Individualisierte Therapie des CUP-Syndroms - Fakt oder Fiktion -

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1 Individualisierte Therapie des CUP-Syndroms - Fakt oder Fiktion - Alwin Krämer Klinische Kooperationseinheit Molekulare Hämatologie/Onkologie Medizinische Klinik V, Universität Heidelberg und Deutsches Krebsforschungszentrum

2 Cancer of Unknown Primary 3% 5% of all malignancies Seventh most frequent malignancy Fourth most frequent cause of cancer-related death Primary identified in 10-20% during life time Primary identified in 50-75% at autopsy Median overall survival 9 months Massard C, Loriot Y, Fizazi K: Carcinomas of an unknown primary origin diagnosis and treatment (2011) Nat Rev Clin Oncol 8:

3 CUP Subsets ESMO Classification Patient with a carcinoma of unknown primary (CUP) Favorable prognosis CUP subset Poor prognosis CUP subset Women with isolated axillary lymph node metastases from adenocarcinoma Women with papillary serous carcinoma restricted to the peritoneum Squamous cell carcinoma restricted to cervical / inguinal lymph nodes Adenocarcinoma with lower gastrointestinal profile Poorly differentiated CUP with midline distribution Neuroendocrine CUP Metastatic melanoma of unknown primary Men with osteoblastic metastases and elevated serum prostate-specific antigen CUP restricted to a single metastatic site Specific treatment PS 1 Normal LDH Favorable prognosis: Median survival = 12 months Consider 2-drug chemotherapy PS 2 and / or Elevated LDH Poor prognosis: Median survival = 4 months Chemotherapy or best supportive care 15% - 20% of CUP patients 80% - 85% of CUP patients Fizazi et al., on behalf of the ESMO Guidelines Committee: Cancers of unknown primary site: ESMO clinical guidelines for diagnosis, treatment and follow-up. Ann Oncol. 26: v133-v138, 2015

4 Patients with Disseminated Adeno- or Undifferentiated CUP Have Low Survival Rates Minnie Pearl Cancer Research Network CUP Patients Treated in Phase II Studies using platinum-based combination chemotherapy year survival: 38% 5 year survival: 10% 10 year survival: 8% Survival Median survival: 9.1 months 0.2 N = Greco, F.A., Hainsworth, J.D.: Cancer of unknown primary site, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 9). Philadelphia, P.A., J.B. Lippincott, 2011, pp

5 Patients with Disseminated Adeno- or Undifferentiated CUP Have Low Survival Rates Unchanged survival rates over the last five decades Relative survival Years after diagnosis of CUP Randén, M., et al. (2009) Acta Oncologica 48:

6 Tissue of Origin (TOO) Test Core premise: Different tissue types have distinct mrna profiles Uncertain specimen RNA profile generated >1,500 genes RNA profile compared with known tissue profiles Similarity Scores Colorectal 88.2 Pancreas 4.4 NSCLCC 2.3 Breast 2.1 Gastric 1.2 Kidney 0.6 Hepatocellular 0.3 Ovarian 0.3 Soft Tissue Sarcoma 0.1 NHL 0.1 Thyroid 0.1 Prostate 0.1 Melanoma 0.1 Bladder 0.1 GCT 0.0

7 Gene expression profiling in CUP

8 Disseminated Adeno-/Undifferentiated CUP Gene expression profiling identifies responsive patients with CUP treated with carboplatin, paclitaxel and everolimus Response rate Overall survival Progression-free survival Yoon et al., Ann Oncol 2016

9 Disseminated Adeno-/Undifferentiated CUP Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in CUP patients Hainsworth et al., J Clin Oncol 31: , 2013

10 Disseminated Adeno-/Undifferentiated CUP Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in CUP patients Hainsworth et al., J Clin Oncol 31: , 2013

11 GEFCAPI 04 Phase III Trial (NCT ) Control arm: Empiric chemotherapy (Cisplatin-Gemcitabine) CUP R Tissue Of Origin Test Primary site-directed treatment n = 202 pts (HR = 0,62 for PFS) Pathwork to provide the TOO test Gross-Goupil et al.: Identifying the primary site using gene expression profiling in patients with carcinoma of an unknown primary (CUP): a feasibility study from the GEFCAPI. Onkologie 35: 54-55, 2012

12 Mutational Spectrum of Adeno-CUP High diversity of genomic alterations and a long tail distribution observed across ACUP samples 55% 50% 45% 40% Substitution/Indel Gene amplification Gene homozygous deletion Truncation Gene fusion/rearrangement Samples, % 35% 30% 25% 20% 15% 10% N = 125 Adeno-CUP 5% 0% Ross, J.S., et al. (2015) JAMA Oncol 1:40-9

13 Panel Sequencing of CUP Cases About 30% of CUP Samples Contain Potentially Druggable Genetic Alterations at Evidence Levels 2/3 (n=150) Level 2 alterations 23/150 (15.3%) ERBB2 amplification BRAF-V600E Level 3 alterations 25/150 (16.7%) Varghese et al., Ann Oncol 2017

14 Tumor Mutational Burden in CUP 6116 CUP cases Tumor Mutational Burden - TMB CUP Type Cases Median Age TMB high (%) Average TMB Maximum TMB TMB high 20 Mut/Mb TMB intermediate < 20 and 6 Mut/Mb TMB low < 6 Mut/Mb CUP NOS Adeno CUP Squamou s CUP Malignant Neoplasm NOS Gay et al., ASCO 2017

15 Example Case I Crizotinib Treatment of a CUP Patient with MET Amplification Abdominal mass + brain lesion (resected) Poorly differentiated carcinoma Progress after multiple cycles of carboplatin/docetaxel Durable response +15 months with crizotinib Ross et al., JAMA Oncol 2015 Palma et al., Case Rep Oncol 2014

16 Example Case II 44 year old female patient initial diagnosis of poorly differentiated soft tissue sarcoma progression after surgery and irradiation progression after trabectidin poorly differentiated adeno-cup Pembrolizumab at 24 mo after diagnosis Durable remission +14 mo with pembrolizumab 0 months 2 months 6 months Pembrolizumab Gröschel et al., Mol Case Studies 2016

17 CUP - Molecular Panel Sequencing in Heidelberg Oncomine Comprehensive Panel 143 Genes / Gene fusions In collaboration with the Institute of Pathology Heidelberg In clinical routine since March 2016 (formalin-fixed paraffin-embedded tissue (FFPE)) Fusions Mutations (total coding sequence) FGFR1 MTOR MYD88 RAC1 PTEN APEX1 GNA11 FGFR3 MYCL CTNNB1 IL6 FGFR2 PNP MAP2K2 PDGFRA MPL RHOA EGFR IFITM1 NKX2-1 JAK3 ALK MAGOH BAP1 CDK6 IFITM3 NKX2-8 CCNE1 ROS JAK1 GATA2 MET HRAS MAX PPP2R1A RET NRAS FOXL2 SMO WT1 AKT1 CSNK2A1 RAF1 BCL9 PIK3CA BRAF CD44 KNSTRN BCL2L1 BRAF MCL1 SOX2 EZH2 CCND1 MAP2K1 SRC NTRK1 DDR2 ATP11B RHEB BIRC3 IDH2 ZNF217 TMPRSS2 MDM4 DCUN1D1 FGFR1 BIRC2 IGF1R GNAS HMBS MYCN FGFR3 MYC ATM TSC2 U2AF1 TBP DNMT3A PDGFRA JAK2 CBL CDH1 MAPK1 MYC ALK KIT CD274 KRAS TP53 SMARCB1 LMNA MSH2 KDR PDCD1LG2 ACVRL1 MYO18A CHEK2 AXL-MBIP XPO1 TET2 CDKN2A ERBB3 TIAF1 NF2 CDK4-UBA1 NFE2L2 FBXW7 PAX5 CDK4 NF1 ARAF SLC45A3-ERG SF3B1 TERT GNAQ MDM2 ERBB2 AR PAX8-PPARG IDH1 PIK3R1 PTCH1 PTPN11 STAT3 MED12 ETV6-NTRK3 ERBB4 APC ABL1 HNF1A BRCA1 BTK EML1-ABL1 VHL CSF1R TSC1 FLT3 SPOP MAGI3-AKT3 PPARG NPM1 NOTCH1 BRCA2 RPS6KB1 WIPF2-ERBB2 RAF1 FGFR4 GATA3 RB1 SMAD4 ITGB7 MLH1 ESR1 RET GAS6 STK11

18 MX39795 Study Design Screening Inclusion criteria Histologically confirmed CUP (non-specific subset) No prior lines of therapy ECOG PS measurable lesion N=790 Genomic profiling Tissue* and blood 315 gene panel + MSI + TMB plus select biomarkers (e.g. PD-L1) Induction Carboplatin + paclitaxel or cisplatin + gemcitabine (3 cycles) Responders CR, PR or SD n=472 (60%) Category 1 R 3:1 Investigator choice (following Molecular Tumour Board advice) n=354 n=118 Alectinib (ALK or RET rearrangements) Erlotinib + bevacizumab (EGFR Mut+) Trastuzumab + pertuzumab + continued induction chemo (ERBB2) Vismodegib (PTCH1, SUFU or SMO) Vemurafenib + cobimetinib (BRAF Mut V600 ) Ipatasertib (AKT1 or PI3K) Olaparib (BRCA1, BRCA2 or HRD) Atezolizumab (TMB high or MSI-high) Atezolizumab + continued induction chemo (patients with no other option) Carboplatin + paclitaxel or cisplatin + gemcitabine (3 cycles) Primary endpoint: pooled PFS from 9 molecularly guided regimens vs chemo in responders to induction chemo [PFS1] Non-responders PD or intolerable toxicity n=318 (40%) Category 2 Investigator choice (following Molecular Tumour Board advice) Assigned as per randomised arm Secondary endpoint: OS

19 MX39795 Patient Selection Patient with a carcinoma of unknown primary (CUP) Favorable prognosis CUP subset Poor prognosis CUP subset Women with isolated axillary lymph node metastases from adenocarcinoma Women with papillary serous carcinoma restricted to the peritoneum Squamous cell carcinoma restricted to cervical / inguinal lymph nodes Adenocarcinoma with lower gastrointestinal profile Poorly differentiated CUP with midline distribution Neuroendocrine CUP Metastatic melanoma of unknown primary Men with osteoblastic metastases and elevated serum prostate-specific antigen CUP restricted to a single metastatic site Specific treatment PS 1 Normal LDH Favorable prognosis: Median survival = 12 months Consider 2-drug chemotherapy PS 2 and / or Elevated LDH Poor prognosis: Median survival = 4 months Chemotherapy or best supportive care Adapted from Fizazi, K., et al. (2015) Ann Oncol 26(suppl 5):v133-8

20 Selected Inclusion Criteria Eligible for platinum-based doublet chemotherapy Histologically confirmed metastatic or advanced unresectable CUP 1 ECOG performance status of 0 or 1 No prior lines of therapy Life expectancy 12 weeks Adequate hematologic and end-organ function Inclusion criteria Sufficient tumor tissue sample for: 1) diagnosis of CUP at the study site s local laboratory, and 2) FoundationOne comprehensive genomic profiling at a central reference pathology laboratory At least one lesion that is measurable (RECIST v1.1) ECOG, Eastern Cooperative Oncology Group Fizazi, K., et al. (2015) Ann Oncol 26(suppl 5):v133-8

21 Selected Exclusion Criteria Favorable prognostic subset (e.g., resectable) Central nervous system (CNS) metastases Non-epithelial CUP neoplasms Exclusion criteria Leptomeningeal disease Immunohistochemistry profile that provides a definitive clinical suspicion of a primary cancer with a specific treatment Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated without evidence that disease has been clinically stable for 2 weeks prior to randomization ECOG, Eastern Cooperative Oncology Group Fizazi, K., et al. (2015) Ann Oncol 26(suppl 5):v133-8

22 Country Selection

23 German Sites 13 Sites Augsburg Berlin Dresden Düsseldorf Essen Frankfurt Hamburg Heidelberg Jena Mainz Mannheim München Oldenburg/Hst. Essen Mannheim Heidelberg Oldenburg Augsburg Jena Status as of November 2017

24 Acknowledgement Arbeitsgruppe CUP-Syndrom der Arbeitsgemeinschaft Internistische Onkologie (AIO) in der Deutschen Krebsgesellschaft e. V. Gerdt Hübner Gunnar Folprecht Michael Stahl Klinische Kooperationseinheit Molekulare Hämatologie/Onkologie, DKFZ & Universitätsklinik Heidelberg Harald Löffler Tilmann Bochtler Pathologisches Institut, Universitätsklinik Heidelberg Volker Endris Albrecht Stenzinger Peter Schirmacher Institut für Pathologie, Universität Zürich Holger Moch Institut für Pathologie, Technische Universität München Wilko Weichert

25 Mutational Profiling of 4650 CUP Samples 4650 CUP cases: 3058 ACUP 1592 UCUP 2027 cases (43.6%) with aberration relevant to targeted study treatment 420 (9%) with aberration relevant to >1 study treatment strategy Number of Samples Also Relevant for Other Therapy Therapy Class Samples (n) ALKi EGFRi HER2i SMOi BRAFi AKTi PARPi anti- PD-L1 ALKi EGFRi HER2i SMOi BRAFi AKTi PARPi anti-pd-l

26 MX39795 Study Objective To compare the efficacy and safety of molecularly-guided therapy versus standard platinum-containing chemotherapy in patients with cancer of unknown primary site

27 Summary Disseminated adeno-/undifferentiated CUP comprises 80-85% of CUP cases and is associated with a poor prognosis 15-20% of cases belong to more favorable subgroups Treatment standard for disseminated adeno-/undifferentiated CUP is platinum-based (carboplatin/paclitaxel, cisplatin/gemcitabine) chemotherapy Whether primary identification by gene expression profiling and tissue-oforigin specific treatment improves survival remains unclear Genome sequencing approaches can identify potentially druggable mutations A large clinical trial analyzing the impact of targeted treatments and immunotherapy will start in April 2018