Thoracic malignancies other than NSCLC

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1 1 Thoracic malignancies other than NSCLC Rolf Stahel University Hospital of Zürich Amsterdam,

2 2 Emerging new approaches to SCLC Bunn, JTO 2016

3 DDL3 DLL 3 localized in Golgi apparatus DLL 3 inhibits Notch activation DLL 3 may mediate Notch inhibition by ASCL1 (critical transcription factor for

3 3 DDL3 DLL 3 localized in Golgi apparatus DLL 3 inhibits Notch activation DLL 3 may mediate Notch inhibition by ASCL1 (critical transcription factor for pulmonary neuroendocrine cancer DLL 3 is overexpressed in SCLC and LCNES An attractive target! Kume J Angiogen Res 2009; Saunders, Science Transl Med 2015

4 Safety and activity of rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate in SCLC Data available as of July 2015 included

4 4 Safety and activity of rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate in SCLC 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

$model of refractory SCLC Saunders L,$

5 5 Preclinical activity of rovalpituzumab tesirine Efficacy in DDL+ cell lines Sustainable response in PDX model (somewhat more impressive than chemotherapy) Efficacy in PDX model of refractory SCLC Saunders L, Science Transl Med 2015

6 Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent SCLC: a first-in-human, first-in-class, open-label, phase 1 study Main adverse events grade

6 6 Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent SCLC: a first-in-human, first-in-class, open-label, phase 1 study 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%) Rudin, Lancer Oncol 2017

7 7 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 Autoantibody analysis correlates with treatment benefitand toxicity and warrants further investigation Ariola, JTO 2016

8 8 PD-L1 expression by two complementary diagnostic assays and mrna in situ hybridization in SCLC Yu, JTO 2017

9 NSCLC and SCLC display manymore mutations thanaverage, with~200 nonsynonymousmutations per tumor. Lung cancers fromsmokershave 10 times as manysomaticmutations as those from nonsmokers. What about other thoracic malignancies? Vogelstein, Science 2013; Lawrence, Nature, 2013

10 10 Ipilimumab in ED SCLC (anti-ctla4 monoclonal antibody) Reck, Annals Oncol 2013

11 11 Ipilimumab in ED SCLC N = 1132 Chemo naïve Platinum/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

12 12 KEYNOTE-028 Pembrolizumab SCLC cohort Ott, ASCO 2015

13 13 Ongoing clinical trials Keynote 068/EORTC 1416

14 14 Nivolumab alone and nivolumab plus ipilimumab in recurrent SCLC (CheckMate 032): a multicentre, open-label, phase 1/2 trial RR 10% RR 23% RR 19% RR 10% Antonia, Lancet Oncol, 2016

15 15 Nivolumab alone and nivolumab plus ipilimumab in recurrent SCLC (CheckMate 032): a multicentre, open-label, phase 1/2 trial Antonia, Lancet Oncol, 2016

16 16 Nivolumab alone and nivolumab plus ipilimumab in recurrent SCLC (CheckMate 032): a multicentre, open-label, phase 1/2 trial Antonia, Lancet Oncol, 2016

17 17 Ongoing clinical trials

18 18 STIMULI: SCLC LD amended protocol Screening: LD SCLC FDG-PET-CT or CT Brain MRI or CT Chemo-Radiotherapy: cis-/carboplatin + etoposide 4 cycles Biomaterial for translational research: Serum Whole blood Biopsy: FFPE block or slides RT RT PCI Tumour evaluation: yes PD off no R induction combination nivolumab/ipilimumab observation Consolidation vs observation: from start of chemotherapy after randomisation Week CT RT (Thoracic Radiotherapy): CT scans for tumour assessment accelerated schedule preferred - up to 18 months: every 9 weeks start: 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 Serum Whole blood Serum Whole blood maintenance nivolumab CT max 1 year At progression: Serum 27 Voluntary re-biopsy: FFPE block 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

19 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%).

19 19 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

20 20 Targeting mesothelin with monoclonal antibodies and immunoconjugates Ametumab ravtansine (maytansinoid tubulin inhibitor) Preclinical activity in mesothelioma Golfier, Mol Cancer Ther 2014 Phase I in patients with metastatic mesothelioma Hassen, WCLC 2015

21 21 Phase 3 trial anetumab ravtansine plus pemetrexed and cisplatin in first line malignant pleural mesothelioma

22 22 PD-L1 expression in malignant pleural mesothelioma No. of patients Mansfield et al 1 Cedrés et al 2 Thapa et al 3 Combaz-Lair Antibody used 5H1-A3- mouse monoclonal E1L3N- Rabbit IgG (cell signalling) E1L3N- Rabbit IgG (cell signalling) E1L3N- Rabbit IgG (cell signalling Criteria of >5% membranous 1% membranous 1% membranous >5% membranous positivity and/or cytoplasmic and/or cytoplasmic and/or cytoplasmic staining staining staining staining PD-L1 positivity All 40% 20.7% 41.7% 29% Epitheloid 33% 20% 33% 23% Non-epitheloid 38% 73% 42%* 37% *Strong positivity predominantly in non-epitheloid tumors 1 Mansfield, JTO 2014, 2 Cedres, Plos One 2015, 3 Thapa, ASCO 2016, 4 Combaz-Lair, Human Pathol 2016

23 23 Mesothelioma mutational load 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 Bueno, Nat Gen 2016

24 24 T-cell inflamed microenvironment by tumor entity across TCGA solid tumors Slide 6 Luke, ASCO 2016

25 25 Tremelimumab in second or third line versus placebo in malignant mesothelioma Kindler ASCO 2016

26 26 Summarizing available results on immune checkpoint inhibitors Study Keynote-028 PD-L1+ NivoMes Unselected Avelumab Unselected Patient Number 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 response Both PD-L1 positive and negative patients responded to Avelumab Response to Avelumab was not associated with TIL or tumour PD-L1 staining

27 27 Avelumab in mesothelioma cohort pretreated with platin/pemetrexed Hassan, ASCO 2016

28 28 MAPS-2 phase II trial in mesothelioma

29 29 Malignant pleural mesothelioma after/on one previous line of chemotherapy Progression of disease PROMISE-meso: Pembrolizumab in advanced pretreated malignant pleural mesothelioma R Pembrolizumab 200mg fixed dose i.v. day 1 of each 3-week cycle 1 : 1 Chemotherapy by institutional choice Gemcitabine 1000 mg/m 2 d1/d8, q3w i.v. or Vinorelbine 30 mg/m 2 d1/d8, q3w i.v. or Vinorelbine 60 mg/m 2 d1/d8 q3w p.o. Week CT FFPE Blood Microbiology samples Blood Microbiology samples CT CT CT CT Progression of disease CT (FFPE) Blood Microbiology samples until PD by irrecist, for max 2 years 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

30 30 CA : 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 Study design: ClinicalTrials.gov Identifier: NCT

31 31 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 Giaccone, ASCO 2016

32 32 Avelumab in thymic carcinoma PRs 4/8 patients Grade 4/4 toxicities in 5/8 patients Rajan WCLC, Heery Lancet Oncol 2017

33 NIVOTHYM: nivolumab in patients with thymic carcinoma

single arm, phase II trial, EORT sponsored Primary objectives: To

Relapsed/advanced thymic carcinoma and type B3 thymom Sample

33 33 NIVOTHYM: nivolumab in patients with thymic carcinoma previously treated with chemotherapy Study design: Multicentre, single arm, phase II trial, EORT sponsored Primary objectives: To assess the PFS rate of nivolumab a 6 months Patient selectiion: Relapsed/advanced thymic carcinoma and type B3 thymom Sample size: Two stage design, with saferty assessment after 10 pts randomized patients

34 Thomas Hart Benton America Today

Weitere Kombinationspartner der Immunotherapie

1 Weitere Kombinationspartner der Immunotherapie Rolf Stahel University Hospital of Zürich Zürich, 9.12.216 2 Immunotherapy in a multimodality approach NSCLC Advanced disease Checkpoint inhibitors for