CUP: Treatment by molecular profiling

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1 CUP: Treatment by molecular profiling George Pentheroudakis Professor of Oncology Medical School, University of Ioannina Greece Chair, ESMO Guidelines September 2018

2 Enterprise Interest No disclosures.

3 CUP: What is it? Metastases from a primary we simply cannot locate? Tumours with a distinct pro-metastatic biological signature, common for most CUPs? 3

4 Survival: CUP vs KPM Swedish Cancer Registry: 2881 CUP vs 6745 KPM Riihimäki et al. BMC Cancer 2013, 13:36

5 What do we mean by TREATMENT WITH MOLECULAR PROFILING? 1. FIND THE TISSUE OF ORIGIN Molecular assays may identify a primary site of origin but does primary-specific therapy improve outcomes? 2. FIND THE MOLECULAR TARGET Does the screening for, and targeting of molecular aberrations improve outcomes? 5

6 Premise of tissue of origin classifier example of Cancer Genetics platform Similarity Scores a Colorectal 88.2 CUP RNA profile 2,000 genes Compare with known tissue profiles Pancreas 4.4 NSCLC 2.3 Breast 2.1 Gastric 1.2 Kidney 0.6 HCC 0.3 Ovarian 0.3 Premise: Each tumor type has a distinct molecular profile Soft Tissue Sarcoma 0.1 NHL 0.1 Thyroid 0.1 Prostate 0.1 Melanoma 0.1 Adapted from Cancergenetics.com Bladder 0.1 Testicular Germ Cell 0.0 a Similarity Scores of all possible primaries add up to 100

7 Research attention has focused on large panels of markers to identify tissue of origin TOO classifiers: 10-2,000 genes analyzed simultaneously Platform molecule class # genes # of claimed distinguishable cancer types BioTheranostics mrna 92 ~50 Cancer Genetics mrna ~2, Veridex mrna 10 6 Agendia mrna Rosetta microrna EPICUP DNA methylation 485,577 CpG sites a 38 a Examined in development phase (Moran et al 2016) Dolled-Filhart and Rimm 2012 Cancer Cytopatholology

8 Sarah Cannon trial examined TOO classifier-directed therapy (enrolled ) CUP Treatment-naïve 289 enrolled TOO testing a 252 Successful assay (87% [252/289]) 194 Received classifierdirected Rx (67% 194/289]) TOO classifier-directed therapy Non-randomized CRC Ovary Pancreas Prostate Others b FOLFOX(IRI) + bev Carbo/Taxol + bev Gem + erlotinib Androgen ablation Standard 1st-line Rx guidelines Hainsworth et al. JCO 2012 a Biotheranostics (92-gene microarray) b Total of 26 different tissues of origin were predicted

9 Site-specific therapy for CUPs confers improved survival: Prospective studies Hainsworth et al., J Clin Oncol 2013 Varadhachary et al., Clin Cancer Res 2011

10 RCT to address whether TOO classifierdirected therapy can improve outcomes French trial (GEFCAPI04) CUP (N = 223) Treatmentnaïve Not limited to certain TOO profiles R TOO testing a with result unmasked TOO testing a with result masked Classifierdirected therapy c Gemcitabine + cisplatin Primary endpoint: PFS Status: Enrolled ~200 pts (as of 04/2017) Estimated date to report primary outcome: a Biotheranostics CancerTYPE ID. c Classifier-directed therapy is not publicly available Data accessed from clinicaltrials.gov (NCT )

11 Druggable targets in CUP tumors Foundation One Mutation analysis of 236 genes and rearrangements in 19 genes (NGS) N = 200 CUP tumors Caris Life Sciences Mutation analysis of 47 genes (eg, NGS); IHC 23 markers; FISH/CISH of 7 genes N = 1,806 CUP tumors But for many genes, a small subset of tumors was analyzed NSG = next generation sequencing IHC = immunohistochemistry FISH/CISH = fluorescence in situ hybridization Ross et al. JAMA Oncology 2015 Gatalica et al Oncotarget 2014

12 Summary of CUP aberrations

13

14 Challenges of tumor-agnostic approach (SHIVA): First randomized trial comparing molecularly targeted vs other in tumor-agnostic setting Solid tumor (N = 741 screened) Molecular profiling a Targetable alteration identified and randomized (n=195) b R Molecularly targeted agent c Open label Investigator choice d Primary endpoint PFS a Targeted NGS, IHC, copy number alteration b Most exclusions due to incomplete molecular profile (n ~240), no targetable alteration (n ~200), other (n~100). Included only patients with molecular alteration in one of 3 pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK) c One of 10 regimens: erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen. d Almost all received cytotoxic therapies (monotherapy, n=70; combination, n=19; none, n=3) Le Tourneau et al Lancet Oncology 2015

15 SHIVA: Failed to meet primary endpoint of PFS MD choice HR 0.88 (p =.41) Molecular targeted therapy Potential reasons cited by investigators: Treatment based on single (vs multiple) molecular alteration Mostly monotherapy Limited choice of targeted agents a RR = 4.1% experimental vs 3.4% control a For example, dual MTORC inhibitor may be better than everolimus to target PI3K/AKT/mTOR pathway NOTE: only 2 patients in control arm received molecularly targeted agent

16 Challenges of tumor-agnostic approach: importance of cellular context Example of BRAF V600 treated with vemurafenib melanoma N = 132 RR = 53% NSCLC N = 20 RR = 42% colorectal N = 27 Vemurafenib + cetuximab RR = 4% Sosman et al NEJM 2012; Hyman et al. NEJM 2015

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18 mirna CUP SIGNATURE N=150 CUP Compare the expression of a library of 900 micrornas between: - CUPs biologically classified - Metastases from equivalent known primary tumours (KPM) IS THERE A mirna CUP SIGNATURE? Pentheroudakis et al, Clin Exp Metastasis 2013;30(4):

19 Conclusions Molecular designation of a tissue of origin resulting in primary tumour-specific therapy: There is no high-level evidence yet establishing a survival benefit. Use of NGS panels for identification of actionable genetic aberrations: Lack of randomized clinical trials proving a survival benefit. CUP-specific molecular signature: still elusive. Molecular or tumour-agnostic strategies need validation of clinical validity and utility, rather than leaps of faith Presented by:

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