La biopsia liquida dei tumori: il viaggio. Paola Gazzaniga Liquid Biopsy Unit Dept. Molecular Medicine Sapienza University of Rome

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1 La biopsia liquida dei tumori: il viaggio Paola Gazzaniga Liquid Biopsy Unit Dept. Molecular Medicine Sapienza University of Rome

2 Must Know Necessary Travel Tips

3 There is lack of drugs to treat all the gene variants identified through next-generation sequencing of cell-free DNA. The challenge is, what do we do with all the information? not even been demonstrated that liquid biopsies improve outcomes in patients with different types of metastatic disease, much less in undiagnosed individuals. I would trust the prospective trial more than a retrospective database analysis. Too many retrospective studies. This is a bizarre way to proceed

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5 1) Point of departure Tissue sampling bias Clonal evolution of cancer Intratumor heterogeneity

6 Tumor heterogeneity exists and cancer researchers, pathologists and oncologists ignore heterogeneity at their own peril.

7 2) A destination Can we use a liquid biopsy to overcome single biopsy bias?

8 3) Mode of transport Which liquid biopsy?

9 Evidence level I (mts breast mts colon and prostate) III II I preclinical Gold et al, J. Mol Diagn,17: , 2015

10 3) Mode of transport Which liquid biopsy?

11 4) The baggage 1. Concordance tissue/plasma: the case of lung cancer On June 1, 2016, the U. S. Food and Drug Administration approved Cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.) using plasma specimens as a companion diagnostic test for the detection of exon 19 deletions or exon 21 (L858R) substitution mutations in the epidermal growth factor receptor (EGFR) gene to identify patients with metastatic non-small cell lung cancer (NSCLC) eligible for treatment with erlotinib The concordance rate between ctdna and the tumor was 87%, with sensitivity of 76.7% and specificity of 98%.

12 Patients with positive cobas EGFR Mutation Test v2 test results using plasma specimens for the presence of EGFR exon 19 deletions or L858R mutations are eligible for treatment with erlotinib Patients who are negative for these mutations by this test should be reflexed to routine biopsy and testing for EGFR mutations with the FFPET sample type.

13 The baggage 1. Concordance tissue/plasma: the case of colorectal cancer Overall agreement (concordance) was 90% The high concordance of plasma and tissue results demonstrates that blood-based RAS mutation testing is a viable alternative to tissue- based RAS testing Grasselli J et al, Ann Oncol Jun 1;28(6):

14 Progression-free survival after anti-egfr plus irinotecan-based therapy is the same for tissue wtras and plasma wtras Grasselli J et al, Ann Oncol Jun 1;28(6):

15 Our assay is not intended to compare the analytical performance of one method for plasma testing with that of one method for tissue testing, but rather to examine the value of plasma analysis versus tissue analysis under standard management care. Much more mutations were found by ctdna analysis: 59%, 11.8% and 14.4% of the patients were found KRAS, NRAS and BRAF mutant by ctdna analysis instead of 44%, 8.8% and 7.2% by tumor-tissue analysis. Altogether, the clinical data with respect to the anti-epidermal growth factor receptor response of those discordant patients do not appear contradictory to the mutational status as determined by plasma analysis. Thierry AR et al, Ann. Oncol, 2017 ; 28:

16 In comparison with tumor-tissue analysis, a blood test appears more cost-effective for genotyping-guided clinical care. Median tumor-tissue data turnaround-time was 16 days while 2 days for ctdna analysis. There is here a clear demonstration that ctdna provides strong evidence for a more rapid data turnaround time than tumor-tissue analysis, irrespective of the methods used. Thierry AR et al, Ann. Oncol, 2017 ; 28:

17 2. ctdna high/low in the assessment of prognosis Association of baseline plasma DNA concentrations with overall survival in patients who received placebo Tabernero J. Et al, Lancet Oncol Aug;16(8):

18 3. Monitoring resistance to targeted therapy: the case of colorectal cancer acquired resistance to EGFR specific antibodies is associated with the emergence of RAS pathway mutations these mutations can be detected in the blood of colorectal cancer patients before disease progression is clinically manifest KRAS mutated alles decline when anti-egfr treatment is suspended. Anti-EGFR induce a SELECTIVE PRESSURE Siravegna et al, 2015

19 While travelling: an air-pocket Clara Montagut, ESMO CRC,Valencia, May 12, 2017

20 Our hand- baggage CT+bev FFPE ctdna 1 ctdna 2 ctdna 3 ctdna 4 G12C wt G12C G12C wt Q61H Q61H wt G12D G12D G12D G13D G13D G12A G12A G12C G12C G12C wt wt wt G12V G12V G12V G12V N-Ras mut wt wt G13D G13D wt wt G12V wt wt wt G 12 D G12D G12V wt wt 7/13 (54%) CT+anti-EGFR wt wt wt wt wt wt wt wt wt wt wt wt wt wt wt wt wt Q61H Q61H wt G12C G12C wt wt wt wt wt wt wt wt wt wt wt G12D wt wt 3/13 (23%)

21 Our hand- baggage ctdna might expand therapeutic options for second line treatment of KRAS mutant mcrc Gazzaniga P et al, ESMO, Madrid, 2017

22 5) The passport EGFR mutations assays in ctdna are the only companion diagnostic tests approved by the regulatory agencies in Europe and in the USA These interventional tests can now be used to guide anti-egfr treatment in EGFR mutated non-small-cell lung cancer patients using blood when access to tissue is impaired.

23 Arrival is not necessarily the final destination Until now, most, if not all, ctdna-based investigations have been in essence proof-of-concept reports. Additional interventional studies are required to demonstrate the clinical utility of a liquid biopsy, i.e., its capacity inform to adopt or to reject a therapeutic action.

24 6) The purpose of the journey The real voyage of discovery consists, not in seeking new landscapes, but in having new eyes. Marcel Proust

25 Open label, single-arm, Phase II trial. The trial has been designed to prove or disprove whether a third line rechallenge with panitumumab can achieve an objective response rate (ORR= CR+PR) of 30% or more in a population of RAS wild type mcrc patients selected on the basis of RAS extended clonal evolution in their plasma

26 The ancient Greeks had two words for time, chronos and kairos. Where chronos is quantitative, kairos is qualitative. It measures moments, not seconds. Further, it refers to the right moment, the opportune moment. The perfect moment. The world takes a breath, and in the pause before it exhales, fates can be changed.

27 % mut RAS KAIROS Keeping the Advantage of the Impermanent RAS-wt window Offering Second-line EGFR inhibitors 1 line including anti-angiogenic mras wtras time 2 line including EGFR-inhibitors Gazzaniga P, ESMO Madrid, 2017

28 The purpose of the journey 19% of patients had one or more ctdna alterations associated with an FDA-approved therapy

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30 Finally, although target prioritization is a major stake, it must be emphasized that drug discovery, development and testing will certainly be the major bottlenecks of precision medicine.

31 Cristina Raimondi Chiara Nicolazzo Angela Gradilone Maria Laura Mancini Alain Gelibter Enrico Cortesi Alberto Sobrero Laura Bracci