Abstract 1335P
Background
Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) is a mechanism of immune antitumor activity of IgG1 monoclonal antibodies (mAbs), suggesting as novel therapy in non-small cell lung cancer (NSCLC) combination of anti-Epidermal Growth Factor Receptor (EGFR) Cetuximab (C) and anti-Programmed Death Ligand 1 Avelumab (A).
Methods
We validated LDH release assay to study induction of ADCC by C and A in 13 human lung cancer cell lines, using as effectors natural killers (NK) from healthy donors (HD) or patients (pts). We explored efficacy and safety of C plus A in a single arm proof of concept study in relapsed NSCLC. Potential predictive biomarkers were studied: induction of ADCC by LDH release assay using pts' NK, quantification of total circulating plasma cell-free DNA (cfDNA) levels, genomic profiling.
Results
Treatment with C plus A induced ADCC in vitro, with higher efficacy in cell lines with high EGFR expression. 16 pts were enrolled in the CAVE-Lung trial. Anti-tumor activity was observed in 6 pts (responders, R), with a progression free survival (PFS) ≥ 8 months, of which 4/6 are still on treatment at the time of data lock, May 1st (range, 15-20 months). Of note, 2/4 had received in previous line single agent anti-PD1 drug. In all R pts, clinical benefit was accompanied by a significant induction of ADCC, showed by increase of LDH release at week 8 as compared to baseline (p=0.01) and by early skin toxicity within week 6. Conversely, the other 10 pts (non responders, NR) had a PFS ≤5 months, with no changes in ADCC. Also, baseline cfDNA levels were higher in NR compared to R and HD (p=0.026), with a downregulation at week 8 and 18 in R. Genomic profiling detected 2 KRAS and 1 STK11 mutation (mut) in NR. Among R pts, we found one STK11/TP53 co-mut, and CHK2/ATM/BRCA2 co-mut and MDM2 mut in those 2 pts previously treated with anti-PD1, respectively. These genes belong to DNA damage responsive (DDR) family, that is associated with innate immune activation.
Conclusions
Induction of ADCC assessed by LDH assay, reduction of cfDNA levels and early skin toxicity may predict clinical benefit to C plus A in NSCLC. Moreover, DDR alterations could be correlated with responsiveness to this combination, by affecting interplay between innate and adaptive immunity.
Clinical trial identification
EUDRACT 2017-004195-58.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Merck Serono.
Disclosure
M. Fasano: Spouse/Financial dependant: Merck. A. Morabito: Advisory/Consultancy: Roche, AZ, Boehringer Ingelheim, Pfizer, Takeda, BMS, MSD. E. Maiello: Advisory/Consultancy: Lilly, Sanofi, Celgene, Servier. F. Ciardiello: Advisory/Consultancy: Roche, Amgen, Merck, Pfizer, Sanofi, Bayer, Servier, BMS, Celgene, Lilly; Research grant/Funding (institution): Bayer, Roche, Merck, Amgen, AZ, Ipsen . F. Morgillo: Advisory/Consultancy: MSD, Lilly; Research grant/Funding (institution): AZ. All other authors have declared no conflicts of interest.