Small cell lung cancer:

Size: px

Start display at page:

Download "Small cell lung cancer:"

Maurice Quinn
5 years ago
Views:

1 Bogota, May 1, Small cell lung cancer: Rolf Stahel University Hospital of Zürich

3 3 Pathobiology of SCLC 1924 Oat cell carcinoma of the mediastinum (Bernard) 1961 Primary lung tumor (Watson) 1967 WHO entity 1968 Neurosecretory granules (Bensch) 1980 SCLC cell lines (Gazdar) 1981 Bombesin autocrine loop (Moody) p deletion (Wang-Peng) 1983 Monoclonal antibodies (Mulshine) 1985 Myc amplification (Nau) 1988 Rb mutation (Harbour) 1992 p53 mutation (Mitsudomi) 1994 Bcl-2 hyperexpression (Ikegaki) 2002 Mouse model by conditional inactivation of Rb and p53 (Meuwissen)

Meuwissen, Cancer Cell 2003 4 Induction of SCLC by somatic

4 Meuwissen, Cancer Cell Induction of SCLC by somatic inactivation of TP53 and Rb Neuroendocrine epithelial hyperplasia

5 5 Comprehensive genomic analysisof SCLC George, Nature 2015

6 Histology and immunohistochemistry Cancer cells stain positive for keratin, epithelial membrane antigen and TTF-1 Due to their neuroendocrine

6 6 Histology and immunohistochemistry Cancer cells stain positive for keratin, epithelial membrane antigen and TTF-1 Due to their neuroendocrine origin they usually stain + for at least one neuroendocrine marker, including chromogranin A, neuron specific enolase, NCAM (CD56) and synaptophysin

7 7 Effect of stage, PS and weight loss on SCLC survival based on early VA study group trials Stage (placebo controls): LD MST 11.7 weeks, ED 5.0 weeks Karnofsky status (placebo controls): Weight loss 10 lbs (ED, placebo controls): Present MST 13.1 weeks, absent MST 18.7 weeks Zelen, Cancer Chemotherapy Reports 1973

9 9 Staging and risk assessment Patients are usually staged according to a simple two-stage system developed by the Veteran's Administration Lung Cancer Study Group: Limited disease: The definition is based on the possibility of encompassing all detectable tumour within a 'tolerable' radiotherapy port. Extensive disease:...staging procedures should at least include the following: complete blood count, liver and renal function tests, LDH, sodium, and a CT-scan of chest and upper abdomen. Additional tests to define limited disease in patients with symptoms or abnormal physical examination suggesting metastasis are: a bone scintigraphy, a CT-scan of the brain, and a bone marrow biopsy. ESMO guidelines task force, Ann Oncol 2001

10 10 Treatment of limited disease SCLC Standard regimens, also for patients diagnosed at surgery, are either based on etoposide-platinum or cyclophosphamidedoxorubicin and should be given for 4 6 cycles [/, A]. Maintenance chemo- therapy does not result in any substantial improvement in survival [//, A]. Etoposide/cisplatin is widely regarded as state- of-the-art chemotherapy for limited disease, particularly because this regimen can be combined with concurrent irradiation without unacceptable toxicity [//. A]. ESMO guidelines task force, Ann Oncol 2001

11 11 Treatment of limited disease SCLC Chest radiotherapy increases local control and survival and should be given to all patients with limited disease. Several studies suggest to start thoracic radiotherapy early during chemotherapy [II-III. A]. Prophylactic cranial irradiation is indicated in patients with a complete remission from initially limited disease because it reduces the lifetime risk of cerebral metastases and improves survival [/A B]. ESMO guidelines task force, Ann Oncol 2001

12 12 Treatment of extensive disease SCLC Chemotherapy with the same regimens as for limited disease and given for 4-6 cycles also improves survival for patients with extensive disease and usually is the most effective way to ameliorate clinical symptoms [//, A].

13 13 How 4-6 cycles of chemotherapy became the strandard of care Significant difference in Pts. Cycles Regimen PFS OAS Cullen, /14 CAV N/A Yes Bleehan, /12 CMEV N/A No Spiro, /8 CEV Yes No Lebean, /12 LCAE Yes No Giaccone, /12 CAE Yes No Sculier, /6+12 IEA+EVi Yes No Bleehan, /6 CMEV No No

14 14 How platin and etoposide combination has become the standard chemotherapy Concomitant radiotherapy: Severe toxicity with CAV Outcome: ED similar survival PE and CAV Fukoda, 1991 Median survival (months) No. PE CAV CAV/PE Roth, Meta-analysis: 4% advantage in 1-year survival for platinum containing regimen Pujol, Lung Cancer 2000 LD: Survival advantage of PE over CEV Sundstrom, JCO 2002

15 15 Which progress between and ? Schabat, Lung Cancer 2014

17 17 Staging and risk assessment The prognosis of SCLC strongly depends on the tumour stage. The new tumour-node-metastasis (TNM) version 7 staging system according to the Union for International Cancer Control (UICC) as adopted for non-small-cell lung cancer should also be used for SCLC [I, A]. This classification should replace the former 1989 International Association for the Study of Lung Cancer (IASLC) staging system Früh et al, Ann Oncol 2013

18 18 Staging and risk assessment...an initial computed tomography (CT) scan with contrast of the chest and abdomen is recommended. If the metastatic stage is not obvious on the CT scan or clinical findings suggest bone or brain involvement, further imaging with bone scintigraphy and CT or magnetic resonance imaging (MRI) of the brain are recommended. In case of abnormal blood count or signs of blood bone marrow barrier rupture (e.g. peripheral blood erythroblasts), a bone marrow aspiration and biopsy may be indicated, particularly in patients with otherwise absent metastases [V, C]. Alternatively to CT and bone scintigraphy, a FDG-PET CT scan can be carried out. Früh et al, Ann Oncol 2013

19 19 SCLC survival according totnm stage 100% 80% 60% IA IB IIA IIB IIIA IIIB IV Deaths / N 17 / / 19 8 / / / / / 1439 Median in Months % 20% 0% Years After Enrollment

20 20 SCLC treatment algorithm Früh et al, Ann Oncol 2013

21 21 Treatment of Extensive Stage SCLC Platinum (cisplatin or carboplatin) and etoposide is standard chemotherapy (however no better survival vs CAV) Three-drug combinations or dose intensification have not improved results Highly responsive disease to 1 st line chemotherapy (60-80%) with rapid improvement of symptoms Prolonged chemotherapy administration and maintenance therapy beyond 4-6 cycles have not been shown to offer a survival advantage

22 22 Standard of care: cisplatinum-etoposide Meta-analysis 29 trials 5530 patients (LD, ED) Platinum vs. no platinum: no difference in 6, 12 or 24 month survival No difference OR rate Higher CR rate for platinum Higher toxicity rates with platinum Amarasena et al, Cochrane Library 2009

23 23 COCIS IPD meta-analysis: carboplatin vs. cisplatinbased chemotherapy In poor prognosis &/or ED-SCLC: Four eligible trials - total of 663 patients (329 cisplatin, 334 carboplatin) Median OS 9.6 months with cisplatin & 9.4 months with carboplatin (HR 1.08, 95% CI ; p = 0.69) Haematological toxicity was higher with carboplatin, and non-haematological toxicity was higher with cisplatin OS Key conclusion : no survival difference between cisplatin- and carboplatinbased CT in this setting Carbo - a reasonable alternative to cisplatin in patients with poor prognostic factors PFS Rossi, JCO 2012

24 24 Variations in dose and dose intensification Variable: Standard vs. Experimental Cumulative dose DI Number of cycles Dose per cycle Interval between cycles No survival benefit No survival benefit modest survival benefit Thatcher, JCO 2000 Ý Ý = = Ý Ý Courtesy Corinne Faivre-Finn, 2016

25 25 New chemotherapy combinations in SCLC Study Target Drug Design Result JCOG 9511 SWOG 0124 HOG S0124 Topoismerase Irinotecan PE vs PI* PE vs PI PE vs P PE vs PI Positive Negative Negative Negative Socinski TS Pemetrexed PE vs Pem Negative Von Pawel Topoisomerase Topotecan Topo vs CAV Positive O Brien Topoisomerase Topotecan Topo vs BSC Positive Fink Topoisomerase Topotecan PE vs TE Negative SPEAR Platinum Picoplatin Pico vs BSC Negative EORTC Anthracycline Amrubicin Amb vs AmbC vs PE Negative *Jiang et al. JTO 2010 meta-analysis PI not inferior to PE.but not better Courtesy Corinne Faivre-Finn, 2016

26 26 New chemotherapy combinations in SCLC: Antiangiogenics Study Target Agent Design Result NCI- C/EORTC BAYER ECOG CALGB HOG LLCG MMP Marimastat BAY /- Maintenance +/- Maintenance VEGF BEV (B) Chemo + B Chemo + B Chemo + B Vascular stabilizer Thalidomide Chemo +/- T Negative Negative Positive Negative Negative Negative NCI-C VEGFR TKi ZD /- Maintenance Negative SWOG VEGFR TKi Sorafenib Monotherapy Negative NCI VEGFR TKi ZD 2171 Monotherapy Negative Courtesy Corinne Faivre-Finn, 2016

27 27 New chemotherapy combinations in SCLC: targeted therapy Study Target Drug Design Result Rudin Bcl-2 Oblimersen Chemo +/- Negative Langer Bcl-2 Obatoclax Chemo +/- Negative ECOG mtor CCI-779 +/- Maintenance Negative HOG EGFR gefitinib Monotherapy Negative Johnson Krug Dy Kit Imatinib Monotherapy Monotherapy Monotherapy Negative Negative Negative EORTC GD-3 BEC2/BCG +/- Maintenance Negative SWOG Proteosome Bortezomib Monotherapy Negative SWOG RAS/VEGF Sorafenib Monotherapy Negative Courtesy Corinne Faivre-Finn, 2016

28 28 PCI in ED SCLC HR 0.27 HR 0.68 Slotman, NEJM 2007

29 29 Thoracic radiotherapy for extensive SCLC: the CREST study ES-SCLC, WHO PS 0-2, no upper age limit 4-6 platinum-based chemotherapy Stratification: Centre Presence of intrathoracic disease RANDOMIZE Any response TRT (30 Gy in 10 Fr) PCI No TRT PCI Slotman. Lancet 2014

30 30 Thoracic radiotherapy for extensive SCLC: the CREST study 24 months (95% CI) Thoracic RT : 13 ( ) No Thoracic RT : 3 ( ) p=0 004 Median follow up 24 months Survival 18 Months: p= Months: p= months (95% CI) Thoracic RT : 33% (27 39 ) No Thoracic RT : 28% (22 34) HR = 0.84 (95%CI ) p=0.066 Grade 3+ toxicity<5% Slotman. Lancet 2014

31 Turrisi et al. N Engl J Med Standard chemo-radiotherapy for limited stage SCLC Once daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 Limited Stage Small Cell Lung Cancer RT 45Gy/33D/25F Twice daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 CR PCI If<CR No PCI Registration RT 45Gy/19D/30F Randomisation Restage Chemotherapy (PE) Radiotherapy

OD XRT C O N V E R T BD Limited Stage Small

0-2 No age limit CONVERT STUDY Once daily

SD, PR,CR PCI If<SD No PCI The Christie NHS

32 OD XRT C O N V E R T BD Limited Stage Small Cell Lung Cancer Registration Randomisation PS 0-2 No age limit CONVERT STUDY Once daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 RT 66Gy/45D/33F Twice daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 RT 45Gy/19D/30F Restage Chemotherapy Radiotherapy SD, PR,CR PCI If<SD No PCI The Christie NHS Foundation Trust

33 33 Emerging new approaches to SCLC Bunn, JTO 2016

34 NSCLC and SCLC display many more mutations than average, with~200 nonsynonymousmutations per tumor. Lung cancers from smokers have 10 times as many somatic mutations as those from nonsmokers. What about other thoracic malignancies? Vogelstein, Science 2013; Lawrence, Nature, 2013

35 Ott, ASCO KEYNOTE-028 Pembrolizumab SCLC cohort (second or later line)

36 Immune checkpoint inhibitors: combined ipilimumab and nivolumab (second line) Nivolumab 3 Nivolumab 1 + Ipilimumab 3 150 <1% PD-L1 150 <1% PD-L1 125 1% PD-L1 Not evaluable 125 1% PD-L1 Not

36 36 Immune checkpoint inhibitors: combined ipilimumab and nivolumab (second line) Nivolumab 3 Nivolumab 1 + Ipilimumab <1% PD-L1 150 <1% PD-L % PD-L1 Not evaluable 125 1% PD-L1 Not evaluable Best Reduction From Baseline in Target Lesion (%) Confirmed responders Confirmed responders Evaluable samples (52 of 127) PD-L1 expression level, n (%) <1% 1% Nivolumab 3 (n = 24) 17 (70.8) 7 (29.2) Nivolumab 1 + Ipilimumab 3 (n = 28) 20 (71.4) 8 (28.6) Calvo, ESMO ECCO 2015

37 37 Immune checkpoint inhibitors: combined ipilimumab and nivolumab Calvo, ESMO ECCO 2015

38 38 Ongoing clinical trials Keynote 068/EORTC 1416

39 39 Ongoing clinical trials

40 STIMULI: SCLC LD amended protocol Study design: Multicentre, open label, randomized phase II trial, ETOP sponsored, collaboration with IFCT and other trial groups Primary objectives: PFS and OS

40 40 STIMULI: SCLC LD amended protocol 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 Chemo-Radiotherapy: Consolidation vs observation: Screening: cis-/carboplatin + etoposide 4 cycles Tumour evaluation: induction maintenance max 1 year LD SCLC RT RT PCI yes PD off no R combination nivolumab/ipilimumab observation nivolumab Week from start of chemotherapy after randomisation FDG-PET-CT or CT CT CT Brain MRI or CT Biomaterial for translational research: 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 At progression: Serum Serum Serum Serum Whole blood Whole blood Whole blood Biopsy: FFPE block or slides Voluntary re-biopsy: FFPE block

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

41 41 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

42 Safety and activity of rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate in small cell lung cancer Data available as of July 2015

42 42 Safety and activity of rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate in small cell lung cancer 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

$Efficacy in PDX model of refractory SCLC Saunders L,$

43 43 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

44 Rubin, WLCC Targeting DLL3 in SCLC: Antibody drug conjugate rovalpituzumab tesirine Be st Re sponse (RECIST) Expression H- Score SCLC % High % Medium % Low % Unknown NA -60

45 45 Safety and activity of rovalpituzumab tesirine: Clinical efficacy 60 patients 20% RR 28 patients (DLL3+) 40% RR Second Line 38% RR Third Line Pietanza, ECC 2015

46 46 Safety and activity of rovalpituzumab tesirine: Response duration and tolerance Mean Duration of response: 182 days; dose 0.3 q 6 weeks Mean OS: (227days, dose 0.3 q 6 week) Main adverse events grade III/IV: Fatigue (5%) Thrombocytopenia (15%) Rash (5%) Edema (3%) Pietanza, ECC 2015

47 47 ETOP Name Project Title Presentation Zurich, July 27, 2009

Small cell lung cancer

Small cell lung cancer Prof C Faivre-Finn Manchester Lung Cancer Group Manchester Radiation Related Research Group 17 th ESO-ESMO Masterclass 25 th March 2018 Objectives Standard systemic treatment in