A 50-year-old never-smoker Bulgarian woman, with no comorbidities and no family history of cancer, was diagnosed in June 2015 with stage IV lung adenocarcinoma metastatic to the peritoneum, retroperitoneum, adrenal glands, iliac and inguinal lymph nodes, as revealed by physical examination and computed tomography (CT) scan. Tissue biopsies from the primary tumor and right groin adenopathies revealed an adenocarcinoma, with positive cytokeratin-7 (CK7), epithelial membrane antigen (EMA), thyroid transcription factor-1 (TTF-1) immunohistochemistry (IHC), and negative cytokeratin-20 (CK20) staining. Real-time polymerase chain reaction (RT-PCR) (COBAS 4800 system) showed no epidermal growth factor receptor (EGFR) or v-RAF murine sarcoma viral oncogene homolog B (BRAF) gene V600E mutations. Fluorescence in situ hybridization (FISH) did not detect anaplastic lymphoma kinase (ALK) gene fusions, proto-onocogene 1 receptor tyrosine kinase of ROS (ROS-1) gene rearrangements, or tyrosine-protein kinase Met (hepatocyte growth factor receptor) (MET) gene amplifications. In July 2015, she started chemotherapy with cisplatin plus pemetrexed, developing adrenal insufficiency secondary to bilateral adrenal metastases, which required glucocorticoid and mineralocorticoid supplementation. Four cycles later, a partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was obtained. After maintenance treatment with pemetrexed for 12 cycles, in July 2016 radiological progressive disease (PD) was documented at retroperitoneum and adrenal glands. In August 2016 and September 2016, three cycles of docetaxel were administered with growing metastasis only at the left adrenal gland. With the advent of the ChekMate057 results [], immunotherapy was proposed. PD-L-1 IHC (DAKO 22C3 antibody) on right groin adenopathies resulted in positivity of 30% and tumor sample was exhausted. To make sure the patient did not have any actionable genomic alteration, a comprehensive liquid biopsy Guardant360 test was performed. It reported 97 genomic variants with 19 actionable alterations (six at ARID1A gene, RET fusions, EGFR R776H mutation, BRCA1/2 and CDKN2A mutations). PD-L1 positivity, with the inference of a hypermutator phenotype, was considered to support the choice of immunotherapy with the patient’s agreement. Nivolumab 3 mg/kg intravenously every 2 weeks was administered for 38 cycles. After seven cycles, a PR by RECIST in cancer immunotherapy trials (iRECIST) was achieved (iPR). Immunotherapy was maintained for 19 months, from December 2016 to September 2018, with further confirmed PD iRECIST (iCPD) by solid biopsy of a new metastasis at the right deltoid muscle. The sample of this metastasis went into a multinational, prospective molecular screening program called ARCHE (OncoDNA S.A., Belgium), performing OncoDEEP™ comprehensive panel with 76 genes and personalized tumor immunogram. In the metastasis at the right deltoid muscle, the platform revealed PD-L1 positivity of greater than 50% with CD8+ T cells expression by IHC, and showed MSI with a deleterious c.298C>T (p.R100*) mutL homolog 1 (MLH1) gene mutation (variant allele frequency [VAF] 30%). In December 2018, a PR was achieved with cisplatin plus pemetrexed reintroduction since October 2018, but the disease progressed shortly after. Immunotherapy rechallenge and vinorelbine did not succeed either.