Roma, 5 Febbraio 2016

Esophagus cancer Critical review

Fernando De Vita Oncologia Medica Seconda Università di Napoli

Esophagus cancer Hot topics from ASCO GI 2016

•INDUCTION CT BEFORE CRT (NEOSCOPE TRIAL) • CT+/-AFLIBERCEPT (MEGA TRIAL) • SCOPE-1 TRIAL UPDATE • NIVOLUMAB (CHECKMATE-32) • PEMBROLIZUMAB (KEYNOTE-28 TRIAL) • NIVOLUMAB (ONO-4538-07)

Esophageal and GEJ adenocarcinoma are different diseases from GC

EA GEJA GC

I II III

Etiology

GERD

H. pylori

+++

-

+++

-

+

+/-

+/-

+

-

+++

Lymphatic

Spread

Tumor heterogeneity Location Etiology Histology Geography Treatment Molecular characteristics

Dulak AM , Cancer Res 2012 TCGA ,2014 Nature

Esophagus cancer Induction CT before CRT

NEOSCOPE TRIAL

Study EA+EGJ

(%) Treatment R0

HR for OS

CROSS 75 Preop CRT 0.73

MAGIC 26 Perioperative CT 0.75

FFCD9703 75 Perioperative CT 0.69

Sjoquist na Preop CT 0.83

Sjoquist na Preop CRT 0.75

DATA FROM PHASE III TRIALS AND META-ANALYSIS

Esophageal adenocarcinoma The therapeutic scenario

pCR: periop CT: 2-7%; preop CRT: 20-25%

MAGIC vs CROSS

PRIMARY ENDPOINT: OS (3yrs)

592 pts

ESOPHAGEAL

EGJ I-III

ECF

TP+RT

S

S

ECF

ICORG 10-14/Neo-AEGIS Perioperative CT vs preop CRT

Perioperative CT or preoperative CRT?

Esophagus cancer Induction CT before CRT

Rapid start of treatment Fast improvement of dysphagia Increase of compliance of the following CRT Downstage: increase R0 and pCR ? Early treatment of systemic disease

RATIONALE FOR INDUCTION CT

Esophagus cancer Induction CT before CRT

pCR as surrogate endpoint

Baseline pts characteristics by study group

pCR 80%

No pCR 17.4%

Esophagus cancer Induction CT before CRT

The clinical scenario

Studies PZ INDUCTION CT PRIMARY

ENDPOINT

De Vita, BJC 2011

41 FOLFOX-4+

CETUXIMAB/ CETUXIMAB+RT

pCR

Ilson, Cancer 2012

55 IRI+CDDP/

IRI+CDDP+RT

pCR

Ajani, Ann Oncol 2013

126 FOLFOX-4+RT

FOLFOX-4/FOLFOX-4+RT pCR

Alberts, ASCO 2013

42 FOLFOX-4+RT

DOC/FOLFOX-4+RT pCR

Mukherjee, ASCO GI 2016

43 OX+CAP/OX+CAP+RT

OX+CAP/TP+RT pCR

Esophagus cancer Induction CT before CRT

NEOSCOPE TRIAL: pCR

Esophagus cancer Induction CT before CRT

The clinical scenario

Studies PZ INDUCTION CT PRIMARY

ENDPOINT pCR R0

De Vita, BJC 2011

41 FOLFOX-4+

CETUXIMAB/ CETUXIMAB+RT

pCR 27 80

Ilson, Cancer 2012

55 IRI+CDDP/

IRI+CDDP+RT

pCR 16 69

Ajani, Ann Oncol 2013

126 FOLFOX-4+RT

FOLFOX-4/FOLFOX-4+RT pCR

13 26

83 93

Alberts, ASCO 2013

42 FOLFOX-4+RT

DOC/FOLFOX-4+RT pCR

50 41

100 94

Mukherjee, ASCO GI 2016

43 OX+CAP/OX+CAP+RT

OX+CAP/TP+RT pCR

11.9 27.9

72 81

Esophagus cancer Induction CT before CRT

Ajani J A, Ann Oncol 2013

Esophagus cancer Induction CT before CRT

Ajani J A, Ann Oncol 2013

Esophagus cancer Induction CT before CRT

Toxicities: NEOSCOPE vs CROSS

Induction CT in esophagus cancer More is better?

NEOSCOPE Small underpowered explorative trial Imbalanced for N+ disease and site of tumor Higher than expected hematological toxicity

Esophagus cancer Which news from targeted therapy?

Woo J, Gastroenterol Rep 2015

Antiangiogenesis for esophagus cancer Is there a role?

VEGF negative

VEGF positive

VEGF predicts poor outcome in esophageal cancer

Shih CH, Clin Cancer Res 2000

Antiangiogenesis for esophagus cancer Is there a role?

MEGA TRIAL

Antiangiogenesis for esophagus cancer Is there a role?

Antiangiogenesis for esophagus cancer Is there a role?

Antiangiogenesis for esophagus cancer Is there a role?

Are these results unexpected?

Antiangiogenesis for esophagus cancer Is there a role?

Yoon HH, ASCO 2014

TRIAL I4T-MC-JVBT (NCT01246960)

Antiangiogenesis for esophagus cancer Is there a role?

Yoon HH, ASCO 2014

TRIAL I4T-MC-JVBT (NCT01246960)

Should adenocarcinoma of the esophagus and GEJ be treated in the same way?

Should adenocarcinoma of the esophagus and GEJ be treated in the same way?

GEJ

E

Pohl H, JNCI 2005

Dikken JL, EJC 2012

Should adenocarcinoma of the esophagus and GEJ be treated in the same way?

Dulak AM, Nature Genetics 2013

More A>C transversions at AA sites in genome of EAC vs GEJ

HER2 positivity more common in esophageal vs. GEJ/cardia tumors

Yoon HH, Clin Cancer Res 2012

Cunningham D, NEJM 2006

Treatment effect according to tumor site in MAGIC

Ychou M, JCO 2011

Treatment effect according to tumor site in FFCD 9703

Should adenocarcinoma of the esophagus and GEJ be treated in the same way?

Treatment effect by primary site

Antiangiogenesis for esophagus cancer Is there a role?

The therapeutic scenario

Anti-EGFR for esophagus cancer Is there a role?

Anti-EGFR for esophagus cancer Is there a role?

Anti-EGFR for esophagus cancer Is there a role?

REAL-3 EXPAND

Toxicity and treatment intensity Interaction of cetuximab with backbone regimen Lack of valid biomarker/inclusion of unselected pts

TREATMENT NIVOLUMAB

(CHECKMATE-32) NIVOLUMAB

(ONO-4538-07) PEMBROLIZUMAB

(KEINOTE-28)

E/GE/G (%) 15/53/31 100/0/0

(SCC) 100/0/0

(SCC+AD)

PD-L1 + not mandatory not mandatory mandatory

(44% PD-L1+)

TREATMENT LINES mostly 3rd line

mostly 3rd line

mostly 3rd line

GRADE ¾ AE (%) 17 29.2 17

ORR (%) 14 17.2 30

MED. DURATION OR (mo)

7.6 3 nr

MED.TIME TO RESPONSE (mo)

1.6 1.5 3.7

OS 36%

(12-mo) 12.1 mo ---

Early signals of immunotherapy efficacy in EC

Immunohistochemical staining for PD-L1 in human esophageal cancer

Overall survival of pts with esophageal cancer according to PD-L1 status

Ohigashi Y, Clin Cancer 2005

PD-L1 + PD-L1 -

PD-L1 positive pts have a poorer outcome than negative pts

Immune Checkpoint Inhibitors in EC Who Will Benefit?

PD-L1 as a prognostic marker

Immune Checkpoint Inhibitors in EC Who Will Benefit?

Intratumoral PD-L1 as a Predictive Marker

Setting Treatment Objective Response Rate, %

Unselected PD-L1+ PD-L1–

Solid tumors (n = 42) Nivo 21 36 0

Melanoma (n = 44) Nivo 32 67 19

Melanoma (n = 34) Nivo 29 44 17

Melanoma (n = 113) Pembro 40 49 13

NSCLC (n = 129) Pembro 19 37 11

HNSCC (n = 55) Pembro 18 46 11

Melanoma (n = 411) Pembro 40 49 13

CHECKMATE-032 TRIAL

Immune Checkpoint Inhibitors in EC Who Will Benefit?

Immune Checkpoint Inhibitors in EC Who Will Benefit?

Immune Checkpoint Inhibitors in EC Who Will Benefit?

Early signals of immunotherapy efficacy in EC: the therapeutic scenario

TREATMENT PZ (n) ORR (%) Med.TTP (mo) Med.OS (mo)

DOCETAXEL 49 16 2.5 8.3

FOLFIRI 38 29 3.7 6.4

IRINOTECAN 37 20 2.6 5.2

IRINOTECAN/ DOCETAXEL

49 20 2.7 8.9

PACLITAXEL 38 24 2.1 5.0

Second-line CT in advanced EC

TREATMENT NIVOLUMAB

(CHECKMATE-32) NIVOLUMAB

(ONO-4538-07) PEMBROLIZUMAB

(KEINOTE-28)

ORR (%) 14 17.2 30

MED. DURATION OR (mo)

7.6 3 nr

MED.TIME TO RESPONSE (mo)

1.6 1.5 3.7

OS 36%

(12-mo) 12.1 mo ---

Early signals of immunotherapy efficacy in EC: the therapeutic scenario

Can immunotherapy fulfill an unmet need in EC?

Can immunotherapy fulfill an unmet need in EC?

“A Journey of a Thousand Miles Begins with a Single Step”

Lau Tzu,6th century BC

Thank you for your attention