Thoracic malignancies other than NSCLC

Rolf StahelUniversity Hospital of Zürich

1 |

Amsterdam, 26.5.2017

Emerging new approaches to SCLC2 |

Bunn, JTO 2016

DDL33 |

Kume J Angiogen Res 2009; Saunders , Science Transl Med 2015

• DLL 3 localized in Golgi apparatus

• DLL 3 inhibits Notch activation• DLL 3 may mediate Notch

inhibition by ASCL1 (criticaltranscription factor forpulmonary neuroendocrinecancer

• DLL 3 is overexpressed in SCLC and LCNES

• An attractive target!

Safety and activity of rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate in SCLC

4 |

Data available as of July 2015 included 79 patients (34 q3w and 45 q6w) with a median age of 62 years (range 44–81)

The dose of 0.3 mg/kg q6w was selected as the recommended phase 2 dose

Pietanza, ECC 2015

Preclinical activity of rovalpituzumab tesirine5 |

• Efficacy in DDL+ cell lines

• Sustainable response in PDX model (somewhat moreimpressive than chemotherapy)

• Efficacy in PDX modelof refractory SCLC

Saunders L, Science Transl Med 2015

Rovalpituzumab tesirine, a DLL3-targeted antibody-drugconjugate, in recurrent SCLC: a first-in-human, first-in-class, open-label, phase 1 study

6 |

Rudin, Lancer Oncol 2017

•Main adverse events grade III/IV: •Fatigue (5%)•Thrombocytopenia (15%)•Rash (5%)•Edema (3%)

Main adverse events grade III/IV:

•Fatigue (5%)•Thrombocytopenia(15%)•Rash (5%)•Edema (3%)

Outcome and biomarker analysis from a multicenter phase 2 study of ipilimumab in combination with carboplatin and etoposide as first-Line therapy for extensive-Stage SCLC

7 |

Ariola, JTO 2016

Autoantibody analysis correlates withtreatment benefitand toxicity andwarrants further investigation

PD-L1 expression by two complementary diagnostic assaysand mRNA in situ hybridization in SCLC

8 |

Yu, JTO 2017

Vogelstein, Science 2013;

Lawrence, Nature, 2013

NSCLC and SCLC display many more

mutations than average, with~200

nonsynonymous mutations per

tumor.

Lung cancers from smokers have 10

times as many somatic mutations

as those from nonsmokers.

What about other thoracic

malignancies?

Ipilimumab in ED SCLC (anti-CTLA4 monoclonal antibody)10 |

Reck, Annals Oncol 2013

Ipilimumab in ED SCLC11 |

N = 1132Chemo naïvePlatinum/etoposide+/- ipilimumab/placebo 10mg/kg x4 (cycle 3-6)�ipi/placebo maintenance every 12 w

No difference in OS (11 vs 10.9 mos)No difference in PFS (4.6 vs 4.4 mos)

Anti-CTLA-4 antibody plus chemotherapy does NOT WORK

Reck, JCO 2016

KEYNOTE-028 Pembrolizumab SCLC cohort12 |

Ott, ASCO 2015

Ongoing clinical trials13 |

Keynote 068/EORTC 1416

Nivolumab alone and nivolumab plus ipilimumab in recurrentSCLC (CheckMate 032): a multicentre, open-label, phase 1/2 trial

14 |

Antonia, Lancet Oncol, 2016

RR 10% RR 23%

RR 10%

RR 19%

Nivolumab alone and nivolumab plus ipilimumab in recurrentSCLC (CheckMate 032): a multicentre, open-label, phase 1/2 trial

15 |

Antonia, Lancet Oncol, 2016

Nivolumab alone and nivolumab plus ipilimumab in recurrentSCLC (CheckMate 032): a multicentre, open-label, phase 1/2 trial

16 |

Antonia, Lancet Oncol, 2016

Ongoing clinical trials17 |

STIMULI: SCLC LD amended protocol18 |

Chemo-Radiotherapy:

cis-/carboplatin + etoposide 4 cycles

Biomaterial for translational research:

Consolidation vs observation:

induction maintenance

max 1 year

combination nivolumabnivolumab/ipilimumab

observation

Screening:

LD SCLC PCI

Tumourevaluation:

PD

off

Voluntary re-biopsy: → FFPE block

yes

noR

• • •

3 6 9 3 6 9 1812after randomisation

RT (Thoracic Radiotherapy) : CT scans for tumour assessmentaccelerated schedule preferred - up to 18 months: every 9 weeksstart: day 1 of chemo cycle 1 or - up to 2 years: every 12 weeks

day 1 of chemo cycle 2 - years 3 & 4: every 6 months- at 5 years

0Week

Serum

At progression:

Whole blood Whole bloodWhole blood

RT

RT

from start of chemotherapy-2

CT

Serum SerumSerum

FDG-PET-CTor CT

Brain MRI or CT

Biopsy: FFPE block

or slides

27 ···

CT • • •

14 16

Study design:Multicentre, open label, randomized phase II trial, ETOP sponsored, collaboration with IFCT and other trial groups

Primary objectives:

PFS and OS

Sample size:

260 randomized patients

Targeting mesothelin with monoclonal antibodies and immunoconjugates

• Amatuximab, a chimeric monoclonal antibody• Combination with cisplatin/pemextrexed:• PRs in 33/89 (40%) and SD in 42 (51%). • Six month-PFS rate was 51%,

median PFS 6.1 months (95% CI: 5.8, 6.4)Hassan, CCR 2014

• Immunotoxin SS1P (Recombinant antibody FV and pseudomonas exotoxin)• Phase I single agent 4/33 minor responses. Neutralizing antibodies and

dose-limiting capillary leak.Weldon, Mol Cancer Therapeutics 2013

19 |

Targeting mesothelin with monoclonal antibodies and immunoconjugates

• Ametumab ravtansine (maytansinoid tubulin inhibitor)

• Preclinical activity in mesotheliomaGolfier, Mol Cancer Ther 2014

• Phase I in patients with metastatic mesotheliomaHassen, WCLC 2015

20 |

Phase 3 trial anetumab ravtansine plus pemetrexed and cisplatin in firstline malignant pleural mesothelioma

21 |

PD-L1 expression in malignant pleural mesothelioma22 |

Mansfield et al 1 Cedrés et al 2 Thapa et al 3 Combaz-Lair 4

No. of patients 106 77 311 58

Antibody used5H1-A3- mouse

monoclonal E1L3N- Rabbit IgG

(cell signalling)E1L3N- Rabbit IgG

(cell signalling)E1L3N- Rabbit IgG

(cell signallingCriteria of positivity

>5% membranous and/or cytoplasmic

staining

≥ 1% membranous and/or cytoplasmic

staining

>5% membranous staining

≥ 1% membranous and/or cytoplasmic

stainingPD-L1 positivity

All40% 20.7% 41.7% 29%

Epitheloid 33% 20% 33% 23%

Non-epitheloid 38% 73% 42%* 37%

1Mansfield, JTO 2014, 2Cedres, Plos One 2015, 3Thapa, ASCO 2016, 4Combaz-Lair, Human Pathol 2016

*Strong positivity predominantly in non-epitheloid tumors

Mesothelioma – mutational load23 |

Bueno, Nat Gen 2016

• Whole-exome sequencing on DNA from 22 MPMs and matched blood samples. Identification of 517 somatic mutations across 490 mutated genes

• Mesothelioma contain an average of 24 protein coding alteration per sample, a rate considerably lower than other types malignancies

T-cell inflamed microenvironment by tumor entity across TCGA solid tumors

24 |

Slide 6

Luke, ASCO 2016

Tremelimumab in second or third line versus placebo in malignant mesothelioma

25 |

Kindler ASCO 2016

Summarizing available results on immune checkpointinhibitors

26 |

Study Keynote-028 PD-L1+

NivoMesUnselected

AvelumabUnselected

Patient Number 25 18 53

PR 7 (28%) 5 (27%) 5 (9.4%)

SD 12 (48%) 4 (22%) 27 (47.2%)

PD 4 (16%) 9 (50%) 18 (34%)

Not assessed 2 (8%)

Level of PD-L1 expression in Keynote-028 did not correlate with responseBoth PD-L1 positive and negative patients responded to AvelumabResponse to Avelumab was not associated with TIL or tumour PD-L1 staining

Avelumab in mesothelioma cohort pretreated withplatin/pemetrexed

27 |

Hassan, ASCO 2016

MAPS-2 phase II trial in mesothelioma28 |

PROMISE-meso: Pembrolizumab in advanced pretreated malignant pleural mesothelioma

29 |

Study design:• Multicentre, randomised, phase

III trial, ETOP sponsored

Primary objectives:• To assess safety and efficacy of

pembrolizumab versus standard chemotherapy in MPM

Primary endpoint:• Progression-free survival (based

on independent radiological review)

Sample size:• 142 randomized patients

Malignant pleural mesotheliomaafter/on one previous line of

chemotherapy

1 : 1R

Pembrolizumab 200mg fixed dose i.v. day 1 of each 3-week cycle

Chemotherapy by institutional choiceGemcitabine 1000 mg/m2 d1/d8, q3w i.v. orVinorelbine 30 mg/m2 d1/d8, q3w i.v. orVinorelbine 60 mg/m2 d1/d8 q3w p.o.

• • •

CTCT

3Week 6 9 18 270≤-4 39

• • •

until PD by irRECIST,for max 2 years

Blood

FFPE

Blood

Microbiologysamples

Microbiologysamples

Blood

Microbiologysamples

CT CT CT CT

Progression of

disease

(FFPE)

Progression of

disease

CA209-743 : A phase III, randomized, open label trial of nivolumab in combination with Ipilimumab versus pemetrexed with cisplatin or carboplatin as first line therapy in unresectable pleural mesothelioma

30 |

ClinicalTrials.gov Identifier: NCT02899299

Study design:

Pembrolizumab in thymic carcinoma

• Phase 2 trial• Key results:

RR 24% (30 patients)• Median PFS 36 weeks• Grade 3/4 toxicities:

4 patients, including severe myositis and myocarditis,and type 1 diabetes

31 |

Giaccone, ASCO 2016

Avelumab in thymic carcinoma

• PRs 4/8 patients• Grade 4/4 toxicities in 5/8 patients

32 |

Rajan WCLC, Heery Lancet Oncol 2017

NIVOTHYM: nivolumab in patients with thymic carcinoma previously treated with chemotherapy

33 |

Study design: Multicentre, single arm, phase II trial, EORT sponsoredPrimary objectives: To assess the PFS rate of nivolumab a 6 months Patient selectiion: Relapsed/advanced thymiccarcinoma and type B3 thymomSample size: Two stage design, with safertyassessment after 10 pts randomized patients

Thomas Hart BentonAmerica Today