LUNG CANCER EARLY MOLECULAR ASSESSMENT KIM MONKHORST WEEK VAN DE PATHOLOGIE 29 MAART

Transcription

1 LUNG CANCER EARLY MOLECULAR ASSESSMENT KIM MONKHORST WEEK VAN DE PATHOLOGIE 29 MAART

2 Disclosure belangen spreker (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties met bedrijven Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding Aandeelhouder Andere relatie, namelijk Zie hieronder Bedrijfsnamen LEMA: Pfizer, Roche, MSD, Novartis, AstraZenica Pfizer, BMS, Roche, MSD NVT NVT

3 VRAAG 1 EGFR gemuteerd NSCLC lijkt minder baat te hebben van immunotherapie A: juist B: onjuist

4 SPONSORS AND PARTICIPATING CENTERS SPONSORS The LEMA project is supported by PI: Michel van den Heuvel, thoraxoncoloog NKI-AVL PARTICIPATING CENTERS 4

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6 DIAGNOSTIC DELAY AND PERFORMANCE STATUS If the patients performance score is too poor: Some patients are not fit enough for chemotherapy or TKI therapy There is not enough time to wait for immunotherapy response (2-3 weeks) >> standard chemotherapy The patient cannot be included in clinical trials In the NKI-AVL there was a 20-30% dropout / month diagnostic delay 6

7 DAILY PRACTICE PREDICTIVE PROFILING FOR NSCLC When a patient presents with stage IV NSCLC Predictive analysis >> EGFR, ALK, ROS1 and PD-L1 Driver >> TKI PD-L1 positive (>50%) >> immunotherapy Chemotherapy Progression: Referral to center for clinical trials, compassionate use and off label drugs Biopsy material for additional predictive analysis Problems: Average time for block to arrive is 7-9 days The block is empty or does not contain enough material TPS < 50% TPS > 50% Rangachari et al. JTO 2017 A new biopsy takes 1-2 weeks average time

8 DAILY PRACTICE PREDICTIVE PROFILING FOR NSCLC Outpatient clinic Waiting for block Molecular analysis Start therapy 5,5 weeks Not sufficient tissue >> new biopsy Molecular analysis Start therapy 8 weeks

9 PREDICTIVE PROFILING FOR NSCLC So predictive profiling for NSCLC must be done within an acceptable timeframe Also: tissue loss must be minimized

10 INCIDENCE OF NSCLC Most recent IKNL data estimated 9289 new cases of NSCLC in NL in 2016 Stage at diagnosis: Stage I-II: 25% Stage III: 25% Stage IV: 50% Many will eventually develop disseminated disease Stage I-II: 44% Stage III: 75% Stage IV: 100% Adding up to a total of well over 7000 patients eligible for systemic treatment each year in the context of stage IV disease 10

11 HYPOTHESIS MOLECULAR PROFILING 15% - 20% have a targetable oncogenic driver mutation For example in: EGFR, ALK, ROS1, BRAF, HER2, MET, RET, NTRK patients per year could be treated with targeted agents Current efficacy of molecular profiling is suboptimal EGFR: 70% coverage in stage IV, lower % in lower stages ALK: 50% coverage in stage IV, lower % in lower stages HYPOTHESIS Early molecular profiling will improve diagnostic yield and increase the number of patients receiving proper targeted treatment. Goal: 85% overall coverage of molecular profiling. 11

12 STUDY DESIGN STUDY POPULATION All treatment naïve patients with suspected thoracic malignancy, main interest in NSCLC FIRST PART: run-in period of half a year in which molecular profiling is performed as is currently standard of care SECOND PART: comprehensive upfront profiling according to local standards 1300 patients total, expected duration 1,5-2 years TISSUE BASED MOLECULAR ANALYSIS Tumor biopsy at baseline and at progression BLOOD BASED MOLECULAR ANALYSIS Blood sampling and ctdna analysis dependent therapy 12

13 STUDY DESIGN Informed Consent Tumour biopsy Blood sample ( Liquid biopsy ) Diagnostics 1 st Line Treatment not targeted/immuno Follow Up 2 nd Line Treatment not targeted/immuno Follow Up Start of treatment Progression

14 3 month interval Diagnostics 1 st Line Treatment not targeted/immuno Follow Up 2 nd Line Treatment targeted/immuno Follow Up Start of treatment Progression 3 month interval Diagnostics 1 st Line Treatment targeted or immuno Follow Up 2 nd Line Treatment targeted or immuno Follow Up Start of treatment Progression

15 TISSUE LOSS MUST BE MINIMIZED All biopsies in a separate cassette They are superficially cut for first H&E If possible cut all slides at once Only necessary immunohistochemistry (TTF1 / P63)

16 PREDICTIVE PROFILING FOR NSCLC Target KRAS, EGFR, HER2, BRAF, MET amplification, MET exon 14 skipping ALK, ROS1 (NTRK) RET (MET amplification) MET exon 14 skipping PD-L1 Technique NGS, other validated techniques Immunohistochemistry / FISH FISH One Step RT NKI-AVL 22C3 (Agilent) and SP142 (Roche)

17 TISSUE BASED ANALYSIS TUMOR BIOPSIES 17

18 TISSUE BASED ANALYSIS TUMOR BIOPSIES 18

19 BLOOD BASED ANALYSIS LIQUID BIOPSIES 19

20 COST-EFFECTIVENESS Costs old Costs new Incremental Cost-Effectiveness Ratio = (ICER) Effects old Effects new Effects: -survival(life years) -QoL (QALY) Costs include e.g.: -chemotherapy/targeted therapy/immunotherapy, -diagnostic work-up (including molecular profiling) -Treatment of adverse events, follow-up visits -palliative care (calculated over the total trajectory from diagnosis until death, including all switches) Acceptance of «upfront molecular profiling» if: ICER < Maximum willingness to pay ( 80,000/QALY)

21 PRIMARY AND SECONDARY ENDPOINTS PRIMARY ENDPOINT: percentage of patients with EGFR mutation or ALK translocation SECUNDARY ENDPOINTS: Percentage of patients with a predefined actionable genetic alteration How does liquid biopsy perform in different stages of disease Influence of the liquid biopsies on the diagnostic yield Cost effect evaluation To explore the reasons for insufficient tumor material available for molecular profiling To explore the epidemiology of the PD-L1 biomarker expression in all stages of NSCLC To explore the epidemiology of MET exon 14 skipping in all stages of NSCLC

22 TIMELINE ENROLMENT 22 22

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25 DETECTION OF ROS1 GENE REARRANGEMENT IN LUNG ADENOCARCINOMA ROS1 (D4D6) rabbit monoclonal (Cell Signaling Technology, Danvers, MA, USA) Conclusion: IHC is a reliable and rapid screening tool in routine pathologic laboratories for the identification of suitable candidates for ROS1-targeted therapy. ROS1 IHC is highly sensitive, but less specific compared with ALK IHC for detection of the corresponding rearrangement. ROS1 IHC-reactive tumors, especially when the tumor is stained with moderate to strong intensity or a diffuse pattern, are recommended to undergo FISH to confirm the gene rearrangement.

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27 KNOWN PD-L1 DIAGNOSTIC ASSAYS DIFFER IN MANY KEY ASPECTS Lead asset Pembrolizumab KEYTRUDA (anti-pd-1) 1 Nivolumab OPDIVO (anti-pd-1) 2 CLIA, Clinical Laboratory Improvement Amendments; EQA, external quality assessment; IC, immune cell; NSCLC, non-small cell lung cancer; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; SCCHN, squamous cell carcinoma of the head and neck; TC, tumour cell; TM, tumour membrane; UC, urothelial carcinoma Durvalumab (anti-pd-l1) 3 Atezolizumab TECENTRIQ (anti-pd-l1) 5 Diagnostic partner Dako Dako Ventana Ventana PD-L1 antibody clone 22C SP263 SP142 Machines utilised Link 48 Link 48 BenchMark ULTRA BenchMark ULTRA Compartment TM TM TM TC/IC Variables % of cells % of cells % of cells % of cells Cut-off used for patient subgroups Diagnostic type Strong(+): 50% >1% TC PD-L1(high): 25% 4 5% IC Companion diagnostic in NSCLC Complementary diagnostic in NSCLC Companion diagnostic in NSCLC, SCCHN and UC Complementary diagnostic in UC 1 Regulatory status Launched Launched Not yet launched Launched Many labs will develop their own PD-L1 assay with a commercially available clone CLIA/EQA schemes offer the sole oversight of the quality of these tests. These assays are laboratorydeveloped tests 1. (accessed 18Aug2016); 2. (accessed 18Aug 2016); 3 = US (accessed 18Aug2016); 4. Rebellato, MC, et al. J ClinOncol 2015;33(15_Suppl.):8033 (abstr); 5. (accessesd18aug2016)

28 Tumour staining (%) RESULTS FROM BLUEPRINT DEMONSTRATE CONCORDANCE BETWEEN THREE ASSAYS WITH RESPECT TO TC STAINING Three assays (22C3, 28 8, SP263) demonstrate similar analytical performance with respect to percentage of TC positive, and dynamic range SP142 consistently labels fewer TC Data points represent the mean score from three pathologists for each assay on each case. Superimposed lines/points indicate identical TC scores. No clinical diagnostic cut-off applied % Tumor Staining Mean tumour cell score per case, based on three readers Cases 22C SP142 SP263 22C3 (Merck) 28 8 (BMS) SP142 (Roche) SP263 (AZ) AZ, AstraZeneca; BMS, Bristol-Myers Squibb; TC, tumour cell Hirsch FR, et al. Oral presentation at AACR 2016b.

29 Tumour staining (%) THE NSCLC CONCORDANCE STUDY SHOWED CORRELATION BETWEEN THE THREE ASSAYS EXAMINED Case rank The Ventana SP142 assay was not commercially available at the time of the study and was therefore not included. AZ, AstraZeneca; BMS, Bristol-Myers Squibb; NSCLC, non-small cell lung cancer 22C3 (Merck) 28 8 (BMS) SP263 (AZ) Figure created using source data in Figure 2 of Ratcliffe MJ, et al. Poster presentation at AACR 2016 (Abstract LB-094) Marianne Ratcliffe personal communication.

30 PD-L1 IMMUNOHISTOCHEMISTRY All sites are trained for the PD-L1 22C3 and the PD-L1 SP142 antibody UMCG developed a LDT IHC protocol for the 22C3 antibody on the Ventana BenchMark Ultra The 22C3 antibody concentrate will be validated using a TMA Trained pathologists score a digital image of 22C3 stained NSCLC TMA at the start of the study and 9 months and 18 months for quality control

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33 The DRUP trial CPCT: SINCE STUDY LAUNCH IN SEPTEMBER participating sites Currently open for inclusion: 1. NKI 2. Erasmus 3. UMCU 4. Meander MC 5. VUMC 6. Radboud 7. LUMC 8. ETZ 9. Franciscus 10. NWZ

34 The DRUP trial 13 STUDY DRUGS AVAILABLE, 6 MORE EXPECTED SOON DRUP@NKI.NL Available Amgen Panitumumab KRAS-BRAF-NRAS WT AstraZeneca Olaparib BRCA 1/2, ATM Bayer Regorafenib RET, VEGFR1, 2, 3, KIT, PDGFRB, RAF-1, BRAF BMS Nivolumab MSI or high mutational load Roche Erlotinib EGFR Trastuzumab + Pertuzumab Vemurafenib + Cobimetinib Vismodegib HER2 BRAF V600 PTCH1 Novartis Dabrafenib BRAF V600 Nilotinib Trametinib KIT, ABL1, PDGFRA, PDGFRB BRAF V600, NRAS Expected BI Afatinib ERBB4, NRG1 Eisai Lenvatinib FGFR1, FGFR2, FGFR3, FGFR4 MSD Pembrolizumab High mutational load Pfizer Axitinib VEGFR1, 2, 3 Crizotinib Sunitinib ALK, MET exon 14 en MET amplificatie, MST1R, ROS1 CSF1R, FGFR1,2,3, VEGFR1, 2, 3, KIT, PDGFRA, PDGFRB, RET, VHL Conclusion Acknowledgements

35 VRAAG 2 Betreffende de verschillende verkrijgbare PD-L1 antilichamen (22C3, 28.8, SP263 en SP142) A: alle zijn uitwisselbaar als predictieve test voor immunotherapy B: het PD-L1 antilichaam 22C3 is een complementary diagnostic voor NSCLC C: SP263 scoort naast de tumorcellen ook het immuuninfiltraat D: alle bovenstaande antwoorden zijn onjuist

36 ACKNOWLEDGEMENTS LEMA Michel van den Heuvel Robert Schouten (PhD student) Irene Schouten (project manager) Alle LEMA sites AKL AVL Daan van den Broek Daan Vessies MD / CFMPB NKI-AVL Maartje Vogel Annegien Broeks Rianne van der Wiel PA-klinische studies NKI AVL Jan-Nico Ridderbos Steven Vanhoutvin (contract manager klinische trials) UMCG LEMA QA PD-L1 Wim Timens Nils t Hart PD-L1 cursussen Milan van Rheenen (MSD) Leonie de Visser (Roche diagnostics) Valesca Retèl Kosten effectiviteits analyse Iedereen die ik vergeten ben! 36