Checkpoint-Inhibitoren beim Lungenkarzinom Dr. Helge Bischoff Thoraxklinik Heidelberg
Survival (%) First-Line: Polychemotherapy vs 9387 patients 778 patients in studies with platinum chemotherapy 1-year surival benefit 1% Median survival benefit: 1.5 months (6 vs 8 months) Significant symptom reduction Best Supportive Care Meta-analysis of 52 randomized trials 1 8 6 4 2 Supportive care Supportive care plus chemotherapy 6 12 18 24 Time From Randomization (months) No. at Risk 416 219 98 47 28 362 125 55 28 16 Non-Small Cell Lung Cancer Collaborative Group. BMJ. 1995;311:899-99.
Metastatic Lung Cancer developments and challenges Reck et al. Lancet 382 (213): 79
RECIST 1.1 guidelines versus irrc guidelines
Verlauf nach 1. Applikation Nivolumab 9.1 27.1
9.1 3.1
Lungenkarzinom IV - Behandlungsempfehlungen Nichtkleinzelliges CA - Erstlinientherapie - Zweitlinientherapie - Mehrlinientherapie Kleinzelliges CA - Erstlinientherapie - Zweitlinientherapie - Mehrlinientherapie
CA184-41: Design of a Phase II trial to evaluate Ipilimumab in combination with chemotherapy* in NSCLC and SCLC 1st line First-line Stage IIIb/IV NSCLC (n=24) ED-SCLC (n=13) Induktion Erhaltung R A N D O M I Z E 1:1:1 Concurrent IPI + Pac/Carbo Phased* IPI + Pac/Carbo Control p + Pac/Carbo C C C C C C IPI IPI IPI IPI p p C C C C C C p p IPI IPI IPI IPI C C C C C C IPI IPI p IPI IPI p Follow-up Follow-up Follow-up * Paclitaxel/Carboplatin p p p p p p q3w q12w Lynch et al, J Clin Oncol 3: 246, Reck et al, Ann Oncol. 213; 24: 75 13
CA184-41: Phase II trial to evaluate Ipilimumab in combination with chemotherapy (carboplatin/paclitaxel) in lung cancer (NSCLC and SCLC): Immunrelated progression free survival Endpoints (months) Control Pbo + chemo. Concurrent IPI + chemo. Phased IPI + chemo. NSCLC 1 n=66 n=7 n=68 Median irpfs 4,6 Median mwho-pfs 4,2 5,5 (HR=,81, P=,13) 4,1 (HR=,88, P=,25) 5,7 (HR=,72, P=,5 a ) 5,1 (HR=,69, P=,2 a ) ED-SCLC 2 n=45 n=43 n=42 Median irpfs 5,3 Median mwho-pfs 5,2 5,7 (HR=,75, P=,11) 3,9 (HR=,93, P=,38) 6,4 (HR=,64, P=,3 a ) 5,2 (HR=,93, P=,37) Data support further evaluation of combination on a phased schedule 1,2 The safety profile was consistent with previous studies of Ipilimumab in other tumour types 1,2 Data from trial CA184-41 a Statistically significant per protocol-stipulated one-sided =.1; P values not adjusted for multiple comparisons HR = hazard ratio; Ipi = ipilimumab; irpfs = PFS by immune-related response criteria (irrc); mwho-pfs = PFS 14 y modified WHO criteria (mwho); Pbo = placebo; PFS = progression-free survival 1. Lynch et al, J Clin Oncol 212; 3: 246; 2. Reck et al, Ann Oncol 213; 24: 75
CA29-3: Design of a Phase I trial to evaluate Nivolumab monotherapy in different tumor types 8-week treatment cycle Rapid PD or clinical deterioration Off study Day 1 a 15 a 29 a 43 a 57 SCANS a Eligibility: Advanced NSCLC, melanoma, RCC, or CRC with PD after 1 5 systemic therapies Unacceptable toxicity CR/PR/SD or PD but clinically stable Follow-up every 8 weeks x 6 (48 weeks) Treat until confirmed CR, worsening PD, unacceptable toxicity, or 12 cycles (96 weeks) In this study, patients (n=36) with advanced NSCLC (n=129), melanoma (n=17), RCC (n=34), colorectal cancer (CRC; n=19), or castrate-resistant prostate cancer (CRPC; n=17) who were enrolled between October 28 and January 212 received Nivolumab,1 1 mg/kg every 2 weeks for a maximum of twelve 8-week treatment cycles Primary Objective: To evaluate the survival and long-term safety profile of patients being treated with Nivolumab Secondary Objective: Assess the efficacy of Nivolumab as monotherapy (Protocol was amended January 212 to evaluate overall survival (OS)) a Dose administered IV every 2 weeks; Hodi et al, Poster presentation at ECC 213:abstract 88 CR = 15 complete response; PD = progressive disease; PR = partial response; SD = stable disease
OS CA29-3: ASCO Update 214 Median OS according to dose (NSCLC) 1,,9,8,7,6,5,4,3,2,1, Zensiert OS Rate % ( 95 % KI) [Patienten unter Progressionsrisiko] Group Died/Treated Median OS (95% KI) 1-Jahr 2-Jahre 1 mg/kg 26/33 9,2 ( 5,3, 11,1) 32 (16,49) [8] 12 (3, 27) [2] 3 mg/kg 2/37 14,9 (7,3, ) 56 (38, 71) [17] 45 (27, 61) [9] 1 mg/kg 48/59 9,2 (5,2, 12,4) 4 (27, 52) [23] 19 (1, 31) [9] 1-year OS Rate 56% (17 patients at risk) 2-year OS Rate 45% (9 patients at risk) 3 6 9 12 15 18 21 24 27 3 33 36 39 42 45 48 51 54 57 Monate seit Behandlung Initiation Patienten unter Progressionsrisiko Nivolumab 1 mg/kg 33 26 21 16 8 6 5 5 2 1 Nivolumab 3 mg/kg 37 34 26 21 17 13 12 11 9 4 1 1 1 1 1 1 1 1 Nivolumab 1 mg/kg 59 51 35 29 23 16 14 12 9 4 3 2 2 2 1 Brahmer et al, oral presentation at ASCO 214 16
Nivolumab (Melanom, NSCLC, RCC) CA29-3: Clinical activity of Nivolumab Tumor Type ORR a n/n (%) [95% KI] Median Duration of Response, b wk (range) Stable Disease, n/n (%) [95% KI] 24 wk Median PFS, mo [95% KI] NSCLC c 22/129 (17,1) [11,, 24,7] 74, (6,1+, 133,9+) 13/129 (1,1) [5,5, 16,6] 2,3 [1,9, 3,7] Squamous 9/54 (16,7) [17,9, 29,3] NR d (16,1, 133,9+) 8/54 (14.8) [6,6, 27,1] 3,7 [1,8, 7,2] Non-squamous 13/74 (17,6) [9,7, 28,2] 63,9 (6,1+, 74,+) 5/74 (6,8) [2,2, 15,1] 2, [1,8, 3,6] MEL e 33/17 (3,8) [22,3, 4,5] 14, (18,4, 117,+) 7/17 (6,5) [2,7, 13,] 3,7 [1,9, 9,1] RCC e 1/34 (29,4) [15,1, 47,5] 56,1 (36,6, 126,7+) 9/34 (126,5) [12,9, 44,4] 7,3 [3,7, 12,9] CI = confidence interval; NR = not reached; ORR = objective response rate; PFS = progression-free survival a ORRS ({[CR + PR] / n} x 1) have been calculated based on confirmed responses. Individual patient responses were adjudicated per RECIST v1. with modification 11 ; b Kaplan-Meier estimate; time form first response to time of documented progression, death, or for censored data (denoted by + ); time to last tumor assessment; c Of 129 patients with NSCLC, 1 had an unknown histology and did not show an OR; d NR indicates that the time point at which the probability that responders progress drops below 5% has not been reached due to insufficient number of events and/or follow-up; e 1 CR was noted in melanoma and 1 CR was noted in RCC Hodi et al, Poster presentation at ECC 213:abstract 88 17
Nivolumab (Melanom, NSCLC, RCC) CA29-3: Treatment-related select AEs that occurred in >1% of all treated patients (n=36) Select AEs Any Grade, n (%) Grade 3 4, n (%) Select AEs Any Grade, n (%) Grade 3 4, n (%) Any select AEs 14 (45,8) 19 (6,2) Skin 75 (24,5) 1 (,3) Rash 45 (14,7) Pruritus 32 (1,5) 1 (,3) Rash pruritic 7 (2,3) Urticaria 6 (2,) Photosensitivity reaction 5 (1,6) Rash macular 4 (1,3) 1 (,3) Gastrointenstinal 44 (14,1) 3 (1,) Pulmonary 17 (5,6) 6 (2,) Pneumonitis c 12 (3,9) 4 (1,3) Infusion reaction 15 (4,9) 2 (,7) Infusion-related reaction 12 (3,9) Hypersensitivity 4 (1,3) 2 (,7) Renal 6 (2,) 1 (,3) Blood creatinine increased 4 (1,3) 1 (,3) Diarrhea 41 (13,4) 3 (1,) Colitis 6 (2,) 2 (,7) Endocrinopathies 29 (9,5) 3 (1,) Blood thyroid-stimulating hormone increased 11 (3,6) 1 (,3) Hypothyroidism 11 (3,6) 1 (,3) Hyperthyroidism 4 (1,3) 1 (,3) Hepatic 18 (5,9) 4 (1,3) Alanine aminotransferase increased 11 (3,6) 1 (,3) Aspartate aminotransferase increased 9 (2,9) a Select AEs with potential immune-related causality were defined as AEs requiring vigilant monitoring and/or unique intervention and were based on a prespecified list of MedDRA Terms, as determined by the sponsor; b Select AEs occuring in 1% of patients included lung infiltration (n=3; 1,%), acute respiratory distress syndrome (n=1;,3%), acute respiratory failure (n=1;,3%), diabetes mellitus (n=1;,3%), hypophysitis (n=1;,3%), renal failure (n=3; 1,%), and tubulointerstitial nephritis (n=2;,7%); c There were 3 (1%) deaths in patients with pneumonitis (2 NSCLC, 1 CRC) Hodi et al, Poster presentation at ECC 213: abstract 88 18
LBA43: Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non-small cell lung carcinoma (NSCLC) Garon E et al Study objective To evaluate the efficacy and safety of pembrolizumab among a number of cohorts of patients with EGFR+ or ALK+ advanced NSCLC Nonrandomised (n=33) PD-L1 + tumours a 2 previous therapies Nonrandomised (n=4) PD-L1 tumours a 2 previous therapies b Randomised (n=144) PD-L1 + tumours a 1 previous therapy b R (3:2) Randomised (n=45) PD-L1 + tumours a Treatment naïve R c (1:1) Nonrandomised (n=45) PD-L1 + tumours a 1 previous therapy b Pembro 1 mg/kg Q3W Pembro 1 mg/kg Q2W Pembro 1 mg/kg Q3W Pembro 1 mg/kg Q2W Pembro 2 mg/kg Q3W Pembro 1 mg/kg Q3W Pembro 1 mg/kg Q2W Pembro 2 mg/kg Q3W Primary endpoint ORR a Tumour PD-L1 expression was determined by a prototype assay to inform enrolment. Samples were independently reanalysed using a clinical trial IHC assay b Including 1 therapy platinum-containing doublet. c First 11 patients randomised to 2 mg/kg q3w and 1 mg/kg q3w. The remaining 34 patients were randomised to 1 mg/kg q2w and 1 mg/kg q3w. Analysis cut-off date is September 11, 214 for the nonrandomised cohort of 45 patients treated at 2 mg/kg q3w Secondary endpoints Immune-related response criteria Garon et al. Ann Oncol 214; 25 (suppl 4): abstr LBA43
Progression-free survival, % Overall survival, % LBA43: Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non-small cell lung carcinoma (NSCLC) Garon E et al Key results Robust antitumour activity was observed in both treatment-naïve and previously treated advanced NSCLC observed for all doses and schedules assessed 1 PFS (RECIST v1.1, Central Review) 1 OS Treatment naïve Previously treated 8 6 4 2 8 6 4 2 n at risk Treatment naïve Previously treated Analysis cutoff date: March 3, 214 8 16 24 32 4 48 Time, weeks 45 217 39 159 25 81 11 33 4 13 Treatment naïve Median PFS: 27 weeks (95% CI 14, 45) 24-week PFS: 51% Previously treated Median PFS: 1 weeks (95% CI 9.1, 15.3) 24-week PFS: 26% 2 2 2 4 6 8 1 Time, months 45 217 41 192 38 146 24 77 13 33 12 Treatment naive Median OS: NR (95% CI NE, NE) 6-month OS: 86% Previously treated Median OS: 8.2 months (95% CI 7.3, NR) 6-month OS: 59% Garon et al. Ann Oncol 214; 25 (suppl 4): abstr LBA43 7 8 2 14
LBA43: Antitumor activity of pembrolizumab (Pembro; MK-3475) and correlation with programmed death ligand 1 (PD-L1) expression in a pooled analysis of patients (pts) with advanced non-small cell lung carcinoma (NSCLC) Garon E et al Progression-free survival, % Overall survival, % Key results (cont.) - Strong PD-L1 tumour expression correlated with improved response, PFS and OS PFS (RECIST v1.1, Central Review) OS 1 1 8 8 Strong Weak Negative 6 4 2 6 4 2 n at risk Strong Weak Negative 8 16 24 32 4 48 Time, weeks 44 53 49 28 43 3 18 17 15 Conclusions - Pembrolizumab was effective in patients with treatment-naïve or previously treated advanced NSCLC - In particular, patients with strong PD-L1 tumour expression may benefit from this treatment Strong PD-L1 positivity defined as staining in 5% of tumour cells, and weak PD-L1 positivity as staining in 1 49% of tumour cells. Negative staining is no PD-L1 staining in tumour cells. Data cutoff: March 3, 214. 17 12 7 9 6 1 6 3 2 4 6 8 1 Time, months 44 53 49 43 51 42 38 48 38 38 4 34 34 34 29 32 31 26 3 26 21 27 22 14 21 18 8 18 11 6 Garon et al. Ann Oncol 214; 25 (suppl 4): abstr LBA43 9 8 4 8 7 2 12 5 5 5 5 14 4 4
MPDL328A: PCD4989g phase Ia study Expansion phase ongoing q3w dosing DLT window cycle 1 days 1 21 Standard phase I DLT criteria used Standard 3 + 3 at doses.3mg/kg.1mg/kg.3mg/kg.1mg/kg n=1 n=1 n=1.3mg/kg n=3 1mg/kg n=3 3mg/kg n=3 1mg/kg n=6 2mg/kg n=12 Phase Ia expansion ongoing NSCLC n=85 Melanoma RCC Mandatory serial tumour biopsies Other tumour types Patients enrolled at 1, 15 and 2mg/kg UBC TNBC 1 patients with cutaneous or subcutaneous tumours that are amenable to serial excisional or punch biopsy will be enrolled; serial tumour biopsies will be performed for those 1 patients but will be optional for all other patients Hodi, et al. 213; Soria, et al. 213
MPDL328A: PCD4989g phase Ia study NSCLC cohort* Patient demographics and disease characteristics Characteristic All doses (n=85) Median age (range), y 6 (24 84) Male/female, n (%) Most patients were heavily 48 (56)/37 (44) pretreated, with more than ECOG PS, /1, n (%) half the cohort having 27 (32)/58 (68) Histology, n (%) Squamous received more than two lines of prior systemic therapy 2 (24) Nonsquamous 65 (76) Prior systemic regimens, n (%) 1 13 (15) 2 23 (27) 3 47 (55) CNS metastasis, n (%) 4 (5) Current/previous smoker 68 (8) EGFR status, n (%) Wild type 51 (6) Mutant 11 (13) Unknown 23 (27) *Safety evaluable patients (n=85) with NSCLC. Data cutoff 3 Apr 213 Systemic regimens administered in the metastatic, adjuvant or neoadjuvant setting; 3% of patients had no prior systemic regimens Soria, et al. 213
MPDL328A: PCD4989g phase Ia study NSCLC cohort Safety summary Adverse event * No MTD or DLTs No grade 3 5 pneumonitis One treatment-related death ; one immune-related grade 3/4 AE Treatment-related, n (%) (n=85) Any grade * Grade 3/4 Any AE 56 (66) 9 (11) Fatigue 17 (2) 2 (2) Nausea Most AEs were grade 1 or 2 12 (14) 1 (1) and did not require intervention Decreased appetite 1 (12) () Dyspnoea 8 (9) 1 (1) Diarrhoea 7 (8) () Asthenia 6 (7) () Headache 6 (7) () Rash 6 (7) () Pyrexia 5 (6) () Vomiting 5 (6) 1 (1) Upper respiratory tract infection 4 (5) () *Investigator assessed. Data cutoff 3 Apr 213 Patient had sinus thrombosis and cardiac/great vessel invasion by tumour at baseline Diabetes mellitus in patient with large cell neuroendocrine NSCLC Soria, et al. 213
% of patients MPDL328A: PCD4989g phase Ia study NSCLC cohort Efficacy summary (investigator assessed) 5 45 4 35 3 25 2 15 1 5 NSCLC (n=53) Non-squamous (n=42) Squamous (n=11) 23 21 * 27 Efficacy observed in both squamous and non-squamous histologies 17 17 ORR SD for 24 weeks 24-week PFS rate 18 45 44 46 Patients first dosed at 1 2 mg/kg by 1 Oct 212; data cutoff 3 Apr 213 * ORR includes investigator-assessed unconfirmed and confirmed PR where response was confirmed by repeat assessment 4 weeks after initial documentation. Assessment was by RECIST and irrc. Six patients with no post-baseline scan were included as non-responders Soria, et al. 213
MPDL328A: PCD4989g phase Ia study NSCLC cohort Best response by PD-L1 IHC status Diagnostic population (IC)* (n=53) ORR, % (n/n) PD, % (n/n) IHC 3 83 (5/6) 17 (1/6) IHC 2 and 3 46 (6/13) 23 (3/13) The subgroup with the highest proportion of PD-L1+ tumour- IHC 1 3 infiltrating cells also has the 31 (8/26) 38 (1/26) highest ORR All patients 23 (12/53) 4 (21/53) Patients first dosed at 1 2mg/kg by 1 Oct 212; data cutoff 3 Apr 213 * IHC 3: 1% tumour-infiltrating immune cells positive for PD-L1 (IC+); IHC 2 and 3: 5% tumour-infiltrating immune cells positive for PD-L1 (IC+); IHC 1/2/3: 1% tumour-infiltrating immune cells positive for PD-L1 (IC+); IHC /1/2/3: all patients with evaluable PD-L1 tumour IC status; ORR includes investigator-assessed unconfirmed and confirmed PR where response was confirmed by repeat assessment 4 weeks after initial documentation. Assessment by RECIST and irrc All patients includes patients with IHC /1/2/3 and 7 patients have an unknown diagnostic status Soria, et al. 213
Nivolumab + Ipilimumab (NSCLC) CA29-12: Interim Analysis of a Phase I study with Nivolumab and Ipilimumab in First-Line NSCLC Chemotherapy-naïve patients with stage IIIB or IV NSCLC Squamous Non-squamous Squamous Non-squamous Nivolumab 1 mg/kg IV Q3W + Ipilimumab 3 mg/kg IV Q3W (four 21-day cycles) Nivolumab 3 mg/kg IV Q3W + Ipilimumab 1 mg/kg IV Q3W (four 21-day cycles) Nivolumab 3 mg/kg IV Q2W until disease progression or unacceptable toxicity a Primary objective: safety and tolerability Secondary objectives: ORR and PFS rate at 24 weeks a Patients were permitted to continue study treatment beyond RECIST 1.1 defined progression if they were considered to be deriving clinical benefit and tolerating study treatment Antonia et al, Poster at ASCO 214 27
CA29-12: Tumor response in First-Line NSCLC patients Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Squamous (n=9) Non-squamous (n=15) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Squamous (n=9) Non-squamous (n=16) ORR, n (%) [95% CI] 1 (11) [,3, 48] 2 (13) [2, 41] 3 (33) [8, 7] 2 (13) [2, 38] Ongoing responders, n (%) 1 (1%) 2 (1%) 1 (33%) 2 (1%) Best overall response, n (%) Complete response a Partial response a SD Progressive disease Unable to determine 1 (11) 2 (22) 4 (44) 2 (22) 2 (13) 5 (33) 4 (27) 3 (2) 3 (33) 5 (56) 1 (11) Estimated median DOR, b weeks (95% CI) NR NR 21 (12, 21) NR 2 (13) 4 (25) 6 (38) 2 (13) Response duration by patient, weeks 27+ 6+, 45+ 12, 14+, 21 32+, 49+ Patients with ongoing SD, n (%) 1 (2) 1 (2) 1 (25) SD duration, weeks 16, 45 16, 33, 34, 35+, 47 14, 14, 15, 24+, 27 13, 16, 22, 36+ a All complete and partial responses were confirmed by a subsequent tumor assessment per RECIST 1.1. Patients with an unconfirmed response are not shown b Time from first response to documented progression, death within 1 days of last nivolumab dose, or last tumor assessment (for censored + data). Estimated median DORs were determined from Kaplan-Meier curves + = response ongoing; CI = confidence interval; NR = not reached Antonia et al, Poster at ASCO 214 28
CA29-12: Survival outcomes in First-Line NSCLC patients PFS PFS rate at 24 weeks, % (95% CI) Median PFS, weeks (range) OS Median OS, weeks (range) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Squamous (n=9) Non-squamous (n=15) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Squamous (n=9) Non-squamous (n=16) 25 (4, 56) 51 (21, 74) 44 (14, 72) 2 (5, 43) 41 (2, 61) 29 (13, 48) 8,9 (,1+, 44,7) 32,9 (,1+, 54,1+) 2,6 (9,7, 33,3+) 9,9 (4,1+, 58,1+) 16,1 (,1+, 54,1+) 14,4 (4,1+, 58,1+) 44,3 (1,4, 53,1+) NR (4,9+, 54,1+) NR (9,7, 5,1+) NR (8,1, 58,1+) NR (1,4, 54,1+) NR (8,1, 58,1+) Antonia et al, Poster at ASCO 214 29
CA29-12: Treatment-related AEs (based on grade 3/4 AEs reported in 2% of all patients) in First-Line NSCLC patients Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Squamous (n=9) Non-squamous (n=15) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Squamous (n=9) Non-squamous (n=16) Total (n=49) Treatment-related AE, n (%) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Patients with any AE 7 (78) 4 (44) 15 (1) 1 (67) 7 (78) 2 (22) 14 (88) 8 (5) 43 (88) 24 (49) Diarrhea 3 (33) 1 (11) 7 (47) 2 (13) 2 (22) 1 (11) 3 (19) 1 (6) 15 (31) 5 (1) Increased ALT 4 (27) 3 (2) 1 (11) 1 (11) 5 (1) 4 (8) Increased AST 4 (27) 3 (2) 1 (11) 1 (11) 5 (1) 4 (8) Colitis 1 (7) 1 (7) 4 (25) 3 (19) 5 (1) 4 (8) Increased lipase 3 (2) 2 (13) 2 (22) 1 (11) 2 (13) 1 (6) 7 (14) 4 (8) Fatigue 3 (33) 1 (67) 2 (13) 2 (22) 7 (44) 1 (6) 22 (45) 3 (6) Pneumonitis 2 (22) 1 (11) 2 (13) 1 (7) 1 (11) 1 (6) 1 (6) 6 (12) 3 (6) Adrenal insufficiency 1 (11) 1 (11) 1 (7) 1 (6) 1 (6) 3 (6) 2 (4) Increased amylase 3 (2) 1 (7) 1 (11) 2 (13) 1 (6) 6 (12) 2 (4) Rash 1 (11) 4 (27) 1 (7) 2 (22) 5 (31) 1 (6) 12 (24) 2 (4) ALT = alanine aminotransferase; AST = aspartate aminotransferase Antonia et al, Poster at ASCO 214 3
Aktive Studien Immuntherapie Thoraxklinik: 1st Line
Aktive Studien Immuntherapie Thoraxklinik: 2nd Line
Aktive Studien Immuntherapie Thoraxklinik: 3rd Line
Herausforderungen Immuntherapie LC Patientenauswahl Biomarker / Testung NW Mangement Responsebeurteilung Kosten