Targeted therapy for advanced salivary gland carcinoma based on molecular profiling: Results from MyPathway, a phase IIa multiple basket study

BACKGROUND: Systemic therapy options for salivary cancers are limited. MyPathway (NCT02091141), a phase IIa study, evaluates targeted therapies in non-indicated tumor types with actionable molecular alterations. Here, we present the efficacy and safety results for a subgroup of MyPathway patients with advanced salivary gland cancer (SGC) matched to targeted therapies based on tumor molecular characteristics. PATIENTS AND METHODS: MyPathway is an ongoing, multiple basket, open-label, non-randomized, multi-center study. Patients with advanced SGC received pertuzumab + trastuzumab (HER2 alteration), vismodegib (PTCH-1/SMO mutation), vemurafenib (BRAF V600 mutation), or atezolizumab [high tumor mutational burden (TMB)]. The primary endpoint is the objective response rate (ORR). RESULTS: As of January 15, 2018, 19 patients with SGC were enrolled and treated in MyPathway (15 with HER2 amplification and/or overexpression and one each with a HER2 mutation without amplification or overexpression, PTCH-1 mutation, BRAF mutation, and high TMB). In the 15 patients with HER2 amplification/overexpression (with or without mutations) who were treated with pertuzumab + trastuzumab, 9 had an objective response (1 complete response, 8 partial responses) for an ORR of 60% (9.2 months median response duration). The clinical benefit rate (defined by patients with objective responses or stable disease \u3e4 months) was 67% (10/15), median progression-free survival (PFS) was 8.6 months, and median overall survival was 20.4 months. Stable disease was observed in the patient with a HER2 mutation (pertuzumab + trastuzumab, n = 1/1, PFS 11.0 months), and partial responses in patients with the PTCH-1 mutation (vismodegib, n = 1/1, PFS 14.3 months), BRAF mutation (vemurafenib, n = 1/1, PFS 18.5 months), and high TMB (atezolizumab, n = 1/1, PFS 5.5+ months). No unexpected toxicity occurred. CONCLUSIONS: Overall, 12 of 19 patients (63%) with advanced SGC, treated with chemotherapy-free regimens matched to specific molecular alterations, experienced an objective response. Data from MyPathway suggest that matched targeted therapy for SGC has promising efficacy, supporting molecular profiling in treatment determination

Questioning cultural narratives of economic development—an investigation of Kitchener-Waterloo

The version of record [Spigel, B. & Bathelt, H. (2019). Questioning cultural narratives of economic development - An investigation of Kitchener-Waterloo. Canadian Geographer, 63(2), 267-283.] is available online at: https://onlinelibrary.wiley.com/doi/abs/10.1111/cag.12512This paper investigates the relationship between culture and economy and scrutinizes cultural narratives of economic development in Kitchener-Waterloo, southern Ontario. It argues for the need to carefully conceptualize the link between culture and economic development to avoid boosting deterministic stereotypes. In the case of Kitchener-Waterloo, a notable hub of high-technology firms and technology development, a link is frequently drawn between the German community and culture and the region’s technology economy and entrepreneurial culture. A social capital analysis, however, reveals that the German ethnic community neither has the strong professional internal ties nor the external social ties to other regional communities that could constitute a lead role in economic development. Rather, the legacy of Kitchener-Waterloo’s ethnic German population has been absorbed into the region’s self-image and creates a feeling of belonging and common reference points for joint social and economic initiatives in the region

Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer

Writing assistance was funded by Eli Lilly and Company (no grant numbers apply).Peer reviewedPublisher PD

The participation paradigm in audience research

As today's media simultaneously converge and diverge, fusing and hybridizing across digital services and platforms, some researchers argue that audiences are dead-long live the user! But for others, it is the complex interweaving of continuities and changes that demands attention, especially now that audiencing has become a vital mode of engaging with all dimensions of daily life. This article asks how we should research audiences in a digital networked age. I argue that, while many avenues are being actively pursued, many researchers are concentrating on the notion of participation, asking, on the one hand, what modes of participation are afforded to people by the particular media and communication infrastructures which mediate social, cultural or political spheres of life? And, on the other hand, how do people engage with, accede to, negotiate or contest this as they explore and invent new ways of connecting with each other through and around media? The features of this emerging participation paradigm of audience research are examined in this article

Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort

Abstract Introduction Nivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort. Methods Patients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review. Results Overall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06–4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8–7.6) versus 4.7 months (3.1–8.3). Twenty-four–month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively. Conclusions Whereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy

Top-line results from SUNRISE: A phase III, randomized, double-blind, placebo-controlled multicenter trial of bavituximab plus docetaxel in patients with previously treated stage IIIb/iv non-squamous non-small cell lung cancer

Background: Exposed phosphatidylserine (PS) in the tumor microenvironment is highly immunosuppressive. Bavituximab targets PS in the presence of β2GP1 as a high affinity complex and repolarizes myeloid derived suppressor cells and M2 macrophages to M1, resulting in production of pronflammatory cytokines such as IFNγ and IL-12, maturation of dendritic cells and induction of tumor specific cytotoxic T lymphocyte immunity. In a prior double-blind Phase II trial in 2nd line non-squamous NSCLC, bavituximab 3 mg/kg plus docetaxel was well-tolerated and demonstrated 60% improvement (11.7 vs 7.3 month) in median overall survival (OS) compared to control. Methods: We accrued 597 patients with Stage IIIb/IV non-squamous NSCLC who progressed on platinum-doublet chemotherapy in a 1:1 ratio to receive up to six 21-day cycles of docetaxel in combination with either weekly 3 mg/kg bavituximab (B + D) or placebo (D) until progression or toxicity. The primary endpoint was OS and secondary endpoints included progression-free survival, overall response rate and safety. Exploratory testing of immune correlatives is ongoing

Planktonic events may cause polymictic-dimictic regime shifts in temperate lakes

Water transparency affects the thermal structure of lakes, and within certain lake depth ranges, it can determine whether a lake mixes regularly (polymictic regime) or stratifies continuously (dimictic regime) from spring through summer. Phytoplankton biomass can influence transparency but the effect of its seasonal pattern on stratification is unknown. Therefore we analysed long term field data from two lakes of similar depth, transparency and climate but one polymictic and one dimictic, and simulated a conceptual lake with a hydrodynamic model. Transparency in the study lakes was typically low during spring and summer blooms and high in between during the clear water phase (CWP), caused when zooplankton graze the spring bloom. The effect of variability of transparency on thermal structure was stronger at intermediate transparency and stronger during a critical window in spring when the rate of lake warming is highest. Whereas the spring bloom strengthened stratification in spring, the CWP weakened it in summer. The presence or absence of the CWP influenced stratification duration and under some conditions determined the mixing regime. Therefore seasonal plankton dynamics, including biotic interactions that suppress the CWP, can influence lake temperatures, stratification duration, and potentially also the mixing regime