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P3.02c-089 ImmunoCHIC: A Prospective Nivolumab Monotherapy Cohort in Advanced Non-Small Cell Lung Cancer Patients in Routine Clinical Practice
S1332
Journal of Thoracic Oncology
Vol. 12 No. 1S
Background: Programmed death-1 (PD-1) axis inhibitors are increasingly being used to treat patients with advanced NSCLC. Despite durable responses relative to chemotherapy, resistance to such therapy develops in the majority of responders, with median duration of response from 12-17 months. Mechanisms of acquired resistance (AR) to PD-1 axis inhibitors are poorly understood.
Conclusion: Lymph nodes may be a particularly susceptible area to AR to PD-1 axis inhibitors. Defects in B2M leading to loss of tumor MHC-1 presentation may represent a unique mechanism of AR to immune checkpoint inhibitors. Further studies to determine the frequency of defects in antigen presentation machinery in tumors with resistance to PD1 axis inhibitors are warranted.
Methods: Patients with advanced NSCLC and acquired resistance (AR) to PD-1 axis inhibitor therapy were enrolled to an IRB approved repeat biopsy protocol allowing collection of clinical data, archived and fresh tumor tissue, and blood for analysis. Molecular analyses including whole exome sequencing of pre- and posttreatment tumor specimens were performed. Results: Twelve cases were available for analysis (table 1). Eight and two patients developed resistance limited to lymph nodes (LNs) and adrenal gland respectively. The two remaining patients experienced tumor progression in LNs with other sites of tumor growth (one in liver, one in lung). Nine patients had sufficient archived pre- PD-1 axis inhibitor tumor tissue for analysis/ comparison, leaving three unpaired cases. Genomic analysis of tumor specimens identified two patients with acquired tumor beta-2-microglobulin (B2M) defects at resistance. A patient derived xenograft generated from one of the resistance samples (patient #6) lacked production of B2M protein and did not express surface MHC-1. Additional analyses including immunophenotyping with multiplexed quantitative immunofluorescence on these and other patient samples are ongoing.
Keywords: Acquired resistance, beta-2 microglobulin, PD-1, PD-L1
P3.02c-089 ImmunoCHIC: A Prospective Nivolumab Monotherapy Cohort in Advanced Non-Small Cell Lung Cancer Patients in Routine Clinical Practice Topic: IT Biomarkers Shobanya Elvarathnam,1 Christos Chouaid,2 Nadine Thiriat.,1 Laurence Jabot,2 Gaelle Rousseau-Bussac,2 Caroline Jaskowiec,1 Florent Vinas,2 Stephanie Poullain,1 Isabelle Monnet2 1 Pharmacy, Chi Creteil, France/France, 2Chest Departement, Grc Oncoest Creteil, Creteil/France Background: In France, in May 2015, Nivolumab early access program was established for patients with advanced NSCLC progressing during or after platinumbased chemotherapy. There is little evidence of Nivolumab use out of clinical trials. We report here one year of Nivolumab use in a French University hospital. Methods: Observational prospective review of patients with advanced NSCLC treated with Nivolumab monotherapy (3 mg/kg/2weeks) in our center, in routine clinical practice. Patients in clinical trial were excluded. Analyze was done on clinico-pathological features, tolerance and outcomes. Results: 63 patients were included (men: 76.1%, age: 65 (range: 40e78), squamous: 33.3%; smoker: 93.7%%, EGFR/ALK negatives: 98.4%, unknown PDL1: 70%; at least one significant comorbidity: 54%; performans status 0/1/2: 34%/49%/17%; cerebral metastasis: 38%; nivolumab as second, third and more than third lines: 38%/38%/24%. Median number of nivolumab cycles: 6 (1-24), more than 12 cycles: 20.6% Disease control rate : 59% (3 complete responses) ; Clinically significant adverse event: 13 (20%) patients (asthenia: 4 patients, grade 2 to 4 colitis: 3 patients, pneumoniae: 3 patients,
January 2017
nephritis: 1 patient). After Nivolumab, 50% of the patients received an another systemic therapy. Two patients were able to go back to work. Conclusion: In real life setting, nivolumab had the efficacy level reported by pivotal clinical trial but with a higher rate of clinically significant adverse events, particularly colitis. Keywords: outcomes, real world setting, Immunotherapy, non-small cell lung cancer
P3.02c-090 The Role of ERCC-1 Polymorphisms as Predictive Biomarker of Response to Nivolumab in Advanced NSCLC Topic: IT Biomarkers Marco Aiello,1 Hector Soto Parra,1 Laura Noto,1 Nunzio Restuccia,1 Paolo Vigneri,1 Sabrina Paratore2 1 Medical Oncology, A.O.U. Policlinico Vittorio Emanuele, Catania/Italy, 2Pathology, A.O.U. Policlinico Vittorio Emanuele, Catania/Italy Background: Programmed death1 (PD-1) pathway is a negative feedback system limiting T cell activity in normal tissues, frequently upregulated by tumors to escape from immune destruction. Blockade of this pathway with anti PD-1 antibodies has shown significant clinical activity in different cancer types; nevertheless it is still unclear why some patients respond to immunotherapies while others do not. Recently it was observed that cancers with higher somatic mutation burden, as tumors with genome instability due to DNA repair defects, develop more elevated anti PD-1 induced neoantigen specific T cell response which results into increased susceptibility to PD-1 blockade. We hypothesize that NSCLCs with polymorphisms of ERCC-1 gene (encoding for a key enzyme of DNA nucleotide excision repair pathway) may be more responsive to PD-1 blockade than ERCC-1 proficient NSCLCs as result of higher rates of mutation due to their genetic instability. Methods: We evaluated the rs11615, rs3212986 and rs2298881 ERCC-1 polymorphisms by pyrosequencing analysis on tumor DNA of stage IV previously treated NSCLC patients receiving nivolumab 3 mg/kg q2w. Results: Between Jul 8, 2015 and Jan 19, 2016, we enrolled 24 NSCLC patients to receive nivolumab. Patient characteristics were as follows: M/F ¼18/6; median age (range) ¼ 65 (49-80); ECOG PS, 0/1 ¼ 22/2; sqNSCLC/ non sq NSCLC ¼ 6/18; smokers/nonsmokers/former smokers ¼ 10/2/12; EGFR status, mutant/wild type/
Abstracts
S1333
unknown ¼ 2/11/11; median nivolumab cycles delivered (range) ¼ 9 (1-22). No patients presented rs11615 and rs2298881 polymorphisms. 8 patients were positive for the rs3212986 polymorphism. The rate of objective response for the entire population was 25% (95% CI, 10 to 47). The ORR was significantly higher in NSCLC patients positive for rs3212986 polymorphism than wild-type NSCLC patients (62.5% [95% CI, 25 to 92] vs. 6% [95% CI, 0 to 30], P¼0.006). Among patients positive for rs3212986 polymorphism, median PFS was not reached. In contrast wild-type patients presented a median PFS of 2.0 months (0.21; 95% CI, 0.07 to 0.58; P¼ 0.004). Conclusion: This study suggested that rs3212986 ERCC1 polymorphism is associated with a higher RR and PFS in advanced NSCLC patients treated with nivolumab. Confirmation of these results in a validation set is ongoing. Keywords: PD-1, ERCC-1, Nivolumab, Polimorphisms
P3.02c-091 Final Phase Ib Results of RNActive® Cancer Vaccine BI 1361849 and Local Radiation as Maintenance Therapy for Stage IV NSCLC Topic: IT Clinical Alexandros Papachristofilou,1 Martin Sebastian,2 Christian Weiss,3 Martin Früh,4 Miklos Pless,5 Richard Cathomas,6 Wolfgang Hilbe,7 Georg Pall,8 Thomas Wehler,9 Jürgen Alt,10 Helge Bischoff,11 Michael Geissler,12 Frank Griesinger,13 Jens Kollmeier,14 Madeleine Hipp,15 Fatma Doener,15 Mariola Fotin-Mleczek,15 Henoch Hong,15 Karl-Josef Kallen,16 Ute Klinkhardt,17 Sven Koch,15 Birgit Scheel,15 Andreas Schröder,17 Claudia Stosnach,17 Ulrike Gnad-Vogt,17 Alfred Zippelius18 1Klinik Für Strahlentherapie Und Radioonkologie, Universitätsspital Basel, Basel/ Switzerland, 2Medical Clinic Ii, University Hospital Frankfurt, Goethe University, Frankfurt/Germany, 3Klinik Für Radioonkologie U. Strahlentherapie, Klinikum Darmstadt GmbH, Darmstadt/Germany, 4Innere Medizin, Kantonsspital St. Gallen, St. Gallen/Switzerland, 5 Medizinische Onkologie, Kantonsspital Winterthur, Winterthur/Switzerland, 6Medizinische Onkologie; Dpt. Innere Medizin, Kantonsspital Graubünden, Chur/ Switzerland, 71. Med. Department, Wilhelminenspital Wien, Wien/Austria, 8Klinik Für Pneumologie, WaldburgZeil Kliniken, Fachkliniken Wangen, Wangen/Germany, 9 Internal Medicine V, University Hospital Saarland,
Journal of Thoracic Oncology
Vol. 12 No. 1S
Background: Programmed death-1 (PD-1) axis inhibitors are increasingly being used to treat patients with advanced NSCLC. Despite durable responses relative to chemotherapy, resistance to such therapy develops in the majority of responders, with median duration of response from 12-17 months. Mechanisms of acquired resistance (AR) to PD-1 axis inhibitors are poorly understood.
Conclusion: Lymph nodes may be a particularly susceptible area to AR to PD-1 axis inhibitors. Defects in B2M leading to loss of tumor MHC-1 presentation may represent a unique mechanism of AR to immune checkpoint inhibitors. Further studies to determine the frequency of defects in antigen presentation machinery in tumors with resistance to PD1 axis inhibitors are warranted.
Methods: Patients with advanced NSCLC and acquired resistance (AR) to PD-1 axis inhibitor therapy were enrolled to an IRB approved repeat biopsy protocol allowing collection of clinical data, archived and fresh tumor tissue, and blood for analysis. Molecular analyses including whole exome sequencing of pre- and posttreatment tumor specimens were performed. Results: Twelve cases were available for analysis (table 1). Eight and two patients developed resistance limited to lymph nodes (LNs) and adrenal gland respectively. The two remaining patients experienced tumor progression in LNs with other sites of tumor growth (one in liver, one in lung). Nine patients had sufficient archived pre- PD-1 axis inhibitor tumor tissue for analysis/ comparison, leaving three unpaired cases. Genomic analysis of tumor specimens identified two patients with acquired tumor beta-2-microglobulin (B2M) defects at resistance. A patient derived xenograft generated from one of the resistance samples (patient #6) lacked production of B2M protein and did not express surface MHC-1. Additional analyses including immunophenotyping with multiplexed quantitative immunofluorescence on these and other patient samples are ongoing.
Keywords: Acquired resistance, beta-2 microglobulin, PD-1, PD-L1
P3.02c-089 ImmunoCHIC: A Prospective Nivolumab Monotherapy Cohort in Advanced Non-Small Cell Lung Cancer Patients in Routine Clinical Practice Topic: IT Biomarkers Shobanya Elvarathnam,1 Christos Chouaid,2 Nadine Thiriat.,1 Laurence Jabot,2 Gaelle Rousseau-Bussac,2 Caroline Jaskowiec,1 Florent Vinas,2 Stephanie Poullain,1 Isabelle Monnet2 1 Pharmacy, Chi Creteil, France/France, 2Chest Departement, Grc Oncoest Creteil, Creteil/France Background: In France, in May 2015, Nivolumab early access program was established for patients with advanced NSCLC progressing during or after platinumbased chemotherapy. There is little evidence of Nivolumab use out of clinical trials. We report here one year of Nivolumab use in a French University hospital. Methods: Observational prospective review of patients with advanced NSCLC treated with Nivolumab monotherapy (3 mg/kg/2weeks) in our center, in routine clinical practice. Patients in clinical trial were excluded. Analyze was done on clinico-pathological features, tolerance and outcomes. Results: 63 patients were included (men: 76.1%, age: 65 (range: 40e78), squamous: 33.3%; smoker: 93.7%%, EGFR/ALK negatives: 98.4%, unknown PDL1: 70%; at least one significant comorbidity: 54%; performans status 0/1/2: 34%/49%/17%; cerebral metastasis: 38%; nivolumab as second, third and more than third lines: 38%/38%/24%. Median number of nivolumab cycles: 6 (1-24), more than 12 cycles: 20.6% Disease control rate : 59% (3 complete responses) ; Clinically significant adverse event: 13 (20%) patients (asthenia: 4 patients, grade 2 to 4 colitis: 3 patients, pneumoniae: 3 patients,
January 2017
nephritis: 1 patient). After Nivolumab, 50% of the patients received an another systemic therapy. Two patients were able to go back to work. Conclusion: In real life setting, nivolumab had the efficacy level reported by pivotal clinical trial but with a higher rate of clinically significant adverse events, particularly colitis. Keywords: outcomes, real world setting, Immunotherapy, non-small cell lung cancer
P3.02c-090 The Role of ERCC-1 Polymorphisms as Predictive Biomarker of Response to Nivolumab in Advanced NSCLC Topic: IT Biomarkers Marco Aiello,1 Hector Soto Parra,1 Laura Noto,1 Nunzio Restuccia,1 Paolo Vigneri,1 Sabrina Paratore2 1 Medical Oncology, A.O.U. Policlinico Vittorio Emanuele, Catania/Italy, 2Pathology, A.O.U. Policlinico Vittorio Emanuele, Catania/Italy Background: Programmed death1 (PD-1) pathway is a negative feedback system limiting T cell activity in normal tissues, frequently upregulated by tumors to escape from immune destruction. Blockade of this pathway with anti PD-1 antibodies has shown significant clinical activity in different cancer types; nevertheless it is still unclear why some patients respond to immunotherapies while others do not. Recently it was observed that cancers with higher somatic mutation burden, as tumors with genome instability due to DNA repair defects, develop more elevated anti PD-1 induced neoantigen specific T cell response which results into increased susceptibility to PD-1 blockade. We hypothesize that NSCLCs with polymorphisms of ERCC-1 gene (encoding for a key enzyme of DNA nucleotide excision repair pathway) may be more responsive to PD-1 blockade than ERCC-1 proficient NSCLCs as result of higher rates of mutation due to their genetic instability. Methods: We evaluated the rs11615, rs3212986 and rs2298881 ERCC-1 polymorphisms by pyrosequencing analysis on tumor DNA of stage IV previously treated NSCLC patients receiving nivolumab 3 mg/kg q2w. Results: Between Jul 8, 2015 and Jan 19, 2016, we enrolled 24 NSCLC patients to receive nivolumab. Patient characteristics were as follows: M/F ¼18/6; median age (range) ¼ 65 (49-80); ECOG PS, 0/1 ¼ 22/2; sqNSCLC/ non sq NSCLC ¼ 6/18; smokers/nonsmokers/former smokers ¼ 10/2/12; EGFR status, mutant/wild type/
Abstracts
S1333
unknown ¼ 2/11/11; median nivolumab cycles delivered (range) ¼ 9 (1-22). No patients presented rs11615 and rs2298881 polymorphisms. 8 patients were positive for the rs3212986 polymorphism. The rate of objective response for the entire population was 25% (95% CI, 10 to 47). The ORR was significantly higher in NSCLC patients positive for rs3212986 polymorphism than wild-type NSCLC patients (62.5% [95% CI, 25 to 92] vs. 6% [95% CI, 0 to 30], P¼0.006). Among patients positive for rs3212986 polymorphism, median PFS was not reached. In contrast wild-type patients presented a median PFS of 2.0 months (0.21; 95% CI, 0.07 to 0.58; P¼ 0.004). Conclusion: This study suggested that rs3212986 ERCC1 polymorphism is associated with a higher RR and PFS in advanced NSCLC patients treated with nivolumab. Confirmation of these results in a validation set is ongoing. Keywords: PD-1, ERCC-1, Nivolumab, Polimorphisms
P3.02c-091 Final Phase Ib Results of RNActive® Cancer Vaccine BI 1361849 and Local Radiation as Maintenance Therapy for Stage IV NSCLC Topic: IT Clinical Alexandros Papachristofilou,1 Martin Sebastian,2 Christian Weiss,3 Martin Früh,4 Miklos Pless,5 Richard Cathomas,6 Wolfgang Hilbe,7 Georg Pall,8 Thomas Wehler,9 Jürgen Alt,10 Helge Bischoff,11 Michael Geissler,12 Frank Griesinger,13 Jens Kollmeier,14 Madeleine Hipp,15 Fatma Doener,15 Mariola Fotin-Mleczek,15 Henoch Hong,15 Karl-Josef Kallen,16 Ute Klinkhardt,17 Sven Koch,15 Birgit Scheel,15 Andreas Schröder,17 Claudia Stosnach,17 Ulrike Gnad-Vogt,17 Alfred Zippelius18 1Klinik Für Strahlentherapie Und Radioonkologie, Universitätsspital Basel, Basel/ Switzerland, 2Medical Clinic Ii, University Hospital Frankfurt, Goethe University, Frankfurt/Germany, 3Klinik Für Radioonkologie U. Strahlentherapie, Klinikum Darmstadt GmbH, Darmstadt/Germany, 4Innere Medizin, Kantonsspital St. Gallen, St. Gallen/Switzerland, 5 Medizinische Onkologie, Kantonsspital Winterthur, Winterthur/Switzerland, 6Medizinische Onkologie; Dpt. Innere Medizin, Kantonsspital Graubünden, Chur/ Switzerland, 71. Med. Department, Wilhelminenspital Wien, Wien/Austria, 8Klinik Für Pneumologie, WaldburgZeil Kliniken, Fachkliniken Wangen, Wangen/Germany, 9 Internal Medicine V, University Hospital Saarland,