Dual EGFR inhibition in combination with anti-VEGF treatment: a phase I clinical trial in non-small cell lung cancer.

BackgroundPreclinical data indicate EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic in animal models.MethodsWe conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response.ResultsThirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p less than 0.01).ConclusionThe combination of erlotinib, cetuximab, and bevacizumab was well-tolerated and demonstrated antitumor activity in heavily pretreated patients with NSCLC

Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response.

BackgroundThis retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval.MethodsEighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival.ResultsRetreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156).ConclusionOur data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed

Observation of a 4ΣHe Bound State in the H4e(K−,π−) reaction at 600MeV/c

We have observed a clear peak below the Σ+-production threshold in the 4He(K−,π−) reaction at 600MeV/c and θKπ=4∘. This is confirmation of the existence of the bound state of 4ΣHe, which was reported in the 4He(stoppedK−,π−) reaction. As in the case of stopped kaons, no such peak was found in the 4He(K−,π+) spectrum. Quantitatively reliable parameters for this level have been established. The binding energy and the width of the bound state are 4.4±0.3(stat)±1(syst) MeV and 7.0±0.7(stat)+1.2−0.0(syst) MeV, respectively

The Normative Agency of Regional Organizations and Non‐governmental Organizations in International Peace Mediation

This article analyzes the increasingly prominent role of regional organizations (ROs) and non‐governmental organizations (NGOs) in promoting norms in mediation processes. In particular, we seek to understand the processes by which RO and NGO mediators promote the inclusivity norm to negotiating parties and the outcomes that result. We employ the concepts of local agency and social practices in examining the normative agency of ROs and NGOs in promoting and redefining the inclusivity norm. Through illustrative case studies of peace processes in South Sudan and Myanmar, we argue that ROs’ and NGOs’ mediation practices reflect their claims to alternative resources of power, such as long‐standing expertise and insider status in the context, and build congruence with strong local norms. We provide nuanced theoretical insights on RO and NGO mediators’ claims to agency and provide empirical illustrations on how these claims contribute to constitutive changes to norms

Erratum: Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies.

The Abstract is incorrect in PubMed. The corrected Abstract is provided here