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Revisione poster

Giuseppe L. Banna

Oncologia Medica

A.O. Cannizzaro Catania

Outline

Survival and prognosis

New drugs and targetable targets

Tumor biomarkers

Survivors: toxicity and follow-up

Survival and prognosis

Author Trial Pts Tx Results Conclusions

Jenny J. Ko, et al

Canada

(Abs 472 -

ORAL)

Retrospective

MT-GCT

(1990-2012)

942 pts

GCT

IGCCCG:

Fav 63%

Int 19%

Poor 16%

First-line

mFU 99mo

2-year conditional

survival: survival since

curative treatment

2-yrCOS in poor risk

from 71% (IGCCCG) to

93%

ND in Se vs NonSe

Older pts (≥40yr) < 2y-

COS 0-18 mo. ND after

18 mo.

2yCOS ND in

Poor vs

Fav/Int= a

Poor risk pt

after 2y =DFS

and OS than

Fav/Int

Adra N, et al

Indianapolis

(Abs 491)

Retrospective

M-GCT

(1998-2012)

Indiana Univ.

615 pts

GCT

(8% Med)

CDDP-

based CT

mFU 5 yr

Poor:

-5yr OS 78%

-5yrPFS 49%

Med:

-5yr OS 58%

-5yrPFS 49%

Improvement

in OS in Poor

(salvage

therapy) but

not in Med

Good Prognosis

• Any primary site • No non-pulmonary visceral metastases • Normal AFP, any hCG, any LDH

90% of seminomas 5-year PFS 82% 5-year OS 86%

Poor Prognosis

No patients classified as poor prognosis

Analysis on 5202 non-Se and 660 Se pts treated with plat inum- based CT between 1975-1990

(IGCCCG, JCO 1997)

Seminoma

Non

Seminoma

• Testis/retroperitoneal primary • No non-pulmonary visceral metastases • Good markers all of: - AFP < 1.000 ng/ml - hCG < 5.000 IU/L - LDH < 1,5 x upper limit of normal

56% of non-seminomas 5-year PFS 89% 5-year OS 92%

Good Prognosis

• Testis/retroperitoneal primary • No non-pulmonary visceral metastases • Intermediate markers any of: - AFP > 1. 000 and < 10.000 ng/ml or - hCG > 5. 000 and < 50.000 IU/L or - LDH > 1, 5 x N and < 10 x N

28% of non-seminomas 5-year PFS 75% 5-year OS 80%

I ntermediate Prognosis

• Mediast inal pr imary • Non- pulmonary visceral metast ases • Poor markers any of: - AFP > 10.000 ng/ml or - hCG > 50.000 IU/L or - LDH > 10 x upper limit of normal

14% of all GCTs 16% of non-seminomas 5-year PFS 41% 5-year OS 48%

Poor Prognosis

I ntermediate Prognosis

• Any primary site • Non- pulmonary visceral metastases • Normal AFP, any hCG, any LDH

10% of seminomas 5-year PFS 67% 5-year OS 72%

Prognosis – I GCCCG classif icat ion of advanced disease

Survival and prognosis

Take-home messages

Prognosis of IGCCG poor risk pts has been

improved in the last years (IGCCG data are

1975-1990 lasted) thanks to appropriate first

line and salvage therapy

PMNSGCTs represent a current challenge

Author Trial Pts Tx Results Conclusions

Necchi A, et al.

ITA

(Abs. 481)

PII (ongoing)

Pazotest-01

32/43 pts

Resistant

GCT

16% PMNSGCT

47% HDCT

(05/2013-

07/2015)

Pazopanib

800 mg/die

64.5% clinical benefit (1

PR, 19 SD)

mPFS 2.73 mo

mOS 4.9 mo.

mFU 15.7 mo.

Pazopanib

active in very

pretreated pts

Narayan et al.

USA

(Abs 474)

PII-Cohort 12 pts

Mature

teratoma

Rb(+)

Palbociclib

CK4/6-Inh.

mEFS 16.2 mo.

mPFS 5.3 mo.

mFU 38 mo.

Events: CT o RT start,

Surgery debulking or

other invasive procedures

Palbociclib

active in this

incurable

population

Necchi A, et al.

ITA

(Abs 480)

PII (ongoing) 9/24 pts

CD30+

Recurrent

GCT

5 HDCT

(07/13-

04/15)

Brentuximab

Vedotin

1.8mg/kg q21

Anti-CD30 Ab

+ Antitubulin

(MMAE)

ORR 22% (1CR+1PR)

78% STM decline

3m-PFS 11%

6m-OS 86%

>HLA-DR, Ki67,

Granzyme B in CD4/CD8

T cells; <PD1+/CD8+ T

cells in CR pt

Active, induce

immuno-

modulatory

effects

New drugs

Targetable targets

Author Trial Pts Tx Results Conclusions

Bagrodia A, et al.

USA

MSK

(Abs. 473)

Retrospective

76 pts

Cis-Refr

NonSe=6

4 (84%)

Good 34%

Int 13%

Poor 53%

MSK-

IMPACT

341 cancer-

related

genes

51 potentially

actionable alterations in

36/76 (47%) pts

- TP53: 7 MDM2 ampl, 4

MYCN ampl) – nutlin-3

Inh.

- TK pathway: 3 Kit mut, 1

KDR ampl, 1 MET ampl –

TKI

- RAS: 11 KRAS mut, 3

NRAS mut, 3 BRAF mut,

2 RAC1 mut – Ras inh.

- PI3-K, WNT, chromatin

mod.,…

Targeted

sequencing

may enrich

future CTs

Elvin JA et al

USA

(Abs 477)

Retrospective 28 pts

Recurrent

NSGCT

Comprehen

sive

genomic

profiling

57% 12p ampl (>6cp)

89% at least one GA not

on 12p

CRGA: CRKL (11%), MCL1

(11%), MDM2 (11%), GNAS

(11%), KRAS (7%), AURKA

(7%) KIT (7%).

One pt w STK11/PIK3R2:

everolimus SD lasting 5

mo.

High

frequence of

GA not 12p

ampl in

recurrent/resis

tant NSGCT

CGP may be

useful for

treatment

Targetable targets

Author Trial Pts Tx Results Conclusions

Bernard BD,

eta l.

USA/France

DFCI/IGR

(Abs. 473)

Retrospective

171 pts

GCT (1987-2014)

preCT

74% at

DFCI

postCT

85%

at IGR

IHC

Anti-PD-L1

Ab E1L3N

TC and IC

Different

scoring

between

DFCI and

IGR

PD-L1 in IC higher in Se

than NonSe (DFCI 87%

vs. 52%, IGR 92% vs.

51.5%, p=0.003 and

p=0.006)

PD-L1 in TC 5/89 DFCI

and 14/82 IGR, all

NonSe but one Se

More +ve CC

Higher PD-L1 not

associated with OS

PD-L1 +ve as

histological

marker for CC

among NSe

IT in Se and

CC (?)

New drugs and Targetable targets

Take-home messages

Genome sequencing for actionable targets

may be a useful option for testing new drugs in

recurrent/resistant GCTs

Pazopanib and Brentuximab Vedotin seem to

be active in heavily pretreated resistant GCT

Palbociclib active in mature teratoma

PD-L1 could be a target for Se and CC ?

Brentuximab Vedotin may act by enhancing

immune response (rationale for IT?)

Author Trial Pts Tx Results Conclusions

Lewin JH, et al.

Canada

(Abs 493)

Retrospective

(2000-2012)

57 pts

Stage I

Se and

NonSe

All active

surveill.

Gene-

expression

signature

(Illumina

WG DASL

Human HT-

12 V4

BeadChip)

Discrimination between

R and NR but not

separately for NSe and

Se.

27/57 Rel, 50% Rel in Se,

median Rel time 5.6 (2.5-

18.1) in Non Se and 19.3

(4.7-65.3) in Se.

Biological

relevance to

be determined

Salman T et al.

Turkey

(Abs 475)

Prospective

65 pts

Early

stage

TGCT

41 (63%)

NonSe

24 (37%)

Se

C-kit

expression

CD117

Rabbit Anti

c-kit

Significant c-kit

expression in Se

(p<0.0001)

ND in 5-yrPFS between

c-kit+ and c-kit-

c-kit not

prognostic

Hatakeyama

S, et al.

Japan

(Abs 489)

Prospective 14 TGCT

28 ctrls

(serum)

N-glycan

profiling

6 N-glycans

significantly high

intensity in TGCT than

ctrls

Serum N-

glycan

analysis a

potential

approach for

new

biomarkers

Tumor biomarkers

Genomic profiling may be an useful tool when

active surveillance is the standard option for

stage I TGCT, but is not ready for prime time

cKit significantly expressed in Se than in

NonSe but not prognostic (nor targetable

with imatinib in a previous experience)

N-glycan analysis is a novel approach that

could be explored to identify new biomarkers

in TGCT

Tumor biomarkers

Take-home messages

Author Trial Pts Tx Results Conclusions

Howard SAH,

et a al.

USA

DFBCI

(Abs 478)

Prospective

Iterative

reconstructio

n tecniques

(IRT) of

modern CT

scanners vs.

filtered back

projection

(FBP)

7 vs. 16 scans

5 yr (NCCN

2009 GL)

24 pts

Stage I

All active

surveill.

CT scans

with Toshiba

Aquilion 64

CT before

and after

IRT

software

installation

ECD of 7 scan regimen

is 53.9 mSv with IRT vs.

87.5 mSv FBP

LAR 0.28% vs.0.46%

ECD of 16 scan regimen

is 123.3 mSv with IRT vs.

200mSv FBP

LAR 0.65% vs.1.00%

LAR: lifetime attributable

risk of dying of radiation-

associated solid tumor

IRT should

reduce CT-

related risks

by about 39%;

combined with

newer AS

regimen

further lowers

potential

imaging-

related

mortality

Toner GC, et

al.

AUSTRALIA

(Abs 487)

Prospective

longitunal

145 pts

Early

stage

TGCT

BEP/EP

(=41)

Carbo

(=20)

Ctrls

(=41)

CogHealth

(10min

online

playing-card

tool)

QoL,

fatigue,

anxiety,

depression,

SP-

cognition

ND for cognitive tasks

(psychomotor, complex

decision, visual learning

and attention, working

memory, SP-cognitive

function)

Fatigue, anxiety,

wellbeing worse with

BEP/EP vs. Carbo/Ctrls,

but improved over time

Follow-up (12-18mo.)

No statistically

significant

difference for

cognitive

scores or self-

reported

cognitive

function

Survivors: toxicity and follow-up

Author Trial Pts Tx Results Conclusions

Oualla K, et a

al.

MOROCCO

(Abs 482)

Systematic

literature

review

53 arms

26 PII-III RCTs

dichotom. By

BLM-CT

6.498 pts

5.093

BLEO

1.405

No BLEO

15% Med

(median)

44% Lung

(median)

Median

dose and n.

BLEO:

360mg and

12 doses

11.7% vs. 1.7% all grade

pulmonary toxicity

Univariate:

OR 7.57 (2.84-20.18) all

grade

OR 5.19 (1.57-17.16) G3-

G4

Multivariate + only for all

grede, NS ifor G3-G4

mFU 52 and 53mo.

BLEO

significantly

associated

with the

development

of pulmonary

toxicity in first

line

Biswas B, et

al.

INDIA

(Abs 488)

Retrospective (06/2011-12/2014)

25 pts

TGCT

P-based

(68%)

Carbo

(20%)

Surv

(12%)

Early

metabolic

syndrome

(MS)

assesment

36% complete MS (9/25)

44% partial MS (11/25)

mFU 15 mo.

Early

metabolic

syndrome

(complete or

partial) in 80%

of TGCT, also

in AS

Survivors: toxicity and follow-up

A 7-scan regimen for AS along with the use of

modern CT scanners (with IRT software) may

significantly reduce the already small potential mortality

of imaging associated cancers

Cognitive function of TGCT patients treated with CT

(BEP/PE or Carbo) is not impaired

Pulmonary toxicity of BLEO should be taken into

account in first-line (no BLEO containing regimens?)

Metabolic syndrome affect a significant (up to 80%)

proportion of treated and untreated TGCT pts

requiring early intervention

Survivor: toxicity and follow-up

Take-home messages

Grazie

“Meglio aggiungere vita ai giorni che

non giorni alla vita” Rita Levi Montalcini

Anno 2015

Carcinoma della

prostata

Anno 2016

Cancro del

testicolo

e Consiglio Direttivo IGG