Η ανοσοθεραπεία στον καρκίνο του πνεύµονα Ιωάννης Ξανθάκης

BMS

Roche

Δήλωση συµφερόντων - συµµετοχή σε advisory boards: Novartis

Amgen

Genesis

Pfizer

Εισαγωγή❑ Lung cancer accounts for 1.6 million new cases and 1.4

million deaths annually

❑ NSCLC constitutes 85% to 90% of all lung cancers

❑ Despite advances in chemotherapy and molecular targeted

therapy, survival remains poor with a 5-yr OS of 4–5%

❑ The advent of immunotherapy in NSCLC has begun to

change the landscape of the management of this disease

❑ Offers a potential for prolonged responses and survival

Jemal et al. 2011, Howlader et al. 2014

The cancer immunity cycleAdapted from Chen & Mellman, Immunity, 2013

1

2

3

4

5

6

Release of cancer cell antigens (cancer cells)

Antigen presentation (DC, APCs)

Priming and activation

(DC, T cells)

Trafficking to tumors (CTLs)

Tumour infiltration

(CTLs, endothelial cells)

Recognition (CTLs, cancer cells)

Killing of cancer cells (CTLs, cancer cells)

7

αCTLA-4

αPD-1

Focus on two actionable immune synapses

+

Immunotherapy checkpoint inhibitors: the New Players in the NSCLC space Checkpoint inhibitors: tumors express “checkpoint” proteins on their cell surface to escape detection from the immune system; targeted inhibition towards these receptors enhances T cell response towards the tumor

http://sitn.hms.harvard.edu/flash/2014/blocking-the-brakes-helping-your-immune-system-battle-cancer/

! Patients with SQ NSCLC have a worse prognosis and limited therapeutic options vs non-SQ after front-line chemotherapy1,2

! Second-line therapy with docetaxel has modest clinical activity and is associated with significant toxicity2-8

–mOS = 5–8 mo, ORR = 3–9% ! Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody,

demonstrated efficacy and manageable safety in pretreated patients with advanced or metastatic NSCLC across histologies9,10

–Phase II single-arm trial (CheckMate 063; NCT01721759) demonstrated clinical activity of nivolumab in refractory SQ-NSCLC (mOS = 8.2 mo, 1-yr OS = 41%, and ORR = 15%)10

! This randomized global phase III study evaluated the efficacy and safety of nivolumab vs docetaxel in patients with advanced SQ-NSCLC after failure of platinum-based chemotherapy

1. Heist RS, et al. J Thorac Oncol 2012;7:924–33; 2. NCCN Guidelines®. NSCLC. V4.2015; 3. Fossella FV, et al. J Clin Oncol 2000;18:2354–62; 4. Shepherd FA, et al. Clin Oncol 2000;18:2095–103; 5. Hanna et al. J Clin Oncol 2004;22:1589–97; 6. Reck M, et al. Ann Oncol 2014;25:iii27–39; 7. Garassino M, et al. Lancet Oncol 2013;14:981–8; 8. Kim ES, et al. Lancet 2008;372:1809–18; 9. Gettinger SN, J Clin Oncol Apr 20. pii: JCO.2014.58.3708; 10. Rizvi NA, et al. Lancet Oncol 2015;16(3):257–65. mo = months; mOS = median overall survival; ORR = objective response rate; OS = overall survival; PD-1 = programmed death-1

Second line single agent chemotherapy improves survival

The database for a survival advantage of 2nd line chemotherapy is small and based on only one study of docetaxel vs BSC

Shepherd, J Clin Oncol 2000

Primary Objective •Overall survival (OS) Secondary Objectives •ORR •PFS •ORR and OS by PD-L1 status •Duration of OR •Time to OR •Proportion of patients exhibiting disease-related symptom progression (Lung Cancer Symptom Scale)

Docetaxel

Nivolumab

Docetaxel

Nivolumab

CA209-017 NCT01642004

(Phase 3; N = 264)

Patients with stage IIIb/IV squamous

cell NSCLC

CA209-057 NCT01673867

(Phase 3; N = 574)

Patients with stage IIIb/IV non-squamous cell

NSCLC

Nivolumab phase III trial Squamous & non-squamous

2nd line vs docetaxel

SCC-Overall SurvivalNivolumab

n=135Docetaxel

n=137

mOS mo (95% CI)

9.2 (7.33, 12.62)

6.0 (5.29, 7.39)

# events 103 122

HR=0.62 (0.48, 0.81); P=0.0004

Minimum follow-up for survival: 18 months •Survival was monitored until death or withdrawal of consent

Docetaxel18-month OS rate=13%

OS

(%)

Time (months)

0614253751576986113135 0NivolumabNumber of Patients at Risk

047111722334669104137Docetaxel 1

Nivolumab18-month OS rate=28%

100

90

80

70

60

50

40

30

10

0

20

332724211815129630 30

RR: 20% vs 9%

Reckhamp, WCLC 2015

Efficacy by PD-L1 Expression

Based on December 2014 DBL

12-mo OSa 18-mo OSb

Nivo (n = 292) Doc (n = 290) Nivo (n = 292) Doc (n= 290)

mOS, mos 12.2 9.4 12.2 9.4

1-year OS rate, % 51 39 51 39

18-mo OS rate, % – – 39 23

No. of events, n/N

190/292 223/290 206/292 236/290

HR (96% CI) = 0.73 (0.59, 0.89)P = 0.0015

HR (95% CI) = 0.72 (0.60, 0.88)Post-hoc P = 0.0009c

Non-SCC Overall Survival

100

90

80

70

60

50

40

30

10

0

20

27181596 211230 24 30

NivolumabDocetaxel

Number of patients at risk (18-mo OS)b

292 233 195 171 148 128 107 55 427290 244 194 150 111 89 61 23 4

006

NivolumabDocetaxel

NivolumabDocetaxel

Number of patients at risk (12-mo OS)a

292 232 194 169 146 123 62 32 09290 244 194 150 111 88 34 10 05

18-mo OS rate = 23%

18-mo OS rate = 39%

1-yr OS rate = 39%

1-yr OS rate = 51%

Time (Months)

OS

(%)

RR: 12% vs 9% Horn, ESMO 2015

OS by Baseline PD-L1 Expression

PD-L1 expression level

Nivon

Docn

Unstratified HR (95% Cl)

InteractionP-valuea

OS≥1% 123 123 0.59 (0.43,

0.82) 0.0646<1% 108 101 0.90 (0.66,

1.24)≥5% 95 86 0.43 (0.30, 0.63) 0.0004

<5% 136 138 1.01 (0.77, 1.34)≥10% 86 79 0.40 (0.26, 0.59) 0.0002

<10% 145 145 1.00 (0.76, 1.31)Not quantifiable 61 66 0.91 (0.61, 1.35)

PFS≥1% 123 123 0.70 (0.53,

0.94) 0.0227<1% 108 101 1.19 (0.88,

1.61)≥5% 95 86 0.54 (0.39, 0.76) <0.0001

<5% 136 138 1.31 (1.01, 1.71)≥10% 86 79 0.52 (0.37, 0.75) 0.0002

<10% 145 145 1.24 (0.96, 1.61)Not quantifiable 61 66 1.06 (0.73, 1.56)Based on a March 18, 2015 DBL

aInteraction p-value from Cox proportional hazard model with treatment, PD-L1 expression and treatment by PD-L1 expression interaction

PD-L1 expressors PD-L1 non-expressors PD-L1 not quantifiable

1.00.5 2.00.25Nivo Doc

Horn, ESMO 2015

Treatment-related AEs (≥10% of patients)Nivolumab (n = 131)

Docetaxel (n = 129)

Any Grade

Grade 3–4

Any Grade

Grade 3–4

Total patients with an event, % 58 7 86 55

Fatigue 16 1 33 8Decreased appetite 11 1 19 1Asthenia 10 0 14 4Nausea 9 0 23 2Diarrhea 8 0 20 2Vomiting 3 0 11 1Myalgia 2 0 10 0Anemia 2 0 22 3Peripheral neuropathy 1 0 12 2

Neutropenia 1 0 33 30

Febrile neutropenia 0 0 11 10

Alopecia 0 0 22 1

Treatment-related Select AEs

• Select AEs: AEs with potential immunologic etiology that require frequent monitoring/intervention

aNo cases of increased bilirubin occurred in the nivolumab arm. bGrade 5 event. cNo cases of renal failure were reported in the nivolumab arm.dIncludes rash, pruritus, erythema, maculopapular rash, skin exfoliation, urticaria and palmar plantar erythrodysasthesia syndrome.

Nivolumab (n = 131)

Docetaxel (n = 129)

Any Grade Grade 3–4 Any Grade Grade 3–4

Endocrine, % Hypothyroidism

4 4

0 0

0 0

0 0

Gastrointestinal, % Diarrhea

Colitis

8 8 1

1 0 1

20 20 0

2 2 0

Hepatic,a % ALT increased AST increased

2 2 2

0 0 0

2 1 1

1 1 1

Pulmonary, % Pneumonitis

Lung infiltration Interstitial lung disease

5 5 1 0

1 1 0 0

1b 0 0 1b

0 0 0 0

Renal,c % Blood creatinine increased Tubulointerstitial nephritis

3 3 1

1 0 1

2 2 0

0 0 0

Skin,d % 9 0 9 2

Hypersensitivity/Infusion reaction, %

Hypersensitivity Infusion-related reaction

1 0 1

0 0 0

2 2 1

1 1 0

LCSSa: A Lung Cancer-specific PROAverage Symptom Burden Index

(0–100)

(MID ≥ 10; higher is worse)

3-Item Index (0–300)

(MID ≥ 30; higher is better)

aSecondary study end point; b100 mm visual analogue scale. Hollen PJ, et al. Cancer.1994;73:2087–98; Gralla RJ, et al. J Thorac Oncol. 2014;9:1243–8.

Symptom Distressb

Interference with

activity levelb

Health-related quality of life

(HRQoL)b

Anorexiab Fatigueb

Coughb Dyspneab

PainbHemoptysisb

MID: minimally important difference

12 24 30 36 42 48 54 60

30

40

20

10

0

-10

-20

-30

-40

LCSS Symptom Burden Index(on-treatment)

LCSS

Sym

ptom

Bur

den

Inde

x C

hang

e fr

om B

asel

ine

Week

Higher scores indicate greater symptom burden. Mean scores (±SD) at baseline were 29.6 (±16.4) for nivolumab and 29.6 (±14.7) for docetaxel. Only time points that had PRO data available for ≥5 patients in either treatment arm are plotted on the graph. MID consists of a change of ≥10 points. Gralla RJ, et al. WCLC; September 6–9, 2015; Denver, CO; Abstract 743.

47 29 29 20 17 12 12 8Nivolumab (n = 97)

29 9 5 5 4 4 2 1Docetaxel (n = 89)

Wor

seB

ette

rDocetaxelNivolumab

0

017 - Summary• Nivolumab is the first PD-1 inhibitor to demonstrate a survival benefit

versus standard-of-care docetaxel in pre-treated patients with advanced SQ NSCLC

– 41% reduction in risk of death (HR 0.59 - ASCO),38% (HR 0.62 - ESMO)

– 1-yr OS: 42% vs 24%(ASCO) , 18m-OS: 28% vs 13% (ESMO) – mOS: 9.2 vs 6.0 mo

• Nivolumab demonstrated superiority over docetaxel across all secondary efficacy endpoints

– ORR: 20% vs 9% (P = 0.0083) – 1-yr PFS: 21% vs 6.4%; mPFS: 3.5 vs 2.8 mo (HR 0.62; P = 0.0004)

• Nivolumab benefit was independent of PD-L1 expression • The safety profile of nivolumab was favorable versus docetaxel and consistent

with prior studies

057 - Summary• Nivolumab is the first PD-1 inhibitor to significantly improve OS vs

docetaxel in previously treated patients with advanced non-SQ NSCLC – 27% reduction in risk of death (HR = 0.73 - ASCO 2015), – 28% (HR=0.72 – ESMO 2015)

• Objective responses were observed across subgroups • Nivolumab demonstrated clinical benefit in PD-L1 expressors and

non expressors • Magnitude of benefit greater among patients whose tumors express

PD-L1 • Safety profile of nivolumab was favorable vs docetaxel and consistent with

prior studies • CheckMate 057 is the second phase III trial to demonstrate superior

survival of nivolumab over docetaxel in advanced NSCLC

Approval Status

• FDA (March 2015) and EMA (July 2015) : Approval for 2nd line squamous NSCLC patients - all comers ( without restriction to PDL1 status )

Approval Status • FDA Approval ( October 2015 ) for 2nd line non

squamous - all comers: no restriction for PDL1 status.

• FDA has, at the same time, approved BMS and diagnostic partner DAKO’s PD-L1 as complementary diagnostic test.

• EMA Approval April 2016 without restriction to PDL1 status

Additional PD-1 / PD-L1 inhibitors in development to treat patients with NSCLC

Pembrolizumab (Keytruda): Human monoclonal antibody directed against the programmed death-1 (PD-1) receptor of the T Cell; binding to PD-1 blocks its interaction with programmed cell death ligand 1 (PD-L1) and PD-L2 on the tumor cell;

Durvalumab (MEDI4736): Human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). PD-L1 binds to the PD-1 receptor, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response

Atezolizumab (MPDL3280A): Human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). PD-L1 binds to the PD-1 receptor, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response

anti- PD-1

anti- PD-L1

23% in third line and beyond

KEYNOTE-010: Summary of Key Conclusions

• Pembrolizumab associated with significant OS benefit for patients with previously treated (≥ 1 regimen), PD-L1(+) (≥ 1% of tumor cells), advanced NSCLC compared with docetaxel

• Median OS: – 2-mg/kg pembro vs docetaxel: 10.4 vs 8.5 months (HR: 0.71, P = .0008) – 10-mg/kg pembro vs docetaxel: 12.7 vs 8.5 months (HR: 0.61, P < .0001)

• For patients with ≥ 50% PD-L1–expressing tumor cells, both OS and PFS significantly longer for pembro vs docetaxel – Median OS: – 2-mg/kg pembro vs docetaxel: 14.9 vs 8.2 mo (HR: 0.54, P = .0002) – 10-mg/kg pembro vs docetaxel: 17.3 vs 8.2 mo (HR: 0.50, P < .0001)

• Validates the use of PD-L1 expression as a biomarker for a pembrolizumab benefit

• Pembrolizumab associated with fewer adverse events (AEs) vs docetaxel – Grade 3-5 treatment-related AEs: 13% with 2-mg/kg pembro, 16% with 10-

mg/kg pembro, 35% with docetaxel – Immune-mediate AEs occurred at manageable rates

• Pembrolizumab received FDA approval for the treatment of patients with metastatic NSCLC whose tumors express PD-L1, as determined by an FDA approved companion diagnostic test

A similar and significant tail of the curve across trials

A similar and significant tail of the curve across trials

Soria, ESMO 2015

IgG engineered anti-PD-L1 ab

Poplar: atezolizumab vs docetaxel OS data according to PD-L1 level

Vansteenkiste, ESMO 2015

o IHC SP142 assay Sensitive and specific, measures PD-L1 expression on both TC and IC, predictive diagnostic biomarker for atezolizumab in NSCLC

• Atezolizumab was granted Breakthrough Therapy Designation by the FDA in February 2015 for the treatment of people with PD-L1-positive NSCLC whose disease has progressed during or after platinum-based chemotherapy (and appropriate targeted therapy for those with an EGFR mutation-positive or ALK-positive tumour). EMA approval is expected in June 2017

Durvalumab (MEDI4736): an engineered anti-PD-L1 antibody• PD-L1 inhibits cancer immunity1

• Durvalumab binds to PD-L1 and allows T cells to recognise and kill tumour cells2

• Durvalumab is a selective, high affinity human IgG monoclonal antibody that blocks PD-L1 binding to PD-1 (IC50 0.1 nM) and CD80 (IC50 0.04 nM)3

Durvalumab is an investigational drug and is not approved for use in any country

1. Zou W, Chen L. Nature Rev Immunol 2008;8:467-77 2. Segal NH, et al. Poster presented at ESMO 2014. Poster 1058PD;

3. Segal NH, et al. Poster presented at ASCO 2015. Poster 3011

• Other key attributes include – No binding to PD-L2, which plays a role in

controlling inflammation in normal lung tissue (with expression in lung macrophages and APCs); this may help to avoid PD-L2-mediated immune-related toxicities, which have been observed in animal models3

– An engineered triple mutation in the Fc domain to remove antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity3

– Low incidence (2%) of anti-drug antibodies3

Safety and Clinical Activity of Durvalumab, an Anti-programmed Cell Death-ligand 1 (PD-L1) Antibody, in Patients

with Non-small Cell Lung Cancer (NSCLC)

Study 1108: NSCLC cohort

Durvalumab is an investigational drug and is not approved for use in any country

N. Rizvi1, J. Brahmer2, S-H. Ou3, N.H. Segal4, S.N. Khleif5, W.J. Hwu6, M. Gutierrez7, P. Schöffski8, O. Hamid9, J. Weiss10, J. Lutzky11, M. Maio12, J. Nemunaitis13, D. Jaeger14, A.

Balmanoukian9, M.C. Rebelatto15, K.E. Steele15, X. Li15, J.A. Blake-Haskins15, S. Antonia16

1Columbia University Medical Center, New York, NY, USA; 2The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; 3University of California Irvine School of Medicine, Orange, CA, USA; 4Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5GRU Cancer Center, Georgia Regent

University, Augusta, GA, USA; 6University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Hackensack University Medical Center, Hackensack, NJ, USA; 8University Hospitals Leuven, Leuven, Belgium; 9The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 10University of North Carolina Lineberger

Comprehensive Cancer Center, Chapel Hill, NC, USA; 11Mount Sinai Medical Center, New York, NY, USA; 12University Hospital of Siena, Siena, Italy; 13Mary Crowley Cancer Research Centers, Dallas, TX, USA; 14National Center for Tumor Diseases, University Hospitals Heidelberg, Heidelberg, Germany; 15MedImmune,

Gaithersburg, MD, USA; 16Moffitt Cancer Center, Tampa, FL, USA

Rizvi N, et al. Poster presented at ASCO 2015. Poster 8032

Summary*

• Safety – 50% of patients experienced drug-related AEs – 8% were Grade 3–4 AEs – 5% led to discontinuation of treatment – No drug-related colitis of any grade, no Grade 3–4 drug-related pneumonitis, and no

drug-related deaths • Antitumour activity

– DCR at 12 weeks of 42%; ORR of 16%; activity observed in both squamous and non-squamous histologies

– ORR: PD-L1+, 23%; PD-L1–, 5% – 66% of patients have ongoing response (duration: 0.1+ to 54.4+ weeks)

• Preliminary OS data are encouraging; patients with PD-L1+ tumours appear to have improved OS compared with those with PD-L1– tumours

• Action on biomarkers is indicative of immune activation in patients with NSCLC – Increased levels of peripheral Th1-associated cytokines and chemokines and an increase in

CD8+ TILs • Current experience supports the accelerated development of durvalumab in NSCLC: pivotal

monotherapy studies are ongoing, as is a combination study with tremelimumab

Study 1108: NSCLC cohort

Rizvi N, et al. Poster presented at ASCO 2015. Poster 8032

Phase 3 anti PD1/PD-L1 Combination Trials in First-Line Advanced NSCLC (>10’000 patients)

Durvalumab MYSTIC

Atezolizumab Impower 110

Ant

i-PD

-1/P

D-L

1

Nivolumab CHECKMATE 227

Primary endpoints: OS, PFS

Nivolumab

Nivolumab + ipilimumab

Platinum-based chemotherapy

Treatment-naïve or recurrent NSCLC N=1980

Atezolizumab

Gemcitabine + cisplatin or carboplatin

Primary endpoint: PFS

Stage IV squamous PD-L1+ NSCLC N=400

Atezolizumab + carboplatin + paclitaxel

Bevacizumab + paclitaxel + carboplatin

Primary endpoint: PFS

Atezolizumab + bevacizumab + paclitaxel + carboplatin

Stage IV non-squamous NSCLCN=1200

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint: PFS

Stage IV non-squamous NSCLCN=550

Atezolizumab

Carboplatin or carboplatin + pemetrexed

Primary endpoint: PFSStage IV non-squamous PD-L1+ NSCLC N=400

Atezolizumab + carboplatin + nab-paclitaxel

Carboplatin + nab-paclitaxel

Primary endpoint: PFSAtezolizumab + carboplatin + paclitaxel

Stage IV squamous NSCLCN=1200

Primary endpoint: PFS

Durvalumab

Durvalumab + tremelimumab

SOC chemotherapy

Advanced NSCLC N=675

Durvalumab NEPTUNE

Durvalumab + Tremelimumab

SOC chemotherapy

Primary endpoint: OS

First-line metastatic NSCLC N=800

Atezolizumab Impower 111

Atezolizumab Impower 130

Atezolizumab Impower 131

Atezolizumab Impower 150

Pembrolizumab KEYNOTE-189

Primary endpoints: PFS

Pembrolizumab + pemetrexed/platinum

Pemetrexed/platinum

Treatment-naïve non-squamous NSCLCN=580

NivolumabCHECKMATE 026

Nivolumab 3 mg/kg IV Q2W

ICCa with potential for crossoverPrimary endpoint:

PFS

Treatment-naïve non-squamous NSCLC PD-L1–positive NSCLC

N=495

Pembrolizumab KEYNOTE-042

Pembrolizumab 200 mg IV Q3W

SOC chemotherapy

Treatment-naïve non-squamous NSCLC PD-L1–positive NSCLC

N=1240

Primary endpoint: OS

o Οι Immune checkpoint αναστολείς (ανοσοθεραπεία) αποτελούν νέα κατηγορία παραγόντων, µε σηµαντικές υποσχέσεις για τη θεραπεία του NSCLC.

o Πολλοί anti-PD1 /PDL1 παράγοντες βρίσκονται υπό µελέτη για το NSCLC

o Οι Immune checkpoint αναστολείς έχουν µια ιδιαίτερη τοξικότητα, που θα πρέπει να την λαµβάνουµε υπ όψιν.

Περίληψη

Ερωτήµατα

➢ Anti- PD1 έναντι Anti-PDL1;

➢ Ιδανικό σχήµα – διάρκεια θεραπείας ;

➢ Έκφραση PDL1 θα οδηγήσει σε θεραπεία;

➢ Διαδοχική / θεραπεία συντήρησης;

➢ Άριστοι συνδυασµοί;

➢ Ρόλος σαν adjuvant θεραπεία;

➢ Μηχανισµός αντίστασης;

➢ Βιοδείκτες……..

Σας ευχαριστώ