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Trastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor-copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination.

BackgroundIn the Trastuzumab for GAstric cancer (ToGA) study, trastuzumab plus chemotherapy improved median overall survival by 2.7 months in patients with human epidermal growth factor receptor 2 (HER2)-positive [immunohistochemistry (IHC) 3+/fluorescence in situ hybridization-positive] gastric/gastroesophageal junction cancer compared with chemotherapy alone (hazard ratio 0.74). Post hoc exploratory analyses in patients expressing higher HER2 levels (IHC 2+/fluorescence in situ hybridization-positive or IHC 3+) demonstrated a 4.2-month improvement in median overall survival with trastuzumab (hazard ratio 0.65). The ToGA study provides the largest screening dataset available on HER2 overexpression/amplification in this indication. We further analyzed correlation(s) of HER2 overexpression/amplification with clinical and epidemiological factors.MethodsHER2-positivity was analyzed by histological subtype, tumor location, geographic region, and specimen type. Exploratory efficacy analyses were performed.ResultsThe HER2-positivity rate was 22.1 % across analyzed tumor samples. Rates were similar between European and Asian patients (23.6 % vs. 23.9 %), but higher in intestinal- vs. diffuse-type (31.8 % vs. 6.1 %), and gastroesophageal junction cancer versus gastric tumors (32.2 % vs. 21.4 %). Across all IHC scores, variability in HER2 staining (≤30 % stained cells) was observed in almost 50 % of cases, with increasing rates in lower IHC categories, and did not affect treatment outcome. The polysomy rate was 4 %.ConclusionsHER2 expression varies by tumor location and type. All patients with advanced gastric or gastroesophageal junction cancer should be tested for HER2 status, preferably using IHC initially. Due to the unique characteristics of gastric cancer, specific testing/scoring guidelines should be adhered to.Electronic supplementary materialThe online version of this article (doi:10.1007/s10120-014-0402-y) contains supplementary material, which is available to authorized users.

Prophylaxis with emicizumab-a subcutaneously administered, bispecific, humanized, monoclonal antibody-promotes effective hemostasis in persons with hemophilia A (PwHA). The primary efficacy, safety and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHA with/without factor VIII inhibitors who were enrolled in the Phase III HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies have been pooled to establish a long-term efficacy, safety and pharmacokinetic profile. Across a median (interquartile range) efficacy period of 120.4 (89.0-164.4) weeks (data cut-off May 15, 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval, 1.1-1.7). ABRs declined and then maintained at <1 in an analysis of 24-week treatment intervals; at Weeks 121-144 (n=170) the mean treated ABR was 0.7 (0-5.0). During Weeks 121-144, 82.4% of participants had zero treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported zero treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participants discontinued due to adverse events beyond the five previously described. This data-cut includes the previously reported 3 thrombotic microangiopathies (1 in the PwHA with fatal rectal hemorrhage), and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use; and additionally, a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHA of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified. Clinical trials registered as NCT02622321, NCT02795767, NCT02847637, NCT03020160.