Weitere Kombinationspartner der Immunotherapie

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1 1 Weitere Kombinationspartner der Immunotherapie Rolf Stahel University Hospital of Zürich Zürich, Immunotherapy in a multimodality approach NSCLC Advanced disease Checkpoint inhibitors for patients with tumors with 5 % PD-L1 expression Checkpoint inhibitors combined with chemotherapy I-O combinations Earlier staged of disease SCLC 1

2 3 Nivolumab for first line treatment of advanced NSCLC Response rate: All 23% PD-L1 5%: 5% PD-L1 5%: 31% PD-L1 < 5%: 15% PD-L1 < 1% 14% Gettinger, JCO Results in treatment naïve patients with advanced NSCLC enrolled in KEYNOTE-1 Hui, ASCO 216 2

3 5 KEYNOTE-24: Pembrolizumab vs platinum-based chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 TPS 5% Reck, ESMO KEYNOTE-24: Pembrolizumab vs platinum-based chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 TPS 5% Reck, ESMO 216 3

4 7 KEYNOTE-24: Pembrolizumab vs platinum-based chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 TPS 5% Reck, ESMO KEYNOTE-24: Pembrolizumab vs platinum-based chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 TPS 5% Reck, ESMO 216 4

5 9 Chemotherapy combination trials GP28328 PhIb solid tumours (incl. 1L NSCLC) atezo + chemo (n=58) KEYNOTE-21 PhI/II 1L NSCLC pembro + chemo (n=49) CheckMate 12 PhI 1L NSCLC nivo (N) + chemo (n=56) CheckMate 12 PhI 1L NSCLC nivo (N) + ipi (I) (n=49) Atezo + carbo/ pac Atezo + carbo/ pem Atezo + carbo/ abrax Pembro + carbo/ pac Pembro + carbo/ pem N1 + gem/ cis N1 + pem/ cis N1 + carbo/ pac N5 + carbo/ pac N1 q3w + I1 q3w N1 q2w + I1 q6w N3 q2w + I1 q12w N3 q2w + I1 q6w n 1 8* 17* 16* ORR, % % 35% 45% Grade 3 4 treatmentrelated AEs 71% 54% 85% 32% 38% 25% 47% 73% 29% 29% 35% 29% 28% Refs. Camidge, et al. WCLC 215 Giaccone, et al. ECC 215 Papadimitrakopoulos, et al. ASCO 215 Gettinger, et al. ESMO 214 Rizvi, et al. WCLC Randomized phase-2 study of carboplatin and pemetexed with or without pembrolizumab as first line therapy of advancec NSCLC: Keynote-21 Cohort G Langer, ESMO 216 5

6 11 Randomized phase-2 study of carboplatin and pemetexed with or without pembrolizumab as first line therapy of advancec NSCLC: Keynote-21 Cohort G Langer, ESMO Randomized phase-2 study of carboplatin and pemetexed with or without pembrolizumab as first line therapy of advancec NSCLC: Keynote-21 Cohort G Langer, ESMO 216 6

7 13 CTLA-4 versus PD-1 Ribas, NEJM 2 14 Phase 1 CheckMate 12 study design: First-line nivolumab ± ipilimumab in NSCLC Stage IIIB/IV NSCLC (any histology), no prior chemotherapy for advanced disease, ECOG PS or 1 Nivolumab 3 mg/kg IV Q2W a Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q12W b Nivolumab 3 mg/kg IV Q2W + Ipilimumab 1 mg/kg IV Q6W b Until disease progression c or unacceptable toxicity Primary endpoint: safety and tolerability Secondary endpoints: ORR (RECIST v1.1) and PFS rate at 24 weeks assessed by investigators Exploratory endpoints: OS, efficacy by PD-L1 expression Updated data d presented here are based on median follow-up durations of 22 months (monotherapy) and 16 months (combination cohorts) Overall additional follow-up relative to previous reports: monotherapy, +~18 months; 1 combination cohorts, +6 months 2 ClinicalTrials.gov number NCT145412; a Treatment allocation not randomized; b Treatment allocation randomized; earlier cohorts evaluated other dosing schedules/regimens 2 c Patients tolerating study treatment permitted to continue treatment beyond RECIST v1.1-defined progression if considered to be deriving clinical benefit d Based on a September 216 database lock 1. Gettinger S, et al. J Clin Oncol 216;34: ; 2. Hellmann MD, et al. Lancet Oncol 216 Dec 5. [Epub ahead of print]. Gettinger, WCLC 216 7

8 15 Phase 1 CheckMate 12 response rate by tumor PD-L1 expression: Hellmann, Lancet Oncol Phase 1 CheckMate 12 PFS by tumor PD-L1 expression: Nivo 3 Q2W + Ipi 1 Q6/12W PFS (%) All treated patients (n = 77) 1% PD-L1 (n = 46) 5% PD-L1 (n = 13) Median 8. months (95% CI 4.1, 13.2) Median 12.7 months (95% CI 7.8, 23.) Median NR (95% CI 7.8, NR) Nivo 3 Q2W PFS (%) All treated patients (n = 52) 1% PD-L1 (n = 32) 5% PD-L1 (n = 12) Median 3.6 months (95% CI 2.3, 6.6) Median 3.5 months (95% CI 2.2, 6.6) Median 8.3 months (95% CI 2.2, NR) Months Months Months Based on a September 216 database lock; NR = not reached Gettinger, WCLC 216 8

9 17 Phase 1 CheckMate 12 OAS by tumor PD-L1 expression: 1 All treated patients (n = 77) 1% PD-L1 (n = 46) 5% PD-L1 (n = 13) Nivo 3 Q2W + ipi 1 Q6/12W OS (%) year OS rate: 76% year OS rate: 87% year OS rate: 1% All treated patients (n = 52) 1% PD-L1 (n = 32) 5% PD-L1 (n = 12) Nivo 3 Q2W OS (%) year OS rate: 73% 1-year OS rate: 69% 1-year OS rate: 83% Months Months Months Data are based on median follow-up durations of 16 months (combination cohorts) and 22 months (monotherapy) Based on a September 216 database lock 17 Gettinger, WCLC Phase 1 CheckMate 12 treatment related adverse events: Grade 1 2 Grade 3 4 Patients with an event, % Nivo 3 Q2W (n = 52) 2 2 Nivo 3 Q2W + Ipi 1 Q12W (n = 38) Nivo 3 Q2W + Ipi 1 Q6W (n = 39) 5 33 The safety profile of nivolumab plus ipilimumab with longer follow-up was similar to that reported previously 1 Based on a September 216 database lock; select AEs are those with potential immunologic etiology; a All treatment-related pulmonary events were pneumonitis; rxn = reaction 1. Hellmann MD, et al. Lancet Oncol 216 Dec 5. [Epub ahead of print]. Gettinger, WCLC 216 9

10 19 Phase IIIB/IV saftey trial of flat dose nivolumab in combination with ipilimumab in patients with advanced malignancies 2 A Phase 1/2a dose escalation and cohort expansion study for safety, tolerability, and efficacy of anti-gitr monoclonal antibody in combination with nivolumab in Advanced Solid Tumors Knee, EJC 216 1

11 21 A phase I study of immunotherapy with anti-lag-3 mononconal antibody alone and with nivolumab in patients with advanced solid tumors Anderson, Immunity Immunotherapy in a multimodality approach NSCLC Advanced disease Earlier staged of disease Combined immunotherapy and chemo-radiotherapy in stage III disease Surgery with neoadjuvant or adjuvant immunotherapy Multimodality therapy in oligometastatic disease SCLC 11

12 23 NICOLAS: Nivolumab in stage 3 Screening, eligibility and enrolment Country Centre Number of patients Stage IIIA / B NSCLC Whole body FDG-PET Investigator s choice chemo chemo chemo cycle 1 cycle 2 cycle 3 Radiotherapy Nivolumab: 36 mg every 3 weeks, 4 doses chemo chemo chemo cycle 1 cycle 2 cycle 3 Radiotherapy Nivolumab: 24mg every 2 weeks, 8 doses Nivolumab: 48mg every 4 weeks up to 1 year Spain Vall d Hebron, Barcelona 7 Switzerland University Hospital Zürich 5 Germany Thoracic Oncology Centre Münich 1 Netherlands VU University Medical Center Amsterdam 3 Belgium University Hospital Leuven -- Total 16 CT scans year 1: every 9 weeks, year 2: every 12 weeks, beyond 2 years: every 6 months until progression 24 Neoadjuvant nivolumab in early stage resectable NSCLC Newly diagnosed Resectable stage I (>2cm)/II/III A NSCLC (baseline research core biopsies) Screening Period (less than or equal to 28 days) Nivolumab 3mg/kg IV on Day 28 and Day 14 with repeat CT prior to planned surgical resection on Day Standard of Care Postoperative Treatment Primary Endpoint: Safety and feasibility Exploratory Endpoints: Percent pathologic regression, Radiographic response Changes induced by nivolumab in tissue and blood immune correlates Planned enrollment: 6 patient safety/feasibility run-in followed by expansion to a total enrollment of up to 2 resected patients. Any subjects not resected would be replaced. Subjects followed for safety for 3 days after surgery. Forde, ESMO

13 25 Neoadjuvant nivolumab in early stage resectable NSCLC 63yo M, ex-smoker, adeno, PD-L1 2%+, <1% viable tumor at resection 78yo F, ex-smoker, adeno, PD-L1 1%+, isolated tumor cells in a dense T cell infiltrate at resection Histopathologic Response (N=17)* (% residual viable tumor) % <1% 38 Forde, ESMO 216 Prenivo Postnivo Prenivo Postnivo 1-5% 13 >5% 5 Pathologic downstaging from Pre-treatment Clinical Stage (N=17)* *Only resected patients included for histopathologic response and downstaging exploratory analyses % Yes 39 No PEARLS: Phase III trial of adjuvant pembrolizumab in stages IB-III Co-primary Endpoints: DFS in the PD-L1 strong positive sub-group; DFS in the overall population Secondary endpoints: DFS in the PD-L1 positive population; OS in the PD-L1 strong positive subgroup OS in the PD-L1 positive population OS in the overall population LCSS 13

14 27 Oligometastatic NSCLC multimodality concept 3 mo restaging Mimimum SD Radical Tx of the primary Oligo-metastatic NSCLC Immunotherapy Chemotherapy SBRT to all oligo-metastatic sites PD Palliative CT Radical treatment of primary tumor: All patients are jointly informed about both options of radical surgery and radical RT If both options are possible as radical Tx Local Stage I to stage IIIA single station N2 Surgery preferred Local Stage IIIA multiple station N2 IIIB RCT preferred Special situations: Large necrotic primary: Resection preferred Pneumonectomy necessary: RCT preferred 28 Immunotherapy in a multimodality approach NSCLC Advanced disease Earlier stages of disease SCLC 14

15 29 Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 32): a multicentre, openlabel, phase 1/2 trial Patients with SCLC with progressive disease after 1 prior line of therapy, including a platinum based regimen in first line (unselected by PD L1 expression) (N = 183) RR 1% Nivolumab 3 mg/kg IV Q2W (n = 8) a Nivolumab 1 mg/kg + Ipilimumab 1 mg/kg IV Q3W for 4 cycles (n = 3) b Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg IV Q3W for 4 cycles (n = 47) c Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg IV Q3W for 4 cycles (n = 53) d Nivolumab 3 mg/kg IV Q2W RR 23% Primary objective: ORR per RECIST v1.1 Secondary objective: safety Exploratory objectives: PFS, OS, biomarker analysis Antonia, Lancet Oncol Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 32): a multicentre, open-label, phase 1/2 trial Antonia, Lancet Oncol

16 31 STIMULI: Immuntherapy after chemo-radiotherapy in LD SCLC (amendment 1) Chemo-Radiotherapy: Consolidation vs observation: Screening: cis-/carboplatin + etoposide 4 cycles Tumour evaluation: induction maintenance max 1 year LD SCLC RT RT PCI PD no yes off R combination nivolumab/ipilimumab observation nivolumab from start of chemotherapy after randomisation Week 27 FDG-PET-CT or CT CT CT Brain MRI RT (Thoracic Radiotherapy): CT scans for tumour assessment or CT 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 Biomaterial for translational research: At progression: Serum Whole blood Biopsy: FFPE block or slides Serum Co-primary endpoints: PFS & OS Sample Size: Whole blood Serum Whole blood 26 randomized patients Serum Voluntary re-biopsy: FFPE block 32 Cancer Immunogram Christian U. Blank et al. Science 216;352: