PMID- 35737383
OWN - NLM
STAT- MEDLINE
DCOM- 20220822
LR  - 20230701
IS  - 2374-2445 (Electronic)
IS  - 2374-2437 (Print)
IS  - 2374-2437 (Linking)
VI  - 8
IP  - 8
DP  - 2022 Aug 1
TI  - Efficacy of Ipilimumab vs FOLFOX in Combination With Nivolumab and Trastuzumab in 
      Patients With Previously Untreated ERBB2-Positive Esophagogastric Adenocarcinoma: 
      The AIO INTEGA Randomized Clinical Trial.
PG  - 1150-1158
LID - 10.1001/jamaoncol.2022.2228 [doi]
AB  - IMPORTANCE: In metastatic esophagogastric adenocarcinoma (EGA), the addition of 
      programmed cell death 1 (PD-1) inhibitors to chemotherapy has improved outcomes 
      in selected patient populations. OBJECTIVE: To investigate the efficacy of 
      trastuzumab and PD-1 inhibitors with cytotoxic T-lymphocyte-associated antigen 4 
      (CTLA-4) inhibitors or FOLFOX in first-line treatment of advanced ERBB2-positive 
      EGA. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 multicenter, outpatient, 
      randomized clinical trial with 2 experimental arms compared with historical 
      control individually was conducted between March 2018 and May 2020 across 21 
      German sites. The reported results are based on a median follow-up of 14.3 
      months. Patients with previously untreated, metastatic ERBB2-positive (local 
      immunohistochemistry score of 3+ or 2+/in situ hybridization amplification 
      positive) EGA, adequate organ function, and eligibility for immunotherapy were 
      included. Data analysis was performed from June to September 2021. INTERVENTIONS: 
      Patients were randomized to trastuzumab and nivolumab (1 mg/kg x 4/240 mg for up 
      to 12 months) in combination with mFOLFOX6 (FOLFOX arm) or ipilimumab (3 
      mg/kg x 4 for up to 12 weeks) (ipilimumab arm). MAIN OUTCOMES AND MEASURES: The 
      primary end point was survival improvement with a targeted increase of the 
      12-month overall survival rate from 55% (trastuzumab/chemotherapy-ToGA regimen) 
      to 70% in each arm. RESULTS: A total of 97 patients were enrolled, and 88 were 
      randomized (18 women, 70 men; median [range] age, 61 [41-80] years). Baseline 
      Eastern Cooperative Oncology Group performance status was 0 in 54 patients (61%) 
      and 1 in 34 patients (39%); 66 patients (75%) had EGA localized in the 
      esophagogastric junction and 22 in the stomach (25%). Central post hoc biomarker 
      analysis (84 patients) showed PD-1 ligand 1 (PD-L1) combined positive score of 1 
      or greater in 59 patients (72%) and 5 or greater in 46 patients (56%) and 
      confirmed ERBB2 positivity in 76 patients. The observed overall survival rate at 
      12 months was 70% (95% CI, 54%-81%) with FOLFOX and 57% (95% CI, 41%-71%) with 
      ipilimumab. Treatment-related grade 3 or greater adverse events (AEs) and serious 
      AEs occurred in 29 and 15 patients in the FOLFOX arm and in 20 and 17 patients in 
      the ipilimumab arm, respectively, with a higher incidence of autoimmune-related 
      AEs in the ipilimumab arm and neuropathy in the FOLFOX arm. Liquid biopsy 
      analyses showed strong correlation of early cell-free DNA increase with shorter 
      progression-free and overall survival and emergence of truncating and 
      epitope-loss ERBB2 resistance sequence variations with trastuzumab treatment. 
      CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, trastuzumab, 
      nivolumab, and FOLFOX showed favorable efficacy compared with historical data and 
      trastuzumab, nivolumab, and ipilimumab in ERBB2-positive EGA. The ipilimumab arm 
      yielded similar OS compared with the ToGA regimen. TRIAL REGISTRATION: 
      ClinicalTrials.gov Identifier: NCT03409848.
FAU - Stein, Alexander
AU  - Stein A
AD  - Hematology-Oncology Practice Eppendorf (HOPE), Hamburg, Germany.
AD  - University Cancer Center Hamburg (UCCH), University Medical Center 
      Hamburg-Eppendorf, Hamburg, Germany.
FAU - Paschold, Lisa
AU  - Paschold L
AD  - Department of Internal Medicine IV-Oncology/Hematology, University Hospital, 
      Martin-Luther University, Halle, Germany.
FAU - Tintelnot, Joseph
AU  - Tintelnot J
AD  - University Cancer Center Hamburg (UCCH), University Medical Center 
      Hamburg-Eppendorf, Hamburg, Germany.
FAU - Goekkurt, Eray
AU  - Goekkurt E
AD  - Hematology-Oncology Practice Eppendorf (HOPE), Hamburg, Germany.
AD  - University Cancer Center Hamburg (UCCH), University Medical Center 
      Hamburg-Eppendorf, Hamburg, Germany.
FAU - Henkes, Svenja-Sibylla
AU  - Henkes SS
AD  - Department of Internal Medicine IV-Oncology/Hematology, University Hospital, 
      Martin-Luther University, Halle, Germany.
FAU - Simnica, Donjete
AU  - Simnica D
AD  - Department of Internal Medicine IV-Oncology/Hematology, University Hospital, 
      Martin-Luther University, Halle, Germany.
FAU - Schultheiss, Christoph
AU  - Schultheiss C
AD  - Department of Internal Medicine IV-Oncology/Hematology, University Hospital, 
      Martin-Luther University, Halle, Germany.
FAU - Willscher, Edith
AU  - Willscher E
AD  - Department of Internal Medicine IV-Oncology/Hematology, University Hospital, 
      Martin-Luther University, Halle, Germany.
FAU - Bauer, Marcus
AU  - Bauer M
AD  - Institute of Pathology, University Hospital, Martin-Luther University, Halle, 
      Germany.
FAU - Wickenhauser, Claudia
AU  - Wickenhauser C
AD  - Institute of Pathology, University Hospital, Martin-Luther University, Halle, 
      Germany.
FAU - Thuss-Patience, Peter
AU  - Thuss-Patience P
AD  - Charite-University Medicine Berlin, Berlin, Germany.
FAU - Lorenzen, Sylvie
AU  - Lorenzen S
AD  - Rechts der Isar Hospital, Technical University of Munich, Munich, Germany.
FAU - Ettrich, Thomas
AU  - Ettrich T
AD  - University Hospital Ulm, Ulm, Germany.
FAU - Riera-Knorrenschild, Jorge
AU  - Riera-Knorrenschild J
AD  - University Hospital, Philipps-Universitat Marburg, Germany.
FAU - Jacobasch, Lutz
AU  - Jacobasch L
AD  - Practice for Hematology-Oncology, Dresden, Germany.
FAU - Kretzschmar, Albrecht
AU  - Kretzschmar A
AD  - MVZ-Mitte, Leipzig, Germany.
FAU - Kubicka, Stefan
AU  - Kubicka S
AD  - Kreisklinik Reutlingen, Reutlingen, Germany.
FAU - Al-Batran, Salah-Eddin
AU  - Al-Batran SE
AD  - Institute of Clinical Cancer Research, Krankenhaus Nordwest, Frankfurt, Germany.
FAU - Reinacher-Schick, Anke
AU  - Reinacher-Schick A
AD  - St Josef-Hospital Bochum, University of Bochum, Germany.
FAU - Pink, Daniel
AU  - Pink D
AD  - Klinik und Poliklinik fur Innere Medizin C, University Greifswald, Greifswald, 
      Germany.
AD  - Klinik fur Hamatologie, Onkologie und Palliativmedizin, Sarkomzentrum 
      Berlin-Brandenburg, HELIOS Klinikum Bad Saarow, Bad Saarow, Germany.
FAU - Sinn, Marianne
AU  - Sinn M
AD  - University Cancer Center Hamburg (UCCH), University Medical Center 
      Hamburg-Eppendorf, Hamburg, Germany.
FAU - Lindig, Udo
AU  - Lindig U
AD  - University Hospital, Jena, Germany.
FAU - Hiegl, Wolfgang
AU  - Hiegl W
AD  - AIO Studien gGmbH Berlin, Germany.
FAU - Hinke, Axel
AU  - Hinke A
AD  - CCRC, Dusseldorf, Germany.
FAU - Hegewisch-Becker, Susanna
AU  - Hegewisch-Becker S
AD  - Hematology-Oncology Practice Eppendorf (HOPE), Hamburg, Germany.
FAU - Binder, Mascha
AU  - Binder M
AD  - Department of Internal Medicine IV-Oncology/Hematology, University Hospital, 
      Martin-Luther University, Halle, Germany.
LA  - eng
SI  - ClinicalTrials.gov/NCT03409848
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - JAMA Oncol
JT  - JAMA oncology
JID - 101652861
RN  - 0 (Ipilimumab)
RN  - 0 (Programmed Cell Death 1 Receptor)
RN  - 31YO63LBSN (Nivolumab)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
CIN - JAMA Oncol. 2022 Aug 1;8(8):1158-1159. PMID: 35737402
MH  - *Adenocarcinoma/drug therapy
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects
MH  - Female
MH  - Humans
MH  - Ipilimumab/adverse effects
MH  - Male
MH  - Middle Aged
MH  - *Nivolumab/adverse effects
MH  - Programmed Cell Death 1 Receptor/therapeutic use
MH  - Receptor, ErbB-2
MH  - Trastuzumab/adverse effects
PMC - PMC9227706
COIS- Conflict of Interest Disclosures: Dr Stein reported grants from Bristol Myers 
      Squibb (BMS) during the conduct of the study; and institutional fees for advisory 
      boards from BMS and Merck Sharp & Dohme (MSD) outside the submitted work. Dr 
      Goekkurt reported personal fees from BMS and MSD during the conduct of the study; 
      and personal fees from Servier, Roche, and Sanofi outside the submitted work. Dr 
      Thuss-Patience reported personal fees (advisory board) from BMS, MSD, Merck 
      Serono, AstraZeneca, Pfizer, Lilly, Servier, Novartis, Astellas, Roche, and Amgen 
      outside the submitted work. Dr Ettrich reported grants from Servier, nonfinancial 
      support from Ipsen, and personal fees from MSD, BMS, AstraZeneca, Roche, Eisai, 
      Pierre Fabre, Merck Serono, and Bayer outside the submitted work. Dr Kretzschmar 
      reported personal fees (lecture fees) from Roche and BMS during the conduct of 
      the study. Prof Kubicka reported personal fees from Roche and BMS outside the 
      submitted work. Dr Al-Batran reported grants from BMS, MSD, Sanofi, Ipsen, Roche 
      Hospira, Lilly, Vifor Pharma, Hospira, AstraZeneca, Immutep, and Eurozyto and 
      personal fees from Lilly, AstraZeneca, and BMS outside the submitted work. Prof 
      Reinacher-Schick reported other (honoraria, advisory board member) from Amgen, 
      AstraZeneca, and Pfizer; other (honoraria, travel support) from BMS; other 
      (honoraria) from Lilly; other (honoraria, advisory board member, travel support) 
      from Merck, MSD, and Roche; personal fees (honoraria, advisory board member, 
      travel support) from Servier; and grants from BioNTech, Rafael, and Erytech 
      outside the submitted work. Dr Pink reported grants from PharmaMar, Roche, Lilly, 
      Clinigen, BMS, and EUSA Pharma and personal fees from PharmaMar, Roche, Lilly, 
      and Blueprint Medicines outside the submitted work. Dr Sinn reported personal 
      fees from Amgen, AstraZeneca, BMS, MSD, Sanofi, Servier, Pfizer, Incyte, Pierre 
      Fabre, and Art Tempi outside the submitted work. Dr Lindig reported nonfinancial 
      support, travel paid by BMS. Dr Hinke reported personal fees from German Cancer 
      Society during the conduct of the study. Dr Binder reported grants from BMS 
      covering the translational studies in this trial during the conduct of the study. 
      No other disclosures were reported.
EDAT- 2022/06/24 06:00
MHDA- 2022/08/23 06:00
PMCR- 2023/06/23
CRDT- 2022/06/23 11:34
PHST- 2022/06/24 06:00 [pubmed]
PHST- 2022/08/23 06:00 [medline]
PHST- 2022/06/23 11:34 [entrez]
PHST- 2023/06/23 00:00 [pmc-release]
AID - 2793712 [pii]
AID - coi220026 [pii]
AID - 10.1001/jamaoncol.2022.2228 [doi]
PST - ppublish
SO  - JAMA Oncol. 2022 Aug 1;8(8):1150-1158. doi: 10.1001/jamaoncol.2022.2228.