Individualisierte Therapie des CUP-Syndroms

- Fakt oder Fiktion -

Alwin Krämer

Klinische Kooperationseinheit Molekulare Hämatologie/Onkologie

Medizinische Klinik V, Universität Heidelberg und Deutsches Krebsforschungszentrum

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: 701-710

CUP Subsets – ESMO Classification

Poor prognosis CUP subset

• PS ≤ 1 • Normal LDH

• PS ≥ 2 and / or • Elevated LDH

Consider 2-drug chemotherapy

Chemotherapy or best supportive care

Favorable prognosis: Median survival =

12 months

Poor prognosis: Median survival =

4 months

• 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

Patient with a carcinoma of unknown primary (CUP)

Favorable prognosis CUP subset

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

Ø 15% - 20% of CUP patients Ø 80% - 85% of CUP patients

Patients with Disseminated Adeno- or Undifferentiated CUP

Have Low Survival Rates

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 2033-51.

Minnie Pearl Cancer Research Network - 396 CUP Patients Treated in Phase II Studies

using platinum-based combination chemotherapy

1 year survival: 38% 5 year survival: 10% 10 year survival: 8%

Median survival: 9.1 months

N = 396

Sur

viva

l

1.0

0.8

0.6

0.4

0.2

0 0 12 24 36 48 60 72 84 96 108 120

Patients with Disseminated Adeno- or Undifferentiated CUP

Have Low Survival Rates

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1960 – 69 1970 – 79 1980 – 89 1990 – 99 2000 – 07

1 2 3 4 5 0

Rel

ativ

e su

rviv

al

Years after diagnosis of CUP

Randén, M., et al. (2009) Acta Oncologica 48: 915920

Unchanged survival rates over the last five decades

Tissue of Origin (TOO) Test

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

Core premise: § Different tissue types have distinct mRNA profiles

Uncertain specimen RNA

profile generated

>1,500 genes

RNA profile compared with

known tissue profiles

Gene expression profiling in CUP

Disseminated Adeno-/Undifferentiated CUP

Gene expression profiling identifies responsive patients

with CUP treated with carboplatin, paclitaxel and everolimus

Yoon et al., Ann Oncol 2016

Response rate Overall survival

Progression-free survival

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: 217-223, 2013

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: 217-223, 2013

GEFCAPI 04 Phase III Trial (NCT01540058)

CUP R

Control arm: Empiric chemotherapy (Cisplatin-Gemcitabine)

Tissue Of Origin® Test Primary site-directed treatment

Ø n = 202 pts (HR = 0,62 for PFS) Ø 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

Mutational Spectrum of Adeno-CUP

Ross, J.S., et al. (2015) JAMA Oncol 1:40-9

Substitution/Indel Gene amplification Gene homozygous deletion

Truncation Gene fusion/Rearrangement

55%

50%

45%

40%

35%

30%

25%

20%

15%

10%

5%

0%

N = 125 Adeno-CUP

Sam

ples

, %

High diversity of genomic alterations and a “long tail” distribution observed across ACUP samples

Panel Sequencing of CUP Cases

Varghese et al., Ann Oncol 2017

Level 2 alterations

23/150 (15.3%) ERBB2 amplification BRAF-V600E Level 3 alterations

25/150 (16.7%)

About 30% of CUP Samples Contain Potentially Druggable Genetic Alterations at Evidence Levels 2/3

(n=150)

Tumor Mutational Burden in CUP

Gay et al., ASCO 2017

• TMB high ≥ 20 Mut/Mb

• TMB intermediate < 20 and ≥ 6 Mut/Mb

• TMB low < 6 Mut/Mb

CUP Type Cases Median Age

TMB high (%)

Average TMB

Maximum TMB

CUP NOS

1366 62 11 11.5 445

Adeno CUP

2530 63 8 7.8 278.4

Squamous CUP

618 64 23 18.2 344.1

Malignant Neoplasm NOS

454 59 15 12.5 421.1

6116 CUP cases Tumor Mutational Burden - TMB

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

Example Case II

Gröschel et al., Mol Case Studies 2016

44 year old female patient Ø initial diagnosis of poorly differentiated soft tissue sarcoma Ø progression after surgery and irradiation Ø progression after trabectidin Ø poorly differentiated adeno-CUP

Ø Pembrolizumab at 24 mo after diagnosis Ø Durable remission +14 mo with pembrolizumab

0 months 2 months 6 months

Pembrolizumab

Oncomine Comprehensive Panel

CUP - Molecular Panel Sequencing in Heidelberg

Ø 143 Genes / Gene fusions

Ø In collaboration with the Institute of Pathology Heidelberg

Ø 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

MX39795 Study Design

Inclusion criteria • Histologically confirmed

CUP (non-specific subset) • No prior lines of therapy • ECOG PS 0–1 • ≥1 measurable lesion

N=790

Induction Carboplatin + paclitaxel or

cisplatin + gemcitabine (3 cycles)

Non-responders PD or intolerable

toxicity n=318 (40%)

Responders CR, PR or SD n=472 (60%)

Investigator choice (following Molecular

Tumour Board advice) n=354

Alectinib (ALK or RET rearrangements)

Erlotinib + bevacizumab (EGFR Mut+)

Trastuzumab + pertuzumab + continued induction chemo (ERBB2)

Vismodegib (PTCH1, SUFU or SMO)

Vemurafenib + cobimetinib (BRAF MutV600)

Ipatasertib (AKT1 or PI3K)

Olaparib (BRCA1, BRCA2 or HRD)

Atezolizumab (TMB high or MSI-high)

Atezolizumab + continued induction chemo (patients with no other option)

R 3:1

n=118

Investigator choice (following Molecular

Tumour Board advice) Assigned as per randomised arm

Carboplatin + paclitaxel or cisplatin + gemcitabine (3 cycles)

Screening

Genomic profiling Tissue* and blood‡

315 gene panel + MSI + TMB

plus select biomarkers

(e.g. PD-L1)

Primary endpoint: pooled PFS from 9 molecularly guided regimens vs chemo in responders to induction chemo [PFS1] Secondary endpoint: OS

Category 1

Category 2

MX39795 Patient Selection

Adapted from Fizazi, K., et al. (2015) Ann Oncol 26(suppl 5):v133-8

Poor prognosis CUP subset

• PS ≤ 1 • Normal LDH

• PS ≥ 2 and / or • Elevated LDH

Consider 2-drug chemotherapy

Chemotherapy or best supportive care

Favorable prognosis: Median survival =

12 months

Poor prognosis: Median survival =

4 months

• 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

Patient with a carcinoma of unknown primary (CUP)

Favorable prognosis CUP subset

Selected Inclusion Criteria

Histologically confirmed metastatic or advanced unresectable CUP 1

Eligible for platinum-based doublet chemotherapy

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

No prior lines of therapy

ECOG performance status of 0 or 1

Life expectancy ≥ 12 weeks

Adequate hematologic and end-organ function

ECOG, Eastern Cooperative Oncology Group Fizazi, K., et al. (2015) Ann Oncol 26(suppl 5):v133-8

At least one lesion that is measurable (RECIST v1.1)

Selected Exclusion Criteria

Exclusion criteria

Central nervous system (CNS) metastases

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

Favorable prognostic subset (e.g., resectable)

Leptomeningeal disease Non-epithelial CUP neoplasms

Immunohistochemistry profile that provides a definitive clinical suspicion of a primary

cancer with a specific treatment

ECOG, Eastern Cooperative Oncology Group Fizazi, K., et al. (2015) Ann Oncol 26(suppl 5):v133-8

Country Selection

German Sites

Heidelberg Mannheim

Essen

Augsburg

Oldenburg

Jena

13 Sites Augsburg Berlin Dresden Düsseldorf Essen Frankfurt Hamburg Heidelberg Jena Mainz Mannheim München Oldenburg/Hst.

Status as of November 2017

Acknowledgement

Arbeitsgruppe CUP-Syndrom der Arbeitsgemeinschaft Internistische Onkologie

(AIO) in der Deutschen Krebsgesellschaft e. V.

Gerdt Hübner Gunnar Folprecht

Michael Stahl

Pathologisches Institut, Universitätsklinik Heidelberg

Volker Endris Albrecht Stenzinger Peter Schirmacher

Institut für Pathologie, Technische Universität München

Wilko Weichert

Institut für Pathologie, Universität Zürich

Holger Moch

Klinische Kooperationseinheit Molekulare Hämatologie/Onkologie,

DKFZ & Universitätsklinik Heidelberg

Harald Löffler Tilmann Bochtler

Mutational Profiling of 4650 CUP Samples

Number of Samples Also Relevant for Other Therapy

Therapy Class Samples (n) ALKi EGFRi HER2i SMOi BRAFi AKTi PARPi anti-

PD-L1

ALKi 33 0 0 1 0 3 1 2 EGFRi 99 0 10 0 0 7 4 14 HER2i 334 0 10 3 1 40 20 36 SMOi 53 1 0 3 2 8 7 24 BRAFi 113 0 0 1 2 20 6 12 AKTi 637 3 7 40 8 20 44 99

PARPi 270 1 4 20 7 6 44 56 anti-PD-L1 488 2 14 36 24 12 99 56

4650 CUP cases: w 3058 ACUP w 1592 UCUP

Ø 2027 cases (43.6%) with aberration relevant to targeted study treatment

Ø 420 (9%) with aberration relevant to >1 study treatment strategy

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

Summary

Ø Disseminated adeno-/undifferentiated CUP comprises 80-85% of CUP cases and is associated with a poor prognosis

Ø 15-20% of cases belong to more favorable subgroups

Ø Treatment standard for disseminated adeno-/undifferentiated CUP is platinum-based (carboplatin/paclitaxel, cisplatin/gemcitabine) chemotherapy

Ø Whether primary identification by gene expression profiling and tissue-of-origin specific treatment improves survival remains unclear

Ø Genome sequencing approaches can identify potentially druggable mutations

Ø A large clinical trial analyzing the impact of targeted treatments and immunotherapy will start in April 2018