“Le verità scientifiche”… -...

Stefania Gori

Presidente Eletto AIOM

Dipartimento Oncologia

Cancer Care Center “Sacro Cuore-Don Calabria”

Negrar-VERONA

Associazione Italiana Oncologia Medica

“Le verità scientifiche”…

Reggio Emilia, 23-24 giugno 2016

2° Corso nazionale AIOM per giornalisti medico-scientifici

II SESSIONE- Comunicare l’innovazione in oncologia e lo sviluppo della farmacoeconomia nei media

2° Corso nazionale AIOM per giornalisti medico-scientifici. Reggio Emilia, 24-25 giugno 2016

Antitumoral drug and innovativity: what do we have to consider?

• Benefit (relative and absolute advantage) in terms of chosen main endpoint vs the best comparator.

• Incidence of the specific tumor.

• Availability of alternative therapies.

POSITION PAPER di AIOM, SIF, SIFO, SIHTA: Il SIGNIFICATO DELL’INNOVAZIONE IN ONCOLOGIA. Dec 2012

Evaluation of a clinical trial…..…

Metodologist Medical oncologist

-Clinical relevance -Impact on the clinical practice

- In which way it has been designed? -In which way it has been performed?


Evaluation of a clinical trial. Clinical relevance impact on the clinical practice

-Clinical trials well designed and well conducted -Consistent results

Impact on the clinical practice: Low High

-Clinical trials with “weak” methodology, but with results: 1- biologically plausible 2- consistent with data from other clinical trials

Impact on the clinical practice: High



EXAMPLE A High impact on the clinical practice from:

clinical trials well designed, well performed and with consistent results

IMMUNOTHERAPY TRIALS in NSCLC


Totali Uomini Donne

N. nuovi casi di tumore (esclusi ca.cute) 2015

363.300 194.400 168.900

N. decessi per tumore 2012 (dati Istat)

177.351 99.792 77.559


Prime 5 cause di morte per tumore e proporzione sul totale dei decessi oncologici per sesso. Pool AIRTUM 2007-2011

Prime 5 tumori più frequentemente diagnosticate e proporzione sul totale dei tumori (esclusi i ca. cute) per sesso. Pool AIRTUM 2007-2011. *comprende sia tumori infiltranti che non infiltranti

I NUMERI DEL CANCRO IN ITALIA 2015 AIOM-AIRTUM (www.aiom.it)

Lung carcinoma in Italy: 2015 incidence: 41.000 new cases 2012 mortality: 33.538 deaths 5 y survival: 14-18%




• Incidenza diminuita del 20% da 87.6 a 70.0 casi per 100.000) correlata alla riduzione del consumo di tabacco con −1.4% per anno negli anni più recenti

• Decremento della mortalità −1.5% per anno nel periodo più recente

• Aumento di nuovi casi +2.7% per anno nel 2006-2014 da rapportare all’abitudine al fumo di tabacco

• Aumento della mortalità +1.6% per anno nel periodo 1999-2015

Lung cancer: incidence and mortality in Italy

• Variazione annuale dei tassi di incidenza dell’adenocarcinoma +7.0%; aumento non statisticamente significativo per il carcinoma squamocellulare +1.7%


Lung cancer: incidence in Italy in women by histology

Molecular subsets of lung adenocarcinoma

Pao & Hutchinson Nat Med 2012

3-7%

1-2%

10-15%

20-25%


Median OS in metastatic NSCLC with agents available in 2016

Characteristic Median OS (months)

Percentage of patients

Squamous-cell carcinoma 11-12

85% EGFR/ALK/ROS1 WT non-squamous-cell carcinoma

13-18

EGFR Mutated 22-30

15% ALK/ROS1 Translocated >30



IMMUNOTHERAPY


T cell recognizes tumoral antigens, the proteins induced by neoplastic transformation

Infected host cells

T cells

Tumor cells

T cells

Pathogen proteins Proteins associated with cancer transformation

T cell receptor

HLA


Tumor associated antigens (target of T cell)

Tissue antigens (MUC1, EPCAM, PSA, PSMA, PAP, Mart-1, CEA….…)

Embryonic antigens (MAGE3, NY-ESO1, PRAME….)

Unique mutated antigens or NEO-ANTIGENS (cancer genetic instability)

Anti-tumor immune response

Tumor growth

Subclinical pre-diagnosis phase Clinical phase

ELIMINATION of tumor cells

(partial or complete)

EQUILIBRIUM between

immune response and tumor growth

ESCAPE of tumor cells

from immune control

Imm

un

ose

lect

ion

/ed

itin

g


Immunitary system and tumor: why does an aggressive tumor develop in immunocompetent patients?

The discovery of Immune checkpoint

TUMOR CELL

T CELL

Dendritic cell

Tissue macrophage


Nivolumab Mechanism of Action

• Nivolumab binds PD-1 receptors on T cells, disrupts negative signaling triggered by PD-L1/PD-L2 and may restore T-cell antitumor function.

MHC

PD-L1

PD-1 PD-1

PD-1 PD-1

T-cell receptor T-cell

receptor

PD-L1 PD-L2

PD-L2

MHC

CD28 B7

T cell

NFκB

Other

PI3K

Dendritic cell Tumor cell

IFNγ

IFNγR

Shp-2

Shp-2

Nivolumab is a fully human IgG4 PD-1 inhibitor antibody

PD-1= Programmed Death 1


Nivolumab in metastatic NSCLC

Squamous NSCLC (Checkmate 017)

Non-Squamous NSCLC (Checkmate 057)

Brahmer J et al, NEJM 2015; 373:1627-39

Borghaei H et al, NEJM 2015;373:1627-39


ASCO 2016


Nivo Doc

Nivo Doc

100

90

80

70

60

50

40

30

10

0

20

Time (months)

100

90

80

70

60

50

40

30

10

0

20

24 21 18 15 12 9 6 3 0 27

Time (months)

24 21 18 15 12 9 6 3 0 27

Symbols represent censored observations.

OS by PD-L1 Expression

mOS (mo)

Nivo 10.4

Doc 10.1

mOS (mo)

Nivo

17.2

Doc 9.0

mOS (mo)

Nivo 9.9

Doc 10.3

mOS (mo)

Nivo

19.4

Doc 8.0

Time (months)

≥5% PD-L1 expression level

<5% PD-L1 expression level

mOS (mo)

Nivo

18.2

Doc 8.1

mOS (mo)

Nivo

9.7

Doc 10.1


HR (95% CI) = 0.59 (0.43, 0.82)

Time (months)


OS

(%)

HR (95% CI) = 0.90 (0.66, 1.24)

HR (95% CI) = 0.43 (0.30, 0.63)

HR (95% CI) = 1.01 (0.77, 1.34)

OS

(%)

Time (months)

Time (months)



HR (95% CI) = 0.40 (0.26, 0.59)

HR (95% CI) = 1.00 (0.76, 1.31)

24 21 18 15 12 9 6 3 0 27

100

90

80

70

60

50

40

30

10

0

20

100

90

80

70

60

50

40

30

10

0

20

24 21 18 15 12 9 6 3 0 27

24 21 18 15 12 9 6 3 0 27

100

90

80

70

60

50

40

30

10

0

20

24 21 18 15 12 9 6 3 0 27

100

90

80

70

60

50

40

30

10

0

20

PD-L1 expression is predictive of benefit with nivolumab, starting at the lowest expression level (1%)


Brahmer J et al. NEJM 2015; 373:1627-39 2° Corso nazionale AIOM per giornalisti medico-scientifici. Reggio Emilia, 24-25 giugno 2016

Borghaei H et al. NEJM 2015; 373:1627-39


Lawrence MS et al. Nature 2013;499:214-218


Understanding the immunogenetics of tumours: the prevalence of somatic mutations across human cancer types…

Lawrence MS et al. Nature 2013;499:214-218


Understanding the immunogenetics of tumours: the prevalence of somatic mutations across human cancer types…

Immunotherapy could be effective in all histologies expression of neo-antigens

Checkpoint inhibitors: clinical development in solid tumors

Antibody Molecule Development Stage Approved (US)

Nivolumab

Anti-PD-1

Fully human

IgG4

Phase III in multiple tumors

Advanced melanoma (with or w/o

ipilimumab),

advanced NSCLC after CT,

advanced renal cell carcinoma after

anti-angiogenic therapy,

Hodgkin Lymphoma after HSCT

Pembrolizumab

Anti-PD-1

Humanized

IgG4

Phase III multiple tumors

(HNSCC, melanoma, bladder,

gastric/GE)

Advanced melanoma,

advanced NSCLC with PD-L1

expression after CT

Atezolizumab

Anti-PD-L1

Engineered

human IgG1


(NSCLC, RCC, TNBC)

Locally advanced or metastatic

urothelial carcinoma after CT

Durvalumab

Anti-PD-L1

Engineered

human IgG1


(bladder, NSCLC, HNSCC)

Avelumab

Anti-PD-L1

Fully human

IgG1

Phase III (NSCLC, Merkel

carcinoma)

Ipilimumab

Anti-CTLA4

Humanized

IgG1


(melanoma, NSCLC, SCLC,

CRPC, GBM, RCC)

Advanced melanoma



Olaparib in advanced ovarian cancer

EXAMPLE B High impact on the clinical practice from..

clinical trials with “weak” methodology, but with results : 1- biologically plausible 2- and consistent with data from other clinical trials


Ovarian carcinoma in Italy

2015 Incidence :

4800 new cases in Italy*

2012 Mortality (ISTAT data):

3.251 deaths in Italy

80 %: III e IV stage

20 %: I e II stage

*AIOM-AIRTUM. I NUMERI DEL CANCRO IN ITALIA 2015

Prime 5 cause di morte oncologica e proporzione sul totale dei decessi per tumore per sesso e fascia d’età (sesso femminile ). Pool AIRTUM 2007-2011

WHY is this disease so lethal?

•Early diagnosis is impossible (only in BRCAm women).

• Many treatments are available: they are PFS but not

OS.

•Biology of the tumor is very complex difficulties in

availability of biological drugs.


Patients with ovarian cancer and BRCAm show:

- more favorable prognosis

- sensitivity to platin-based therapy and to PARP-I

Ledermann J, NEJM 2014;15:852-861


The PARP (Poly-ADP-Ribose Polimerase) enzyme plays a key role in the

repair of DNA breaks. Evidence suggests that normal cells can tolerate PARP-

inhibitors by activating repair pathways that depend upon the activity of

BRCA1 and 2 proteins.

Cells deficient in BRCA1/2 do not have this capacity and PARP-Inhitors

show selective cytotoxicity in these cells.

Underhill C, Ann Oncol 2001;22:268-79 Bryant HE, Nature 2005;434:913-17 Farmer H, Nature 2005;434:917-21.

Ledermann J,


Retrospctive analysis after retrospective evaluation of BRCA status (in 96% of pts)

Ledermann J, NEJM 2014; 15:852-61


Ledermann J, NEJM 2014; 15:852-61

The results are biologically plausible (olaparib is efficacy in BRCAm)

1- Subgroup analysis was preplanned (?) but it was not expected the adjustement for multiplicity (risk of false +). 2- Randomisation was not stratified according to BRCA status because it was not available in that moment (risk of bias). 3- BRCA status was evaluated retrospectively.


Author Tumor phase

No pts

BRCA status known

Analysis of efficacy by BRCAm status

PFS in BRCAm pts

OR

Ledermann NEJM 2014

Ovarian cancer Olaparib vs placebo

IIR 265 96% * Preplanned retrospective analysis

11.2 mo vs 4.3 mo

---

Oza AM Lancet Oncol 2015

Ovarian cancer Carbo+paclitaxe+olaparib→ olaparib Carbo+paclitaxel

IIR 173 66%* Prespecified exploratory analysis

NR vs 9.7 mo

64% Vs 58%

Kaufman B JCO 2015

Ovarian, breast, prostate, and pancreatic cancer olaparib

II 298 100% (eligibility criteria)

-- Different in different tumors

26.2%

Mateo J NEJM 2015

Prostate cancer olaparib

II 50 33% (DNA-repair defect)

DNA-repair defect: assessed prospectively

9.8mo vs 2.7 mo

88% in pts with DNA-repair defect

*No stratification for BRCA status BRCA assessed retrospectively

OLAPARIB in phase II trials RESULTS

Ledermann JA, ASCO 2016

Luglio 2015


Grazie!

CANCER CARE CENTER Sacro Cuore -Don Calabria

Negrar-VERONA

“Le verità scientifiche”… -...

Documents

Transcript of “Le verità scientifiche”… -...