforal solution contains larotrectinib sulfate equivalent to 20 mg oflarotrectinib. Indication(s): Larotrectinib as monotherapy isindicated for the treatment of adult and paediatric patients withsolid tumours that display a Neurotrophic Tyrosine ReceptorKinase (NTRK) gene fusion, - who have a disease that is locallyadvanced, metastatic or where surgical resection is likely toresult in severe morbidity, and - who have no satisfactorytreatment options. VITRAKVI® has been authorised under aconditional approval scheme. Posology & method ofadministration: The presence of an NTRK gene fusion in atumour specimen should be confirmed by a validated test priorto initiation of treatment with larotrectinib. For oral use. The oralsolution should be administered by mouth using an oral syringeof 1 mL or 5 mL volume or enterally by using a nasogastricfeeding tube. Do not mix with feeding formulas. Do not take withgrapefruit or grapefruit juice. Adults: 100 mg larotrectinib twicedaily, until disease progression or until unacceptable toxicityoccurs. Children & adolescents: Dosing is based on bodysurface area (BSA). The recommended dose in paediatricpatients is 100 mg/m2 larotrectinib twice daily with a maximumof 100 mg per dose until disease progression or untilunacceptable toxicity occurs. Hepatic impairment: The startingdose of larotrectinib should be reduced by 50% in patients withmoderate (Child-Pugh B) to severe (Child-Pugh C) hepaticimpairment. No dose adjustment is recommended for patientswith mild hepatic impairment (Child-Pugh A). Renalimpairment: No dose adjustment is required. Elderly: No doseadjustment is recommended. Co-administration with strongCYP3A4 inhibitors: Reduce larotrectinib dose by 50%, refer toSmPC. Contra-indications: Hypersensitivity to the active
substance or to any of the excipients. Warnings &precautions: Larotrectinib should only be used if there are notreatment options for which clinical benefit has beenestablished, or where such treatment options have beenexhausted (i.e., no satisfactory treatment options). Neurologicreactions including dizziness, gait disturbance and paraesthesiawere reported in patients receiving larotrectinib. Withholding,reducing, or discontinuing larotrectinib dosing should beconsidered, depending on the severity and persistence of thesesymptoms. ALT and AST increase have been observed,therefore liver function, including ALT and AST assessments,should be monitored before the first dose, and monthly for thefirst 3 months of treatment, then periodically during treatment,with more frequent testing in patients who developtransaminase elevations. Withhold or permanently discontinuelarotrectinib based on severity. If withheld, the larotrectinib doseshould be modified when resumed. Avoid co‐administration ofstrong or moderate CYP3A4/P‐gp inducers with larotrectinibdue to a risk of decreased exposure. Women of childbearingpotential must use highly effective contraception while takinglarotrectinib and for at least one month after stopping treatment.Males of reproductive potential with a non-pregnant womanpartner of child bearing potential should be advised to usehighly effective contraception during treatment with larotrectiniband for at least one month after the final dose. VITRAKVI®20 mg/mL oral solution contains excipients with known effects:sucrose, sorbitol, propylene glycol, methyl parahydroxy-benzoate. Essentially sodium free (