BACKGROUND: Surrogate biomarkers of efficacy are needed for anti-PD1/PD-L1 therapy, given the existence of delayed responses and pseudo-progressions. We evaluated changes in serum IL-8 levels as a biomarker of response to anti-PD-1 blockade in melanoma and non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Metastatic melanoma and NSCLC patients treated with nivolumab or pembrolizumab alone or nivolumab plus ipilimumab were studied. Serum was collected at baseline; at 2-4 weeks after the first dose; and at the time-points of response evaluation. Serum IL-8 levels were determined by sandwich ELISA. Changes in serum IL-8 levels were compared with the Wilcoxon test and their strength of association with response was assessed with the Mann-Whitney test. Accuracy of changes in IL-8 levels to predict response was estimated using receiver operation characteristics curves. RESULTS: Twenty-nine melanoma patients treated with nivolumab or pembrolizumab were studied. In responding patients, serum IL-8 levels significantly decreased between baseline and best response (P <0.001), and significantly increased upon progression (P = 0.004). In non-responders, IL-8 levels significantly increased between baseline and progression (P = 0.013). Early changes in serum IL-8 levels (2-4 weeks after treatment initiation) were strongly associated with response (P <0.001). These observations were validated in 19 NSCLC patients treated with nivolumab or pembrolizumab (P = 0.001), and in 15 melanoma patients treated with nivolumab plus ipilimumab (P <0.001). Early decreases in serum IL-8 levels were associated with longer overall survival in melanoma (P = 0.001) and NSCLC (P = 0.015) patients. Serum IL-8 levels also correctly reflected true response in three cancer patients presenting pseudoprogression. CONCLUSIONS: Changes in serum IL-8 levels could be used to monitor and predict clinical benefit from immune checkpoint blockade in melanoma and NSCLC patients.
Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/drug therapy , Interleukin-8/blood , Lung Neoplasms/drug therapy , Melanoma/drug therapy , Skin Neoplasms/drug therapy , Adult , Antineoplastic Agents, Immunological/pharmacology , Carcinoma, Non-Small-Cell Lung/blood , Cohort Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Lung Neoplasms/blood , Male , Melanoma/blood , Middle Aged , Skin Neoplasms/blood , Survival Analysis
Mutation analysis of epidermal growth factor receptor (EGFR) gene is essential for treatment selection in non-small cell lung cancer (NSCLC). Analysis is usually performed in tumor samples. We evaluated the clinical utility of EGFR analysis in plasma cell-free DNA (cfDNA) from patients under treatment with EGFR inhibitors. We selected 36 patients with NSCLC and EGFR-activating mutations. Blood samples were collected at baseline and during treatment with EGFR inhibitors. Wild-type EGFR, L858R, delE746-A750, and T790M mutations were quantified in cfDNA by droplet digital PCR. Stage IV patients had higher total circulating EGFR copy levels than stage I (3523 vs. 1003 copies/mL; p < 0.01). There was high agreement for activating mutations between baseline cfDNA and tumor samples, especially for L858R mutation (kappa index = 0.679; p = 0.001). In 34 % of advanced NSCLC patients, we detected mutations in cfDNA not previously detected in tumor samples and double mutations in 17 %. Patients with baseline total EGFR copy levels above the median presented decreased overall survival (OS) (341 vs. 870 days, p < 0.05) and progression-free survival (PFS) (238 vs. 783 days; p < 0.05) compared with those with total EGFR copy levels below the median. Patients with baseline concentrations of activating mutations above the median (94 copies/mL) had lower OS (317 vs. 805 days; p < 0.05) and PFS (195 vs. 724 days; p < 0.05). During follow-up, T790M resistance mutation was detected in 53 % of patients. Total and mutated EGFR analysis in cfDNA seems a relevant tool to characterize the molecular profile and prognosis of NSCLC patients harboring EGFR mutations.
Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Lung Neoplasms/pathology , Mutation/genetics , Protein Kinase Inhibitors/therapeutic use , Carcinoma, Non-Small-Cell Lung/classification , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , DNA Mutational Analysis/methods , Drug Resistance, Neoplasm/genetics , Female , Follow-Up Studies , Humans , Lung Neoplasms/classification , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Male , Middle Aged , Neoplasm Staging , Prognosis , Real-Time Polymerase Chain Reaction , Retrospective Studies , Survival Rate
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Compassionate Use Trials , Endometrial Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Sirolimus/analogs & derivatives , Administration, Intravenous/methods , Adult , Breast Neoplasms/mortality , Breast Neoplasms/secondary , Carcinoma/mortality , Carcinoma/secondary , Compassionate Use Trials/methods , Endometrial Neoplasms/mortality , Endometrial Neoplasms/secondary , Female , Follow-Up Studies , Humans , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Lung Neoplasms/mortality , Lung Neoplasms/secondary , Male , Middle Aged , Retrospective Studies , Sirolimus/therapeutic use , Survival Analysis , Treatment Outcome
Antineoplastic Agents/adverse effects , Carboplatin/adverse effects , Drug Hypersensitivity/diagnosis , Hypersensitivity, Delayed/diagnosis , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bevacizumab , Carboplatin/therapeutic use , Drug Hypersensitivity/etiology , Female , Humans , Hypersensitivity, Delayed/etiology , Middle Aged , Ovarian Neoplasms/drug therapy , Paclitaxel/therapeutic use , Peritoneal Neoplasms/drug therapy , Skin Tests/methods