A 56-year-old man with a history of hypercholesterolemia and myocardial infarction presented in December 2013 with a dermatologic lesion in the left lumbar region. The pathologic examination of the excisional biopsy revealed an ulcerated malignant melanoma of 6.5 mm in thickness (Breslow). The type was a superficial spreading melanoma, and the Clark level was 4.
After a wide excision of the lesion with 2 cm margins, the pathologic results of the sentinel lymph nodes showed an invasion of malignant melanoma, requiring a subsequent complete left inguinal lymph node dissection. The pathologic TNM stage was pT4bpN1acM0 according to the 7th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system. The primary tumor exhibited the typical BRAF V600E mutation.
Four months later, in April 2014, the patient presented a locoregional cutaneous and subcutaneous relapse in the lumbar region. First-line treatment consisted of the single-agent BRAF inhibitor vemurafenib, which had to be stopped, despite a clinical response, due to unacceptable toxicities, such as a grade 4 skin rash and a grade 2 daily fever. A shift to dabrafenib in combination with trametinib in a medical need programme was initiated in July 2014 and stopped in December 2014 after clinical progression of the lumbar local relapse and of multiple in-transit metastases.
Between January and March 2015, the patient received 4 injections of ipilimumab, a monoclonal anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibody. The main adverse effect after the fourth injection was excessive fatigue, which was attributed to auto-immune hypophysitis with adrenal and gonadal insufficiencies requiring hormonal substitution of hydrocortisone and topic testosterone, respectively. After 4 doses of ipilimumab, positron emission tomography/computed tomography (PET/CT) unfortunately showed progressive disease and the appearance of lung and lymph node metastases.
Starting in July 2015, the patient was treated with nivolumab (twice every week), a monoclonal anti-programmed cell death 1 (PD-1) antibody, within the framework of a phase II trial. A CT scan performed after 8 weeks of nivolumab treatment demonstrated clear disease progression, including cutaneous and subcutaneous, lymph node, pleuro-pulmonary, renal, and peritoneal metastases (Fig. 1a, b). At this point, biological analyses indicated elevated serum lactate dehydrogenase (LDH) levels.
Two molecular analyses of the tumor, one using OncoDeep (OncoDNA, Gosselies, Belgium) and the other using the TruSeq Illumina Cancer Panel (Illumina Inc., San Diego, CA, USA), were performed after the failure of nivolumab (at the end of August 2015). The results were discordant: the OncoDNA detected only one BRAF V600E mutation, whereas the Illumina Panel (TruSeq Amplicon Cancer Panel) detected BRAF V600E-F-box and WD repeat domain containing 7 R385C mutations (FBXW7), a kinase domain insert receptor Q472H variant (KDR), a V-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue G12D mutation (KRAS), a tumor protein P53 P72R variant (P53), and a polymorphism of Ataxia telangiectasia mutated (ATM) −c.8850 + 60A > G.
Since September 2015, the patient had received 4 cycles of cytotoxic chemotherapy consisting of intravenous injections of dacarbazine (350 mg/m2) and cisplatin (25 mg/m2) for 3 consecutive days, given every 3–4 weeks. An ongoing, impressive, and dramatic response of all metastases (the sizes decreased by more than 80%) was documented after 3 cycles of chemotherapy (Fig. 1c, d).
During chemotherapy, a second biopsy was performed, and the same mutations were detected, but there was a difference in the percentage of cells with the BRAF V600E mutation (41% in August 2015 and 36% in November 2015).
After the failure of checkpoint inhibitors, an immunological biomarker and microenvironment analysis revealed the absence of PD-1/programmed death-ligand 1 (PD-L1) (Ventana biomarker assay) staining, the absence of CD20 (B cells) staining, and diffuse and weak CD3 (T cells) staining.
We summarized the treatment provided to this patient in a flow chart (Fig. 2).