ONCO-INMUNOLOGÍA

Cáncer de Pulmón

Enriqueta Felip, Hospital Vall d’Hebron, Barcelona

XVII Simposio “Revisiones en Cáncer” Tratamiento Médico del Cáncer en el Año 2015

Madrid, 11, 12 y 13 de Febrero 2015

Este ponente ha dispuesto de total libertad para la elaboración de esta ponencia en la recogida y presentación de datos e información científica actualizada y de interés; sin embargo los principios activos y terapias mencionadas en esta ponencia podrían no estar autorizados en todos los países para las indicaciones comentadas. Pembrolizumab no está aún autorizado en la UE.

Lung cancer: most common malignancy and leading cause of cancer-related mortality

1. Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11[Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr. Accessed September 2014; 2. Ferlay J, et al. Eur J Cancer. 2013;49:1374–1403.

Lung Cancer

BreastCancer

ColorectalCancer

Prostate Cancer

0

500

1000

1500

2000 IncidenceMortality

GLOBOCAN 2012 (worldwide, both sexes)1

1.59 million1

(1 in 5) estimated deaths worldwide

1.82 million1

estimated new cases worldwide

More people die from lung cancer than breast, colorectal and prostate cancers

combined1

Within Europe, ~1,000 people die from lung cancer every day1,2

ONCO-INMUNOLOGÍA: cáncer de pulmónOutline

• Rationale for PD1 and PDL1 blockade

• PD1 and PDL1 inhibitors in advanced NSCLC

Rationale for PD1 and PDL1 blockadeHow cancer cells evade immune destruction

• Immune system recognizes and eliminates cancer cells from the body

• T cells, crucial in anti-tumor immune response

T cells require a co-stimulatory signal to become fully activated

Activated T cells recognize tumor antigens

T cells kill tumor cells

• Evading immune control, a hallmark of cancer (Hanahan & Weinberg Cell 11)

Rationale for PD1 and PDL1 blockade

PD1/PDL1 pathway

• Limits activity T cells and plays a role in the tumor immune escape

• PDL1 expression prevalent human tumors and associated with prognosis

• PDL1/PD1 inhibitors promising results

Chen D, Clin Cancer Res 2012

Rationale for PD1/PDL1 blockade in lung cancer

• Target immune system rather than tumor

• Activity in different tumor types including NSCLC, melanoma, renal cancer, bladder carcinoma and head & neck

• May well have greater activity in tumors with a large number of mutations

• Manageable toxicity profile

• Suspected impact on long-term survival

PD1 & PDL1 inhibitors in advanced NSCLC

PD1 & PDL1 inhibitors in NSCLCTarget Antibody N (NSCLC) Efficacy (ORR)

Overall%

According to PDL1 status

N for PDL status

PDL1 +%

PDL1-%

PD1 BMS-936558

MK-3475

12952 (1st line)

21745 (1st line, all

PDL1+)

24 (3 mg/kg)21 (3 mg/kg)

2026

6817

194-

13-15 31

2326

17-1410

9-

PD-L1 MPDL3280AMEDI-4736

53 47

2313

5332

83 39

315

Brahmer ASCO 14; Gettinger ASCO 14; Garon ASCO 14; Rizvi ASCO 14, Herbst Nature 14, Brahmer NEJM 12

Primary endpoints• DLTs• AEs• Response rate (primary RECIST, secondary irRC)• Biomarker expression

Locally-advanced or metastatic disease

Any carcinoma, melanoma, NSCLC

ECOG PS 0–1

MK-3475 in chemo-naïve

NSCLC pts with PD-L1+ (n=84)

MK-3475 in previously treated

NSCLC pts with PD-L1+ or PD-L1-

(n=217)

10mg/kg q2w

10mg/kg q3w

≥2L 10mg/kg q2w; PD-L1+ (n=58)

≥2L 10mg/kg q3w; PD-L1+ (n=86)

≥3L 10mg/kg q2w; PD-L1– (n=40)

≥3L 10mg/kg q3w; PD-L1+ (n=33)

MK-3475 (NCT01295827)treated/untreated NSCLC p. Phase I

Garon ASCO 14, abstr 8020; Rizvi ASCO 14, abstract 8007

Phase I study of MK-3475 in pre-treated NSCLC p

RECIST v1.1 Immune-related response criteria

PDL1+ PDL1- PDL1+ PDL1-n = 159 n= 35 n = 177 n = 40

ORR, % 23 9 19 12 Disease control rate, % 42 31 51 53

Response duration, weeks, median 31 NR NR NR

Rizvi ASCO 14, abstract 8007

Safety and activity of MK-3475 as initial therapy in advanced NSCLC p and PDL1 expressing tumors

• Treatment-related AEs (any grade) occurring in >5% of p: fatigue (22%), pruritus (13%), hypothyroidism (9%), dermatitis acneiform (7%), diarrhoea (7%), dyspnoea (7%) and rash (7%)

RECIST v1.1 per independent

central review

Immune-related response criteria per investigator

assessmentORR, % 26 47 Interim median PFS (95% CI), weeks 27.0 (13.6, 45.0) 37.0 (27.0, NR)

Responses ongoing, n/N (%) 11/11 (100) 19/21 (90)Responders remaining on treatment, n/N (%) 7/11 (64) 18/21 (86)

Rizvi J Clin Oncol 2014; 32 (suppl 5; abstr 8007)

- Strong PDL1 positivity defined as staining in ≥50% of tumour cells, and weak PDL1 positivity as staining in 1–49% of tumour cells. Negative staining is no PDL1 staining in tumour cells

- MK-3475 effective, in particular, p with strong PDL1 tumour expression

Activity of MK-3475 and correlation with PDL1 expression in a pooled analysis of advanced NSCLC p

PFS (RECIST v1.1, Central Review)

0 8 16 24 32 40 48

100

80

60

40

20

0Prog

ress

ion-

free

sur

viva

l, %

Time, weeksn at riskStrongWeakNegative

445349

284330

181715

17127

961

600

300

Ove

rall

surv

ival

, %

StrongWeakNegative

0 2 4 6 8 10

100

80

60

40

20

0

Time, months

445349

435142

343429

272214

21188

18116

550

12

872

984

302621

323126

384838

384034

550

14

440

OS

Garon et al. Ann Oncol 2014; 25 (suppl 4): abstr LBA43

MK-3475 phase I in pre-treated p, activity across NSCLC sub-populations

Subgroup ORR,* % (n/N) [95% CI]

HistologyNon-squamous 16 (4/26) [4, 35]Squamous 33 (2/6) [4, 78]Patients with measurable disease on baseline imaging and an evaluable tumour specimen for PD-L1Score ≥ potential cut point 57 (4/7) [18, 90]Score < potential cut point 9 (2/22) [1, 29]SmokingCurrent/former smokers 26 (NR/129) [19, 35]Never smokers 8 (NR/60) [3, 18]

Garon et al. Ann Oncol 2014

NSCLC responders by histology

Time (Week)0 8 16 24 32 40 48 56 64 72 80 88 96 104 112 120 128 136 144 152 160

Squa

mou

sN

on-s

quam

ous

Duration of response up to discontinuation of therapyOngoing responseTime to responseResponse duration following discontinuation of therapy

Brahmer ASCO 14, poster, abstr 8112

• Similar RR in SCC vs non-SCC (16.7 vs 17.6%)• Responses in PDL1-• Similar OS by PDL1 or molecular (EGFR/KRAS)

status (only 53% tissue disposition)

BMS-936558 in advanced NSCLC p:

OS and clinical activity by subgroup analysis (n=129)

ORR 17% (24% in 3mg/kg)OS by BMS-936558 dose in NSCLC

OS by histology in NSCLC

OS 1 year 56%

OS 2 year 45%

1st-line BMS-936558 monotherapy (3mg/kg q 2 wks):Safety, efficacy, and correlation with PDL1 status (n=52)

• Key results– PDL1 expression status correlate with RR (31% in PDL1+; 10% PDL1-)– Grade 3–4 treatment-related AEs 20%

Rizvi, Chicago 2014

Responders by histology Responders by PDL1

RR 21%: 15% SCC, 23% Non-SCC

IRC Assessed (per RECIST v1.1)a

ORR, % (n) [95% CI] 15 (17) [9, 22]

Disease control rate, % (n) 40 (47)

Median DOR, months (range) NR (2+, 12+)

Ongoing responders, % (n) 76 (13)

Median time to response, months (range) 3 (2, 9)

PFS rate at 1-year, % (95% CI) 20 (13, 29)

Median PFS, months (95% CI) 2 (2, 3)

Phase II study of BMS-936558 in p with advanced, refractory squamous NSCLC (N=117)

Ramalingam, Chicago 14

MPDL3280A phase I: efficacy

Single Agent RECIST 1.1 Response Rate

(ORRa)

SD of 24 Weeks or

Longer24-Week PFS Rate

Overall population (N = 175) 21% 19% 42%

NSCLC(n = 53) 23% 17% 45%

Nonsquamous(n = 42) 21% 17% 44%

Squamous(n = 11) 27% 18% 46%

Herbst RS Nature 2014

Diagnostic Population(n = 53)

ORR% (n/n)

PD Rate% (n/n)

IHC 3 83% (5/6) 17% (1/6)

IHC 2 and 3 46% (6/13) 23% (3/13)

IHC 1/2/3 31% (8/26) 38% (10/26)

All Patients 23% (12/53) 40% (21/53)

MPDL3280A phase I: RR by PDL1 IHC status

Herbst RS Nature 2014

Challenges with PDL1 assessment

• Tumor heterogeneity

• Small tumor sample

• Fresh tumor vs archival samples

• PD-L1 expression may change over time

• Different IHC mAB, different cut-off for PDL1 positivity

Agent Assay Analysis Definition of positivityBMS-936558 Dako automated IHC

assay (28-8 rabbit Ab)Analytically validated

• Archival FFPE •1% and 5% cut-off among >100 evaluable tumour cells

MK-3475 Dako automated IHC assay (22C3 mouse Ab)

• New tumour biopsy within 60 days prior to first dose of pembrolizumab

• Tumour dependent:- Melanoma > 1%- NSCLC

PD-L1 (+): Strong (≥50%) and weak staining (1–49%)PD-L1 (–): no staining

MPDL3280A Ventana automated clinical research IHC assay

• Archival FFPE • PD-L1 (+): IHC 3 (≥10%),IHC 2,3 (≥5%),IHC 1,2,3 (≥1%)

• PD-L1 (–):IHC 0 (<1%)

MEDI-4736 First-generation or Ventana IHC Automated Assay(in development)

• Archival FFPE • Not reported

PD-L1 analysis: differences in evaluation and interpretation

Gettinger S, et al, ASCO 2014 (Abstract 8024); Topalian S, et al. NEJM. 2012; Garon E, et al. ASCO 2014 (Abstract 8020); Gandhi L, et al. AACR 2014 (Abstract CT105); Soria J, et al. at ELCC 2013 (Abstract 3408); 8. Rizvi N, et al, ASCO 2014 (Abstract TPS 8123) Brahmer J, et al. ASCO 2014 (Abstract 8021)

PDL1 expression and EGFR mutation

• Activation of PD1 pathway contributes to immune-escape in EGFR-driven tumors (Akbay Cancer Discov 13)

• PDL1 expression by IHC associated with ADC histology and the presence of EGFR-mutation (D’Incecco Br J Cancer 14)

• PDL1 expression by IHC in 164 resected NSCLC p (Azuma Ann Oncol 14)

– Higher for women, for never smokers, for p with ADC– Presence of EGFR-mut and ADC significantly associated with increased

PDL1 expression, in multivariate analysis

• Best predictive marker for response: PD-L1, smoking history, mutations?

• Optimal cut-off for PDL1 positivity and the best IHC mAB?

• Optimal dose and treatment sequence?

• Best surrogate of efficacy (RECIST vs irRC)?

• Activity in CNS?

• Any role in the adjuvant setting?

PD1 and PDL1 inhibitors: questions to answer

Clinical case

• A 77-yr-old man

• Smoker, 50 packs/year

• November 2013: history of 2-month dry cough, no other symptoms

• Chest-X-ray: mass in right hilus

• Physical examination: normal, ECOG PS 1

• CT-thorax: 8 cm mass in upper right lobe, bilateral mediastinal lymph nodes, contralateral lung metastases

• Blood tests: normal except LDH 467

Clinical case

• Bronchoscopy: tumor in anterior branch of right upper lobe

• Histology: squamous cell-cell carcinoma

• PET-CT: primary tumor, bilateral mediastinal nodes, right supraclavicular lymph node, contralateral lung metastases

• Brain MRI: no brain metastases

• No EGFR mutation or ALK rearrangement

• P was enrolled in an anti-PD1 clinical trial

– Central determination of PD-L1, positive

Clinical case

• In summary, a 77-yr-old man diagnosed with stage IVa squamous cell carcinomas included an anti-PD-1 clinical trial, with a central determination of PDL-1 positivity – December 31, 2013 he started anti-PD-1 (10 mg/kg every 3 wks)

– After 9 wks of treatment a CT-scan revealed PR

– February 3, 2015, still on treatment, maintaining PR

– Toxicity: G1 pruritus

• Long PR > 12 months, no toxicity, good general health

December 31, 2013 February 2, 2015

PD1 & PDL1 inhibitors in advanced NSCLC

• Responses in all histologic types

• Toxicity profiles differ from that of CT; generally much better tolerated

• Identification of biomarkers is complex; PDL1 the most analyzed but some PDL1 negative p also benefit

• PD1 and PDL1 inhibitors, promising results in NSCLC, suspected impact on long-term survival

• Targeting PD1/PDL1 means new hope for NSCLC p

Gracias!!!

efelip@vhebron.net