Epidermal Growth Factor Receptor (EGFR)–Tyrosine Kinase Inhibitors (TKIs) Combined with Chemotherapy Delay Brain Metastasis in Patients with EGFR‑Mutant Lung Adenocarcinoma The article Epidermal Growth Factor Receptor (EGFR)–Tyrosine Kinase Inhibitors (TKIs) Combined with Chemotherapy Delay Brain Metastasis in Patients with EGFR-Mutant Lung Adenocarcinom, written by Changhui Li, Bo Zhang, Jindong Guo, Fang Hu, Wei Nie, Xiaoxuan Zheng, Lixin Wang, Yuqing Lou, Yinchen Shen, Baohui Han, Xueyan Zhang, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 03 July 2019 with open access. With the author(s)’ decision to step back from Open Choice, the copyright of the article changed on 17 July 2019 to © Springer Nature Switzerland AG 2019 and the article is forthwith distributed under the terms of copyright.

The Role of Checkpoint Inhibitors in Glioblastoma Abstract Given its poor prognosis, glioblastoma represents an area of high unmet clinical need. Standard of care for the treatment of glioblastoma in the frontline setting is limited to surgical resection, radiation, and temozolomide, with the more recent addition of Tumor Treating Fields. Several agents, including bevacizumab, lomustine, and carmustine have been approved in the recurrent setting. To date, no therapies have demonstrated substantial survival benefit beyond standard of care. An expanding understanding of the role of the immune system in fighting cancer has led to the development and approval of various immunotherapeutic approaches across solid tumors. In glioblastoma, the notion of a highly immune-restricted central nervous system has also evolved, further providing the rationale for testing therapies that promote immune trafficking to the CNS and infiltration into the tumor to counteract the immunosuppressive mechanisms that support tumor progression. There are five broad categories of immunotherapies currently being tested in GBM: vaccines, cytokine therapy, oncolytic viral therapy, chimeric antigen receptor T cell therapy, and checkpoint inhibitors. This review focuses on checkpoint inhibitors in GBM, the rationale for its use, preclinical data, and early clinical experience. Efficacy data are limited, and while a number of late-stage trials are ongoing, early trials showed no benefit in survival. There is a dizzying array of combinations being tested in clinical studies with an urgent need for a rational approach to determine the role of checkpoint inhibitors in glioblastoma, including the optimal combinations, and identification of biomarkers or predictive models to determine which patients may benefit from immunotherapy.

Combination Treatment with an Antibody–Drug Conjugate (A1mcMMAF) Targeting the Oncofetal Glycoprotein 5T4 and Carboplatin Improves Survival in a Xenograft Model of Ovarian Cancer Abstract Background Recurrence occurs in over 75% of women with epithelial ovarian cancer despite optimal treatment. Selectively killing tumour cells thought to initiate relapse using an antibody–drug conjugate could prolong progression-free survival and offer an improved side-effect profile. A1mcMMAF is an antibody–drug conjugate designed to target cells expressing the tumour-associated antigen 5T4. It has shown to be efficacious in various cell line models and have a greater impact when combined with routine chemotherapeutic regimes. Objectives This study aims to explore the potential for the use of a 5T4 antibody–drug conjugate in women with ovarian cancer both as a monotherapy and in combination with platinum-based chemotherapy. Methods Immunohistochemical analysis was used to assess 5T4 expression in tumours from patients with ovarian cancer. Effectiveness of A1mcMMAF therapy as a single agent and in combination with carboplatin was assessed in vitro in the ovarian cancer cell line SKOV3 and confirmed in vivo using a serial bioluminescence assay in a SKOV3 xenograft model of ovarian cancer. Results 5T4 is confirmed as suitably expressed in epithelial ovarian cancers prior to adjuvant therapy and is an independent predictor of poor survival. A1mcMMAF showed specific activity, both in vitro and in vivo, against SKOV3 ovarian cancer cells. When used in combination with carboplatin, in vivo tumour growth was inhibited resulting in prolonged survival in a SKOV3 xenograft model. Conclusions These data support further investigation of A1mcMMAF in combination with platinum-based chemotherapy in ovarian and other cancer treatments.

Phase I Trial of Targeted EGFR or ALK Therapy with Ipilimumab in Metastatic NSCLC with Long-Term Follow-Up Abstract Background The natural histories of, and treatment options for, epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancers (NSCLCs) are distinctly different from those of lung cancer that lacks actionable mutations. Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor that has been approved in other malignancies. Objective A phase I trial of ipilimumab plus targeted therapy with either erlotinib or crizotinib was performed to assess the safety of the combination in patients with EGFR-mutated or ALK-rearranged advanced NSCLC. Methods Patients with EGFR-mutated or ALK-rearranged NSCLC on a stable dose of erlotinib or crizotinib for > 28 days were eligible for the study. Patients were treated with ipilimumab 3 mg/kg for four cycles plus erlotinib or crizotinib. Results Treatment of the EGFR cohort resulted in dose-limiting toxicity in three of eight patients, with grade 3 diarrhea. The protocol was amended to reduce the ipilimumab dose to 1 mg/kg. Excessive toxicity resulted in the study being closed after 14 patients. Four of 11 EGFR-mutated patients ultimately developed grade 3 colitis. Of three ALK-rearranged patients, one developed hypophysitis and another grade 2 pneumonitis. For 11 EGFR-mutated patients, progression-free survival (PFS) from the start of ipilimumab was 17.9 months. Erlotinib treatment began a median 7.7 months before ipilimumab; therefore, erlotinib PFS was 27.8 months. Median overall survival (OS) has not been reached but will be > 42.3 months from erlotinib initiation. For three ALK-rearranged patients, ipilimumab PFS was 24.1 months. Median OS has not been reached but will be at least 47.2 months from the initiation of crizotinib. Conclusion Erlotinib plus ipilimumab caused excessive short-term gastrointestinal toxicity leading to early study closure. However, PFS and OS were notable; therefore, targeted therapies with immunotherapy in NSCLC merit further study. Clinicaltrials.gov registration number: NCT01998126.

Sunitinib for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis of Real-World and Clinical Trials Data Abstract Background Randomized controlled trials (RCTs) have stringent inclusion criteria and may not fully represent patients seen in everyday clinical practice. Real-world data (RWD) can provide supportive evidence for the effectiveness of medical interventions in more heterogeneous populations than RCTs. Sunitinib is a widely used first-line treatment for patients with metastatic renal cell carcinoma (mRCC). Objective This is the first comprehensive meta-analysis to evaluate the efficacy of sunitinib using the novel approach of combining RCTs and RWD. Methods RCTs and RWD studies published between 2000 and 2017 were identified from PubMed, Ovid, MEDLINE, and EMBASE. Eligible studies contained a cohort of ≥ 50 adult patients with mRCC receiving first-line sunitinib treatment. The meta-analysis combined RWD and RCT treatment groups, adjusting for data type (RCT or RWD). Recorded outcomes were median progression-free survival (mPFS), median overall survival (mOS), and objective response rate (ORR). Publication bias was assessed via review of funnel plots for each outcome measure. A random effects model to account for study heterogeneity was applied to each endpoint. Sensitivity analyses evaluated the robustness of the overall estimates. Results Of the 3611 studies identified through medical database searches, 22 (15 RWD studies, 7 RCTs) met eligibility criteria and were analyzed. mPFS (18 studies), mOS (19 studies), and ORR (15 studies) were reported for aggregate measures based on 4815, 5321, and 4183 patients, respectively. Reported mPFS (RWD, 7.5–11.0 months; RCTs, 5.6–15.1 months) and ORR data (RWD, 14.0–34.6%; RCTs, 18.8–46.9%) were consistent with the overall confidence estimates (95% confidence interval [CI]) of 9.3 (8.6–10.2) months and 27.9% (24.2–32.0), respectively. Reported mOS showed greater variation in RWD (6.8–33.2 months) compared with RCTs (21.8–31.5 months), with an overall confidence estimate (95% CI) of 23.0 (19.2–27.6) months. Inspection of funnel plots and sensitivity analyses indicated that there was no publication bias for any efficacy endpoint. Sensitivity analyses showed no evidence of lack of robustness for mPFS, mOS, or ORR. Interpretation of these results is limited by differences in trial design, cohort characteristics, and missing data. Conclusions This novel, comprehensive meta-analysis validates sunitinib as an effective first-line treatment for patients with mRCC in both RCTs and everyday clinical practice. The methodology provides a framework for future analyses combining data from RCTs and RWD.

Epidermal Growth Factor Receptor (EGFR)–Tyrosine Kinase Inhibitors (TKIs) Combined with Chemotherapy Delay Brain Metastasis in Patients with EGFR-Mutant Lung Adenocarcinoma Abstract Background Whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with chemotherapy can delay the occurrence of brain metastasis (BM) is unclear. Objective This retrospective study aimed to evaluate whether EGFR–TKIs combined with chemotherapy can delay BM and decrease the incidence of BM as initial progression. Patients and Methods The data of 100 patients with EGFR-mutant advanced lung adenocarcinoma were retrospectively reviewed. The patients had no BM at initial diagnosis, and BM occurred during the treatment. Patients received EGFR–TKI only or EGFR–TKI combined with chemotherapy. Intracranial progression-free survival (iPFS), systemic progression-free survival (PFS), and overall survival (OS) were evaluated. Results The overall median OS was 39 months (95% confidence interval (CI), 35.6–42.4 months). The median OS of EGFR–TKI combined with chemotherapy and EGFR–TKI only are 41 months (95% CI 35.5–46.5 months) and 39 months (95% CI 36.8–41.2 months), respectively. Patients in the combination treatment group had longer PFS (16 vs. 10 months; P = 0.030) and iPFS (21 vs. 14 months; P = 0.026). Further, as initial progression, fewer patients developed BM in the combined treatment group compared with the EGFR–TKI-only group (30.6% vs. 52.9%, P = 0.002) with a hazard ratio of 0.64 (95% CI 0.43–0.96). After controlling for significant covariables in a multivariable model, the different treatment strategies were independently associated with improved iPFS. Conclusions In this retrospective analysis, EGFR–TKIs combined with chemotherapy could improve PFS. Further, the combined treatment could delay BM occurrence and decrease the incidence of BM as initial progression.

Predictive Impact of Peripheral Blood Markers and C-Reactive Protein in Nivolumab Therapy for Metastatic Renal Cell Carcinoma Abstract Background Predictive factors that can be routinely used in clinical practice are critically needed for immune checkpoint inhibitor therapy in metastatic renal cell carcinoma (mRCC). Objective To comprehensively analyze the predictive impact of peripheral blood markers and C-reactive protein (CRP) in nivolumab therapy for mRCC. Methods Fifty-eight patients were retrospectively evaluated. We evaluated neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), absolute eosinophil count (AEC), and absolute monocyte count (AMC) as peripheral blood markers as well as serum CRP levels. The primary endpoints were progression-free survival (PFS) and overall survival (OS) after nivolumab initiation. Results Median PFS was significantly shorter in patients with high NLR (≥ 3) versus low NLR (p = 0.0356), high MLR (≥ 0.3) versus low MLR (p = 0.0013), or high PLR (≥ 160) versus low PLR (p = 0.0073), and median OS was significantly shorter in patients with high NLR versus low NLR (p = 0.0025), high MLR versus low MLR (p = 0.0025), high PLR versus low PLR (p = 0.0256), or high CRP (≥ 1.0 mg/dl) versus low CRP (p = 0.0006). Multivariate analyses showed that MLR (HR 2.65, p = 0.0068) was an independent factor for PFS and that NLR (HR 3.34, p = 0.0218), MLR (HR 3.42, p = 0.0381), and CRP (HR 4.98, p = 0.0108) were independent factors for OS. Conclusions The systemic inflammatory factors NLR, MLR, and CRP were predictive factors in nivolumab therapy for mRCC. These easily monitored factors can contribute to effective treatment and follow-up.

Prospective Study of Drug-induced Interstitial Lung Disease in Advanced Breast Cancer Patients Receiving Everolimus Plus Exemestane Abstract Background Everolimus-related interstitial lung disease (ILD) (also: pneumonitis) poses a difficulty for physicians, as it is hard to discriminate ILD from other causes of respiratory symptoms and to decide on safe treatment continuation. Objective We investigated the capability of pulmonary function tests (PFT), plasma biomarkers, everolimus pharmacokinetics, and FDG-PET to discriminate between everolimus-related ILD and other causes of respiratory problems and to predict the severity of ILD. Patients and methods Women starting treatment with everolimus plus exemestane for advanced breast cancer were included. At baseline and during the first 3 months, respiratory symptoms, PFT with diffusion capacity of the lungs for carbon monoxide corrected for hemoglobin (DLCOc) and forced vital capacity, serum plasma biomarkers (including SP-D and YKL-40), everolimus trough concentration, and 18F-FDG-PET were prospectively recorded. Results Twenty-seven (out of 29 included) patients were evaluable for analysis. Fifteen patients (56%) developed everolimus-related respiratory signs or symptoms and four patients (15%) needed everolimus discontinuation and received corticosteroids. Change in DLCOc differentiated ILD from alternative diagnoses with 0.91 sensitivity and 0.78 specificity. Decrease in DLCOc (non-significant) was greatest in patients who needed everolimus discontinuation. Serum SP-D and YKL-40 could differentiate ILD from alternative diagnoses with 0.83 and 0.83 sensitivity, and 0.85 and 0.62 specificity, respectively. 18F-FDG-PET abnormalities did not precede clinical symptoms. No relationship between ILD and everolimus trough concentration was found. Conclusions This study shows that everolimus-related ILD occurs frequently. Prospective monitoring of DLCOc in combination with measurement of serum SP-D and YKL-40 appear useful to discriminate ILD from other causes of respiratory symptoms. Clinicaltrials.gov identifier: NCT01978171.

Relative Efficacy of Systemic Treatments for Patients with Advanced Hepatocellular Carcinoma According to Viral Status: A Systematic Review and Network Meta-Analysis Abstract Background Several clinical trials that tested the efficacy of systemic treatments for advanced hepatocellular carcinoma (HCC) showed a tendency that patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection had different survival benefits from targeted agents. Objective The objective of this study was to assess the comparative efficacy of systemic targeted therapies according to HBV and HCV status in first-line and second- or later-line treatments for advanced HCC. Methods PubMed, EMBASE, Cochrane database, and meeting abstracts were searched through to January 2019. A Bayesian network meta-analysis was performed to estimate hazard ratios (HRs) for overall survival with 95% credible intervals (CrIs) and determine the ranking of the included regimens. Results Sixteen trials involving 6410 patients were included in the meta-analysis. In the first-line treatment setting, lenvatinib was the best agent for both HBV and HCV subgroups, presenting the most favorable HR versus sorafenib (HR 0.83, 95% CrI 0.68–1.01 and HR 0.91, 95% CrI 0.66–1.25, respectively), and was ranked as the best agent [surface under the cumulative ranking curve (SUCRA) value of 87% and 85%, respectively] among the included drugs. In second-line therapy, regorafenib showed the lowest HR versus placebo (HR 0.58, 95% CrI 0.41–0.82) in the HBV subgroup, whereas no agent was significantly more effective than placebo in the HCV subgroup. Conclusions Compared with sorafenib, lenvatinib was more efficacious in the HBV subgroup than in the HCV subgroup, and the relative ranking of sorafenib in the HBV subgroup was lower than in the HCV subgroup. Each targeted agent reported to be the best by viral etiology and line of treatment could be carefully recommended in each subgroup.

A Monoclonal Antibody Against β1 Integrin Inhibits Proliferation and Increases Survival in an Orthotopic Model of High-Grade Meningioma Abstract Background High-grade meningiomas (HGMs; World Health Organization [WHO] classification grade II and III) have high relapse rates and poor clinical outcomes despite surgery and radiation treatments. No effective medical therapy currently exists for HGMs, and developing novel therapeutic strategies depends on the identification of molecular drivers. In cancer, β1 integrin enhances malignant characteristics, including proliferation, invasion, and drug resistance. Objective We conducted this study to investigate whether β1 integrin could be a therapeutic target in HGMs. Patients and Methods Expression of β1 integrin was examined in gene array datasets, with proteomics of clinical meningioma specimens, and in patient-derived HGM xenografts. Anti-tumor activity of OS2966, a first-in-class humanized antagonizing monoclonal antibody against β1 integrin, was tested in vitro and in vivo using an orthotopic mouse model of patient-derived malignant meningioma. Results β1 integrin was expressed in meningiomas of all WHO grades and two xenografts tested. In vitro, OS2966 suppressed the viability of NF2-deficient MN3 sphere cells and NF2-wild-type IOMM-Lee malignant meningioma cells only when plated on laminin-coated plastic. While OS2966 decreased phosphorylation of ERK1/2 in both MN3 cells and laminin-grown IOMM-Lee cells, OS2966 only affected the phosphorylation of FAK (Tyr397) in MN3, and of Akt (Ser473) in IOMM-Lee cells, respectively, indicating differential pathway inhibition. Systemic administration of OS2966 in mice bearing orthotopic MN3 HGMs inhibited HGM cell proliferation and significantly extended overall survival of the treated mice. Conclusions β1 Integrin may be a therapeutic target in HGMs, and further preclinical and clinical development of OS2966 for HGM therapy is warranted.