Efficacy of Margetuximab vs Trastuzumab in Patients With Pretreated ERBB2-Positive Advanced Breast Cancer A Phase 3 Randomized Clinical Trial

Advanced Breast Cancer; Efficacy; MargetuximabCáncer de mama avanzado; Eficacia; MargetuximabCàncer de mama avançat; Eficàcia; MargetuximabImportance ERRB2 (formerly HER2)–positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. Objective To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. Design, Setting, and Participants The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. Interventions Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. Main Outcomes and Measures Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. Results A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P < .001; median, 5.7 vs 4.4 months; September 10, 2019). Margetuximab improved objective response rate over trastuzumab: 22% vs 16% (P = .06; October 10, 2018), and 25% vs 14% (P < .001; September 10, 2019). Incidence of infusion-related reactions, mostly in cycle 1, was higher with margetuximab (35 [13.3%] vs 9 [3.4%]); otherwise, safety was comparable. Conclusions and Relevance In this phase 3 randomized clinical trial, margetuximab plus chemotherapy had acceptable safety and a statistically significant improvement in PFS compared with trastuzumab plus chemotherapy in ERBB2-positive ABC after progression on 2 or more prior anti-ERBB2 therapies. Final OS analysis is expected in 2021.This study was supported by MacroGenics, Inc

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Margetuximab Versus Trastuzumab in Patients With Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results From a Randomized Phase 3 Trial

Margetuximab; Breast cancer; Overall survivalMargetuximab; Cáncer de mama; Supervivencia globalMargetuximab; Càncer de mama; Supervivència globalFinal overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2–positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2–positive breast cancer with different CD16A allelic variants are warranted

The unwarped, resolved, deformed conifold: fivebranes and the baryonic branch of the Klebanov-Strassler theory

We study a gravity solution corresponding to fivebranes wrapped on the $S^2$ of the resolved conifold. By changing a parameter the solution continuously interpolates between the deformed conifold with flux and the resolved conifold with branes. Therefore, it displays a geometric transition, purely in the supergravity context. The solution is a simple example of torsional geometry and may be thought of as a non-K\"ahler analog of the conifold. By U-duality transformations we can add D3 brane charge and recover the solution in the form originally derived by Butti et al. This describes the baryonic branch of the Klebanov-Strassler theory. Far along the baryonic branch the field theory gives rise to a fuzzy two-sphere. This corresponds to the D5 branes wrapping the two-sphere of the resolved conifold in the gravity solution.Comment: 41 pages, 7 figure

Supersymmetric Janus solutions in five and ten dimensions

We explicitly truncate N = 8 gauged supergravity in five dimensions to its SU(3)-invariant sector with dilaton and axion fields. We show that this truncation has a solution which is identical to the super Janus constructed in N = 2 gauged supergravity in five dimensions. Then we lift the solution of the SU(3)-invariant truncation to type IIB supergravity by employing the consistent truncation ansatz. We show that the lifted solution falls into a special case of the supersymmetric Janus solutions constructed in type IIB supergravity. Additionally, we also prove that the lifted solution provides a particular example of the consistent truncations of type IIB supergravity on Sasaki-Einstein manifolds.Comment: 32 pages, 2 figures, version published in JHE

BPS black holes in N=2 D=4 gauged supergravities

We construct and analyze BPS black hole solutions in gauged N=2, D=4 supergravity with charged hypermultiplets. A class of solutions can be found through spontaneous symmetry breaking in vacua that preserve maximal supersymmetry. The resulting black holes do not carry any hair for the scalars. We demonstrate this with explicit examples of both asymptotically flat and anti-de Sitter black holes. Next, we analyze the BPS conditions for asymptotically flat black holes with scalar hair and spherical or axial symmetry. We find solutions only in cases when the metric contains ripples and the vector multiplet scalars become ghost-like. We give explicit examples that can be analyzed numerically. Finally, we comment on a way to circumvent the ghost-problem by introducing also fermionic hair.Comment: 40 pages, 2 figures; v2 references added; v3 minor changes, published versio