We recently conducted Cetuximab-AVElumab-Lung (CAVE-Lung), a proof-of-concept, translational and clinical trial, to evaluate the combination of two IgG1 monoclonal antibodies (mAb): avelumab, an anti-PD-L1 drug, and cetuximab, an anti-epidermal growth factor receptor (EGFR) drug, as second- or third-line treatment in non-small cell lung cancer (NSCLC) patients. We have reported clinically relevant anti-tumor activity in 6/16 patients. Clinical benefit was accompanied by Natural Killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC). Among the 6 responding patients, 3 had progressed after initial response to a previous treatment with single agent anti-PD-1, nivolumab or pembrolizumab.
We report long-term clinical follow-up and additional findings on the anti-tumor activity and on the immune effects of cetuximab plus avelumab treatment for these 3 patients.
As of November 30, 2021, 2/3 patients were alive. One patient was still on treatment from 34 months, while the other two patients had progression free survival (PFS) of 15 and 19 months, respectively. Analysis of serially collected peripheral blood mononuclear cells (PBMC) revealed longterm activation of NK cell-mediated ADCC. Comprehensive genomic profile analysis found somatic mutations and germline rare variants in DNA damage response (DDR) genes. Furthermore, by transcriptomic analysis of The Cancer Genome Atlas (TCGA) dataset we found that DDR mutant NSCLC displayed high STING pathway gene expression. In NSCLC patient-derived three-dimensional in vitro spheroid cultures, cetuximab plus avelumab treatment induced additive cancer cell growth inhibition as compared to single agent treatment. This effect was partially blocked by treatment with an anti-CD16 mAb, suggesting a direct involvement of NK cell activation. Furthermore, cetuximab plus avelumab treatment induced 10-, 20-, and 20-fold increase, respectively, in the gene expression of CCL5 and CXCL10, two STING downstream effector cytokines, and of interferon b, as compared to untreated control samples.
DDR mutations may contribute to innate immunity activation by cetuximab plus avelumab.
Legal entity responsible for the study
C.M. Della Corte.
Merck - CAVE Lung Trial.
C.M. Della Corte: Financial Interests, Institutional, Advisory Role: MSD. M. Fasano: Non-Financial Interests, Personal, Other: Merck. C.M. Gay: Financial Interests, Institutional, Advisory Role: Jazz Pharmaceuticals, AstraZeneca, Bristol Myers Squibb; Financial Interests, Institutional, Speaker’s Bureau: AstraZeneca, BeiGene;. R. Di Liello: Financial Interests, Institutional, Advisory Role: Astellas. T. Troiani: Financial Interests, Institutional, Invited Speaker: Roche, Merck-Serono, Sanofi, Servier, Novartis, Bayer. E. Martinelli: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Amgen, Bayer, Merck-Serono, Roche, Sanofi, Servier, Pierre Fabre;. L. Byers: Financial Interests, Institutional, Advisory Role: AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar SA, Sierra Oncology, Merck, Bristol Myers Squibb, Genentech, Pfizer; Financial Interests, Institutional, Research Grant: AbbVie, AstraZeneca, GenMab, Sierra Oncology, Tolero Pharmaceuticals; F. Morgillo: Financial Interests, Institutional, Advisory Role: MSD, Lilly; Institutional Research Grants: AstraZeneca;. F. Ciardiello: Financial Interests, Institutional, Invited Speaker: Roche, Amgen, Merck-Serono, Pfizer, Sanofi, Bayer, Servier, Bristol Myers Squibb, Cellgene, Lilly; Financial Interests, Institutional, Research Grant: Bayer, Roche, Merck-Serono, Amgen, AstraZeneca, Takeda. All other authors have declared no conflicts of interest.