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Gastroesophageal adenocarcinoma (GEA) is one of the principal causes of death related to cancer globally. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor which is found to be overexpressed or amplified in approximately 20% of GEA cases. In GEA, the identification of HER2-positive status is crucial to activate a specific anti-HER2 targeted therapy. The landmark ToGA trial demonstrated the superiority of adding trastuzumab to platinum-based chemotherapy, becoming the first-line standard of treatment. However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic horizons of various cancers. However, immune-related adverse events have been reported, including interstitial lung diseases. Our aim was to describe the clinical and radiological features and survival of a multicentre cohort of patients who developed ICI-related lung toxicity. Methods: Six Italian centres were involved in the study. Patients who were treated with anti-PD-1/PD-L1 and CTLA-4 mAbs and developed ICI-related lung toxicity were recruited retrospectively to study clinical, radiological, immunological and survival data. Results: A total of 41 patients (25 males, 66.8 ± 9.9 years) were enrolled. Lung toxicity occurred after 204.3 ± 208.3 days of therapy, with ground glass opacities being the most common HRCT pattern (23 cases). Male sex, lung cancer and acute respiratory failure were associated with a shorter latency of toxicity (p = 0.0030, p = 0.0245 and p = 0.0390, respectively). Patients who required high-flow oxygen therapy showed significantly worse survival (p = 0.0028). Conclusions: Our cohort showed heterogeneous clinical and radiological aspects of ICI-related lung toxicity, with a latency not limited to the first year of treatment. Severity was mainly mild to moderate, although life-threatening events did occur. Our data indicate that strict long-term follow-up is needed to enable early diagnosis and appropriate management. [ABSTRACT FROM AUTHOR]

Based on improved survival from the addition of PD-L1 inhibitors in phase III trials, the combination of immunotherapy and platinum-doublet chemotherapy has become the new standard treatment for extended-stage small-cell lung cancer (ES-SCLC). Furthermore, the antiangiogenetic agent bevacizumab showed a longer progression-free survival by targeting VEGF that has pleiotropic effects, including immunosuppressive ones. We, therefore, hypothesized that targeting angiogenesis would improve the efficacy of chemoimmunotherapy. The CeLEBrATE trial is an open-label, multicenter, phase II study designed to assess the efficacy and safety of the combination of carboplatin and etoposide plus bevacizumab and atezolizumab in treatment-naive patients with ES-SCLC. The primary end point is overall survival rate at 1 year, while secondary end points include overall response rate, progression-free survival and toxicity. [ABSTRACT FROM AUTHOR]

Abstract Background Cancer patients receiving chemotherapy are at increased risk of thrombosis. Nadroparin has been demonstrated to reduce the incidence of venous and arterial thrombotic events (TEs) by about 50% in cancer outpatients receiving chemotherapy. The aims of this retrospective analysis were to evaluate the thromboembolic risk and the benefit of thromboprophylaxis according to type of chemotherapy. Methods Cancer outpatients were randomly assigned to receive subcutaneous injections of nadroparin or placebo. The incidence of symptomatic TEs was assessed according to the type of chemotherapy. Results were reported as risk ratios with associated 95% CI and two-tailed probability values. Results 769 and 381 patients have been evaluated in the nadroparin and placebo group, respectively. In the absence of thromboprophylaxis, the highest rate of TEs was found in patients receiving gemcitabine- (8.1%) or cisplatin-based chemotherapy (7.0%). The combination of gemcitabine and cisplatin or carboplatin increased the risk to 10.2%. Thromboprophylaxis reduced TE risk by 68% in patients receiving gemcitabine; with a further decrease to 78% in those receiving a combination of gemcitabine and platinum. Conclusions This retrospective analysis confirms that patients undergoing chemotherapy including gemcitabine, platinum analogues or their combination are at higher risk of TEs. Our results also suggest that outpatients receiving chemotherapy regimens including these agents might achieve an increased benefit from thromboprophylaxis with nadroparin. Clinical Trial registration number: NCT 00951574

Objectives: The prevalence of Skeletal Related Adverse Events (SREs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with bone metastases, treated with modern tyrosine kinase inhibitors (TKIs), has been scarcely investigated. Materials and Methods: We retrospectively evaluated the data of EGFR mutated NSCLC patients with bone metastases treated with TKIs in 12 Italian centers from 2014 to 2019, with the primary aim to explore type and frequency of SREs. Results: Seventy-seven out of 274 patients enrolled (28%) developed at least one major SRE: 55/274 (20%) bone fractures, 30/274 (11%) spinal cord compression, 5/274 (2%) hypercalcemia. Median time to the onset of SRE was 3.63 months. Nine patients (3%) underwent bone surgery and 150 (55%) radiation therapy on bone. SREs were more frequently observed within the 12 months from TKI start than afterwards (71 vs 29%, p 0.000). Patient Performance Status and liver metastases where independently associated with the risk of developing SREs. Median TKI exposure and overall survival were 11 and 28 months, respectively. Bone resorption inhibitors were associated with a lower risk of death (HR 0.722, 95% CI: 0.504–1.033, p = 0.075) although not statistically significant at multivariate analysis. Conclusion: Bone metastatic NSCLC patients with EGFR mutated disease, treated with EGFR TKIs, have a relatively long survival expectancy and are at high risk to develop SREs. The early SRE occurrence after the TKI start provides the rationale to administer bone resorption inhibitors. [ABSTRACT FROM AUTHOR]

Background: Cytidine deaminase (CDA) plays a crucial role in the degradation of gemcitabine. In our previous retrospective study, CDA enzymatic activity was the strongest prognostic biomarker of the activity and efficacy of platinum/gemcitabine combinations. The aim of this prospective study was to validate the prognostic role of CDA activity in the first-line treatment of advanced non-small-cell lung cancer.Methods: A total of 124 untreated patients received standard doses of platinum/gemcitabine. CDA activity was baseline measured in plasma samples by spectrophotometric assay.Results: Using the median CDA level as cut-off, in the patients with high versus low CDA activity the response rate was 25.0% (95% CI, 14.7-37.8) and 54.1% (95% CI, 40.8-66.9), P = 0.0013; the 6-month progression rate was 34.5% (95% CI, 22.6-46.6) and 54.1% (95% CI, 40.9-65.6), HR = 2.01 (95% CI, 1.32-3.06), P < 0.001; the 1-year survival rate was 23.3% (95% CI, 13.6-34.6) and 57.3% (95% CI, 43.9-68.6), HR = 2.20 (95% CI, 1.46-3.34), P = 0.0002, respectively. CDA activity resulted to be an independent prognostic factor for progression and survival at multivariate analysis.Conclusions: This study validated prospectively the prognostic role of the CDA activity and should prompt larger and adequately designed randomised prospective studies to establish the predictive impact of this test in improving the outcome of selected patients. [ABSTRACT FROM AUTHOR]

Background: Patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) have a higher risk of developing brain metastases (BMs) than patients with other NSCLC sub-types. ALK inhibitors have activity in BMs due to ALK+ NSCLC. We performed a systematic review of the literature with the aim of assessing the efficacy of ALK inhibitors on BMs. Material and methods: A systematic search of the literature was performed using the databases Pubmed, EMBASE, Web of Science, The Cochrane Library, and SCOPUS. Relevant publications reporting activity of ALK inhibitors in NSCLC BMs were retrieved. Data were pooled using the number of events/number of evaluable patients according to fixed or random effect models. Intracranial tumour response was assessed through overall response rate (ORR), disease control rate (DCR: ORR + stable disease rate), median progression-free survival (PFS), and overall survival (OS). The primary endpoint was intracranial overall response rate (IC ORR). Results: A total of 1,016 patients with BMs from 21 studies were analysed. In patients receiving ALK inhibitors in the first line setting, the pooled IC ORR was 39.17% (95%CI 13.1–65.2%), while the pooled IC ORR observed in further lines was 44.2% (95%CI 33.3–55.1%). Intracranial disease control rate (IC DCR) was 70.3% and 78.2% in naïve and pre-treated patients, respectively. Patients who had not received brain radiation attained an IC ORR of 49.0%. Conclusions: Based on these data, ALK inhibitors are effective in both naive and pre-treated patients with similar IC ORR and IC DCR, irrespective of the line of therapy. [ABSTRACT FROM AUTHOR]

The activation of lymphocytes by gefitinib treatment has been described. In this phase II pilot trial, we explored the possible synergism between IL-2 and gefitinib for non-small cell lung cancer (NSCLC) treatment. From September, 2003, to November, 2006, 70 consecutive patients with advanced, progressive NSCLC, previously treated with chemotherapy, received oral gefitinib 250 mg daily. The first 39 patients received gefitinib alone (G group). The other 31 also received subcutaneous IL-2 (GIL-2 group): 1 MIU/m2 (Million International Unit/m2)twice a day on Days 1 and 2, once a day on Days 3, 4, 5 every week for four consecutive weeks with a four-week rest period. Median follow-up was 25.2 months. Grade 3-4 toxicity of gefitinib was represented by skin rash (7%), asthenia/anorexia (6%) and diarrhea (7%); patients treated with IL-2 showed grade 2-3 fever (46%), fatigue (21%) and arthralgia (13%). In the GIL-2 group and G-group, we respectively observed: an overall response rate of 16.1% (6.4% complete response) and 5.1% (only partial response); a disease control rate of 41.9% and 41%; a median time to progression of 3.5 (CI 95% = 3.2-3.8) and 4.1 (CI 95% = 2.6-5.7) months; a median overall survival of 20.1 (CI 95% = 5.1-35.1) and 6.9 (CI 95% = 4.9-8.9) months (p = 0.002); and an actuarial one-year survival rate of 54% and 30%. Skin toxicity (p < 0.001; HR = 0.29; CI 95% = 0.16-0.54) and use of IL-2 (p < 0.001; HR = 0.33; CI 95% = 0.18-0.60) were independently associated with improvement of survival. In this consecutive, non-randomized, series of advanced NSCLC patients, the use of IL-2 increased the efficacy of gefitinib. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (CKIs) are therapeutic weapons in several advanced malignancies. Performance status is a validated prognostic variable in cancer patients; it possibly affects the efficiency of the immune system. We performed a systematic review and meta-analysis to investigate the predictive role of PS toward treatment with CKIs in cancer patients. Following PRISMA guidelines, an electronic search from PubMed, The Cochrane Library and Embase was performed, from the inception of each database to May 31, 2018. Inclusion criteria were (1) randomized trials comparing CKI with standard therapy for the treatment of patients with solid tumors; (2) information on overall survival (OS) according to PS; (3) full text available; and (4) reported in English language. Data were pooled using HRs for OS according to random effect model. The effect of experimental versus control arms was evaluated in PS = 0 and 1-2 subgroups, and the heterogeneity between the two estimates was assessed using an interaction test. The OS differences between PS = 0 and PS = 1-2 strata were evaluated in all studies and according to predefined subgroups. Eighteen studies were eligible, with 11,354 patients [PS = 0 group 5217 patients (46%); PS = 1-2 group 6137 patients (54%)]. The pooled HR for OS was 0.78 (95% CI 0.69-0.89) in PS = 0 patients. In PS = 1-2 patients, the pooled OS HR was 0.78 (95% CI 0.71-0.86). The OS difference between PS = 0 and PS = 1-2 patients treated with CKI was not significant (P = 0.99). CKI improves survival irrespective of patients' PS. PS should not guide treatment choice for anticancer immunotherapy. [ABSTRACT FROM AUTHOR]