Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and progression-free survival (PFS) in cancer patients treated with ICIs. Publications that compared steroids with non-steroid users in cancer patients treated with ICIs from inception to June 2019 were identified by searching the EMBASE, PubMed, SCOPUS, Web of Science, and Cochrane Library databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Patients (studies, n = 16; patients, n = 4045) taking steroids were at increased risk of death and progression compared to those not taking steroids (HR = 1.54, 95% CI: 1.24–1.91; p = 0.01 and HR = 1.34, 95% CI: 1.02–1.76; p = 0.03, respectively). The main negative effect on OS was associated with patients taking steroids for supportive care (HR = 2.5, 95% CI 1.41–4.43; p < 0.01) or brain metastases (HR = 1.51, 95% CI 1.22–1.87; p < 0.01). In contrast, steroids used to mitigate adverse events did not negatively affect OS. In conclusion, caution is needed when steroids are used for symptom control. In these patients, a negative impact of steroid use was observed for both OS and PFS.

The role of CTLA-4 in negative regulation of T-cell mediated immune response is particularly well established. Much less is known about its expression and function in tumour cells, and to our knowledge, no data are available on its possible impact on prognosis of NSCLC patients. We investigated CTLA-4 expression and prognostic role in 81 patients with radically resected stage I-III NSCLC. The analysis was performed by tissue microarray immunohistochemistry, and the median H-score of 20 was used as a threshold to define CTLA-4 overexpressing tumours. Correlation with standard prognostic factors was performed by using absolute and relative fold change indexes. Hazard ratios (HR) and corresponding 95% confidence limits (95% CL) were computed through the Cox model. A higher frequency of CTLA-4 overexpression (>20) was found in non-squamous than in squamous NSCLC (52.8 vs. 35.7%) and in Ki67 ≤ 15 expressing tumours, as compared to those with Ki67 > 15 (51.5 vs. 38.7%). A reduced death rate was found in CTLA-4 overexpressing tumours (HR = 0.60, 95% CL = 0.28/1.23), and a further decrease was observed when considering tumours with CTLA-4 > 20 and Ki67 ≤ 15, in comparison with tumours with CTLA-4 ≤ 20 and Ki67 > 15 (HR = 0.41; 95% CL = 0.15/1.13). Our observational and exploratory study provides a first and promising indication for an independent prognostic effect of CTLA-4 overexpression in radically resected NSCLC. We presume that this effect relies on modulation of the interaction of microscopic disease with CTLA-4-ligands expressing cells leading to NSCLC cell death.

Background CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung cancer, respectively. Their role in cancer immunotherapy needs to be elucidated. Methods Patients with advanced non-small cell lung cancer (NSCLC) were treated with nivolumab 3 mg/kg every 2 weeks within the Italian Nivolumab Expanded Access Program. Blood samples were collected at baseline, at each cycle up to cycle 5 and then every two cycles until patient’s withdrawn from the study. All patients underwent a CT-scan after every 4 cycles of treatment and responses were classified according to RECIST 1.1. The biomarkers serum levels were measured with a chemiluminescent microparticle immunoassay for CEA and with an immuno radiometric assay for CYFRA21-1 and NSE. The markers values at baseline and after 4 cycles were used to analyze the relationship between their variation over baseline and the tumor response, evaluated as disease control rate (DCR: CR + PR + SD), and survival (PFS and OS). Results A total of 70 patients were evaluable for the analysis. Overall, a disease control was obtained in 24 patients (35.8%, 4 PR + 20 SD). After 4 cycles of nivolumab a CEA or CYFRA21-1 reduction ≥ 20% over the baseline was significantly associated with DCR (CEA, p = 0.021; CYFRA21-1, p < 0.001), PFS (CEA, p = 0.028; CYFRA21-1, p < 0.001) and OS (CEA, p = 0.026; CYFRA21-1, p = 0.019). Multivariate analysis confirmed the ability of CYFRA21-1 reduction ≥ 20% to predict DCR (p = 0.002) and PFS (p < 0.001). Conclusion The reduction in serum level of CYFRA21-1 or CEA might be a reliable biomarker to predict immunotherapy efficacy in NSCLC patients. NSE was not significant for monitoring the efficacy of nivolumab.

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BackgroundSome concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.MethodsWe present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.Results950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.ConclusionIn this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

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Non-small cell lung cancer is one leading cause of death worldwide, and patients would greatly benefit from an early diagnosis. Since targeted and immunotherapies have emerged as novel approaches for more tailored treatments, repeated assessments of the tumor biology have become pivotal to drive clinical decisions. Currently, tumor tissue biopsy is the gold standard to investigate potentially actionable biomarkers, but this procedure is invasive and may prove inadequate to represent the whole malignancy. In this regard, liquid biopsy represents a minimally invasive and more comprehensive option for early detection and investigation of this tumor. Today, cell-free DNA is the only approved circulating marker to select patients for a targeted therapy. Conversely, the other tumor-derived markers (i.e., circulating tumor cells, miRNAs, exosomes, and tumor educated platelets) are still at a pre-clinical phase, although they show promising results for their application in screening programs or as prognostic/predictive biomarkers. The main challenges for their clinical translation are the lack of reliable cutoffs and, especially for miRNAs, the great variability among the studies. Moreover, no established tool has been approved for circulating tumor cells and exosome isolation. Finally, large prospective clinical trials are mandatory to provide evidence of their clinical utility.

Myocarditis is a rare but serious adverse event of immune checkpoint blockade with nivolumab, which needs to be recognized as soon as possible. This article suggests that troponin, a user-friendly biomarker of myocardial cytotoxicity, might be useful for early detection of immune-mediated myocarditis. However, because troponin abnormalities might also be related to a number of conditions capable of causing myocardial oxygen demand-supply mismatch, a careful cardiac assessment should be performed in non-small cell lung cancer patients in order to properly interpret any troponin increase. According to the available evidence, monitoring troponin during the first weeks of treatment can be considered reasonable.