BackgroundImmune checkpoint inhibitors have changed the paradigm of cancer treatment; however, non-invasive biomarkers of response are still needed to identify candidates for non-responders. We aimed to investigate whether immunotherapy [18F]FDG PET radiomics signature (iRADIOMICS) predicts response of metastatic non-small-cell lung cancer (NSCLC) patients to pembrolizumab better than the current clinical standards.Patients and methodsThirty patients receiving pembrolizumab were scanned with [18F]FDG PET/CT at baseline, month 1 and 4. Associations of six robust primary tumour radiomics features with overall survival were analysed with Mann-Whitney U-test (MWU), Cox proportional hazards regression analysis, and ROC curve analysis. iRADIOMICS was constructed using univariate and multivariate logistic models of the most promising feature(s). Its predictive power was compared to PD-L1 tumour proportion score (TPS) and iRECIST using ROC curve analysis. Prediction accuracies were assessed with 5-fold cross validation.ResultsThe most predictive were baseline radiomics features, e.g. Small Run Emphasis (MWU, p = 0.001; hazard ratio = 0.46, p = 0.007; AUC = 0.85 (95% CI 0.69–1.00)). Multivariate iRADIOMICS was found superior to the current standards in terms of predictive power and timewise with the following AUC (95% CI) and accuracy (standard deviation): iRADIOMICS (baseline), 0.90 (0.78–1.00), 78% (18%); PD-L1 TPS (baseline), 0.60 (0.37–0.83), 53% (18%); iRECIST (month 1), 0.79 (0.62–0.95), 76% (16%); iRECIST (month 4), 0.86 (0.72–1.00), 76% (17%).ConclusionsMultivariate iRADIOMICS was identified as a promising imaging biomarker, which could improve management of metastatic NSCLC patients treated with pembrolizumab. The predicted non-responders could be offered other treatment options to improve their overall survival.

After monotherapy with gemcitabine in low dose in long infusion, promising results in a variety of advanced chemoresistant tumors have been reported. In a previous phase I trial on heavily pre-treated patients, maximum tolerated dose (MTD) of gemcitabine in a 6 h infusion was 250 mg/m. The objective of our phase I-II trial was to test the combination of gemcitabine in a 6-h infusion and cisplatin in the treatment of advanced non-small cell lung cancer (NSCLC). Eligible patients were chemonaive, had locally advanced or metastatic NSCLC, Eastern Oncology Cooperative Oncology Group performance status 0-2 and normal organ function. Treatment consisted of gemcitabine in a 6-h infusion on days 1 and 8, and cisplatin at 75 mg/m on day 2 of a 3-week cycle. During phase I of the trial, the dose of gemcitabine was escalated from 130 to 170, 210 and 250 mg/m. After establishing dose-limiting toxicity (DLT) and MTD of the combination, the trial continued as phase II. Altogether, 61 patients were enrolled, of whom 54 had stage IV disease. In phase I of the trial, groups of six, seven, eight and eight patients were treated at the four dose levels of gemcitabine. In phase II, the remaining 32 patients all received gemcitabine at 250 mg/m. Serious toxicity included a patient with grade 5 ventricular arrhythmia and another with grade 4 cerebrovascular ischemia; four patients had grade 3 anemia. Reversible thrombocytosis with platelets over 500 was recorded in 32 patients; 42 patients had grade 2 alopecia. In general, tolerance to this treatment was good. One patient had complete response and 27 had partial responses, for a 28 of 61 (46%) response rate. Median progression-free survival, median survival and 1-year survival were 6 months, 9.5 months and 40%, respectively. We conclude that this treatment has an acceptable, yet distinct, toxicity profile; routine thromboprophylaxis is recommended. In our population of chemonaive patients, no DLT has been encountered. Due to the remarkable response rate, further research is warranted.

After a favorable experience with gemcitabine at a low dose in a prolonged infusion in combination with cisplatin for advanced non-small-cell lung cancer, here, we present the results from a phase II trial for patients with malignant pleural mesothelioma. Eligible patients had biopsy-proven malignant pleural mesothelioma, were chemo-naive, Eastern Cooperative Oncology Group performance status 0-2, had normal hematopoietic liver and renal function, and gave informed consent. Treatment consisted of gemcitabine 250 mg/m in a 6-h infusion on days 1 and 8 and cisplatin at 75 mg/m on day 2 of a 3-week cycle for four cycles, followed by two additional cycles without cisplatin. Seventy-eight patients (58 men, 20 women; age 33-82 years, median 58) were recruited into the trial. The histologic types were as follows: epitheloid 56 (71.8%); four sarcomatoid (5.1%); mixed 15 (19.2%); and mesothelioma, three not otherwise specified (3.8%). Grades 3-4 toxicity included two (2.6%) patients with anemia, 18 (23.1%) with neutropenia, and one with nausea/vomiting. Reversible thrombocytosis with platelets over 1000-10/l was recorded in 10 (12.8%) patients and grade 2 alopecia in 60 (76.9%). Four (5.1%) patients showed a complete response and 35 (44.9%) showed a partial response with a response rate of 39/78 (50%). Minimal response or stable disease was seen in 35 (44.9%), whereas only four (5.1%) patients progressed during treatment. Most patients reported symptomatic improvement with a higher or a stable quality of life score in 70 (89.7%) cases. The median progression-free survival was 8.0 months (confidence interval 6.9-9.0). The median overall survival was 17.0 months (confidence interval 14.7-19.2). One-year, two-year, and three-year survival rates were 67.3, 32.7, and 19.8%, respectively. Epitheloid histological type was the only statistically significant favorable prognostic factor for progression-free survival and overall survival. Because of the acceptable toxicity, remarkable activity, and reasonable cost, this treatment should be further explored.

BackgroundUncommon response during immunotherapy is a new challenging issue in oncology practice. Recently, new criteria for evaluation of response to immunotherapy immune response evaluation criteria in solid tumors (iRECIST) were accepted. According to iRECIST, worsening of performance status (PS) accompanied to pseudoprogression reflects most probably the true progression of the malignant disease.MethodsA systematic review of the literature was made by using several electronic database with the following search criteria: symptomatic pseudoprogression, atypical response, immunotherapy and lung cancer.ResultsIn the literature, we identified five reports of seven patients treated with immunotherapy that met the inclusion criteria. We also report our experience of patient with pseudoprogression and almost complete response after one dose of immunotherapy.ConclusionsAs seen from our review, iRECIST criteria might be insufficient in distinguishing true progression from pseudoprogression in some patients with advanced NSCLC treated with immunotherapy. More precise assessment methods are urgently needed.