Induction of natural killer antibody-dependent cell cytotoxicity and of clinical activity of cetuximab plus avelumab in non-small cell lung cancer.
ADCC
NK cells
NSCLC
avelumab
cetuximab
Journal
ESMO open
ISSN: 2059-7029
Titre abrégé: ESMO Open
Pays: England
ID NLM: 101690685
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
18
03
2020
revised:
25
05
2020
accepted:
28
05
2020
entrez:
11
9
2020
pubmed:
12
9
2020
medline:
19
8
2021
Statut:
ppublish
Résumé
Antibody-dependent cell-mediated cytotoxicity (ADCC) may mediate antitumour activity of IgG1-isotype monoclonal antibody (mAb), suggesting as potential treatment combination of IgG1-mAbs, anti-epidermal growth factor receptor cetuximab and anti-programmed death-ligand-1 avelumab. We evaluated ADCC induction in lung cancer cells by lactate dehydrogenase (LDH) release assay. Antitumour activity and safety of cetuximab plus avelumab were explored in a single-arm proof-of-concept study in pre-treated non-small cell lung cancer (NSCLC) patients (pt) (Cetuximab-AVElumab-lung, CAVE-Lung). Search for predictive biomarkers of response was done. Avelumab plus cetuximab induced ADCC in NSCLC cells in vitro in presence of natural killers (NK) from healthy donors (HD) or NSCLC pt, as effectors. Sixteen relapsed NSCLC pt were treated with avelumab plus cetuximab. Antitumour activity was observed in 6/16 pt, defined by progression free survival (PFS) ≥8 months, with 4 of them still on treatment at data lock time (range, 14-19 months). Of note, 3/6 responders had received as previous line anti-programmed death-1 therapy. In responders, clinical benefit was accompanied by significant increase in LDH release over baseline at the first radiological evaluation (8 weeks) (p=0.01) and by early skin toxicity; while in the 10 non-responders, that had PFS ≤5 months, LDH release tends to reduce. Baseline circulating DNA levels were higher in non-responders compared with responders and HD (p=0.026) and decrease in responders during therapy. Mutations in DNA damage responsive family genes were found in responders. Cetuximab and avelumab activates NSCLC pt NK cells. Ex vivo evaluation of ADCC, circulating DNA levels and early skin toxicity may predict response to cetuximab plus avelumab in NSCLC.EUDRACT 2017-004195-58.
Sections du résumé
BACKGROUND
Antibody-dependent cell-mediated cytotoxicity (ADCC) may mediate antitumour activity of IgG1-isotype monoclonal antibody (mAb), suggesting as potential treatment combination of IgG1-mAbs, anti-epidermal growth factor receptor cetuximab and anti-programmed death-ligand-1 avelumab.
METHODS
We evaluated ADCC induction in lung cancer cells by lactate dehydrogenase (LDH) release assay. Antitumour activity and safety of cetuximab plus avelumab were explored in a single-arm proof-of-concept study in pre-treated non-small cell lung cancer (NSCLC) patients (pt) (Cetuximab-AVElumab-lung, CAVE-Lung). Search for predictive biomarkers of response was done.
RESULTS
Avelumab plus cetuximab induced ADCC in NSCLC cells in vitro in presence of natural killers (NK) from healthy donors (HD) or NSCLC pt, as effectors. Sixteen relapsed NSCLC pt were treated with avelumab plus cetuximab. Antitumour activity was observed in 6/16 pt, defined by progression free survival (PFS) ≥8 months, with 4 of them still on treatment at data lock time (range, 14-19 months). Of note, 3/6 responders had received as previous line anti-programmed death-1 therapy. In responders, clinical benefit was accompanied by significant increase in LDH release over baseline at the first radiological evaluation (8 weeks) (p=0.01) and by early skin toxicity; while in the 10 non-responders, that had PFS ≤5 months, LDH release tends to reduce. Baseline circulating DNA levels were higher in non-responders compared with responders and HD (p=0.026) and decrease in responders during therapy. Mutations in DNA damage responsive family genes were found in responders.
CONCLUSION
Cetuximab and avelumab activates NSCLC pt NK cells. Ex vivo evaluation of ADCC, circulating DNA levels and early skin toxicity may predict response to cetuximab plus avelumab in NSCLC.EUDRACT 2017-004195-58.
Identifiants
pubmed: 32912860
pii: S2059-7029(20)32693-4
doi: 10.1136/esmoopen-2020-000753
pmc: PMC7484864
pii:
doi:
Substances chimiques
Antibodies, Monoclonal, Humanized
0
Immunoglobulin G
0
avelumab
KXG2PJ551I
Cetuximab
PQX0D8J21J
Banques de données
EudraCT
['2017-004195-58']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e000753Informations de copyright
© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.
Déclaration de conflit d'intérêts
Competing interests: MF: family relation with Merck; AM: Consultancy and Advisory Boards: Roche, AstraZeneca, Boehringer, Pfizer, Takeda, BMS, MSD; EM: Consultancy and Advisory Boards: Eli Lilly, Sanofi, Cellgene, Servier; FC: Advisory Boards: Roche, Amgen, Merck, Pfizer, Sanofi, Bayer, Servier, BMS, Cellgene, Lilly; Institutional Research Grants: Bayer, Roche, Merck, Amgen, AstraZeneca, Ipsen; FM: Advisory Boards MSD, Lilly; Institutional Research Grants: AstraZeneca.
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