Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (STELLA): Design of a confirmatory, double-blind, randomized, controlled study

Background: MB02 is a bevacizumab biosimilar developed to stringent guidelines, including non-clinical and preclinical investigations and a clinical trial as first-line treatment in metastatic colorectal cancer (Romera A et al. Lancet Gastroenterol Hepatol 2018;3 (12): 845-855). A clinical trial (STELLA) has been initiated to confirm there are no clinically meaningful differences between MB02 and reference bevacizumab (Avastin) in terms of efficacy, safety, and immunogenicity (NCT03296163). Methods: STELLA study is a multinational, double-blind, randomized, parallel-group, equivalence study comparing the efficacy and safety of MB02 vs reference bevacizumab plus chemotherapy in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC)

BRCA1 4153delA mutation (”Baltic/Black Sea”) in breast cancer patients in Ukraine

Rak piersi (RP) jest najczęstszą postacią raka występującą w populacji kobiet na Ukrainie.Cel. Analiza najczęstszych mutacji w genach BRCA1/2 u kobiet na Ukrainie Zachodniej chorych na raka piersi (RP), obciążonych genetycznie tą patologią.Materiał i metody. Kliniczne i genealogiczne badanie objęło 335 pacjentek chorych na RP konsultowanych w Oddziale Chemioterapii (Lwowskiego Państwowego Regionalnego Centrum Onkologicznego Leczniczo-Diagnostycznego) w okresie luty–wrzesień 2012 r. w celu stwierdzenia występowania nowotworów złośliwych u krewnych. Poprzez metody molekularno-genetyczne określono obecność siedmiu mutacji w genie BRCA1 (185delAG, 4153delA, 5382insC,188del11, 5396 +1 G> A, 185InsA, 5331 G> A) i 3 mutacje w genie BRCA2 (6174delT, 6293S> G, 6024delTA), odpowiedzialnych za dziedziczne formy RP.Wyniki. Kliniczno-genealogiczne badanie 335 pacjentek chorych na RP wykazało, że u co dziewiątej z nich (u 36, czyliu 10,7%) były stwierdzone przypadki RP wśród krewnych. W grupie 125 kobiet ze stwierdzonym rodzinnym obciążeniem RP w 5 przypadkach (4%) zidentyfikowano mutacje w genach BRCA1/2 (5382insC — 2, 185delAG — 2 i 4153delA — 1). Wszystkie zidentyfikowane mutacje stanowiły trzy najczęściej spotykane przypadki opisane w literaturze w Europie Środkowej i Wschodniej (geograficznie — regionie Morza Bałtyckiego i Czarnego).Wniosek. Wśród wszystkich zidentyfikowanych mutacji (BRCA1 185delAG, 5382insC i 4153delA) u kobiet chorych na RP na Ukrainie Zachodniej stwierdzono trzy najczęściej cytowane mutacje w literaturze Europy Środkowej i Wschodniej oraz siedem mutacji rzadszych.Purpose. To analyze the most common mutations in the genes BRCA1/2 among women from West Ukraine withbreast cancer (BC) who are burdened with a family history of this pathology.Materials and methods. 335 patients with (BC) from West Ukraine studied pedigrees and 125 DNA samples. A molecular-genetic method determined the presence of seven mutations in the gene BRCA1 (185delAG, 4153delA, 5382InsC,188del11, 5396 +1 G> A, 185InsA, 5331 G> A) and 3 gene mutations in BRCA2 (6174delT, 6293S> G, 6024delTA).Results. Only every 9th patient with BC had BC in his family history. It is this group we examined in detail for the BRCA1/2 gene mutations presence. BRCA1/2 gene mutations were found in 5 patients (4%) among 125 women with BC who are burdened with family history of this pathology. In 2 cases diagnosed mutation of the gene BRCA1 (5382 Ins C), and 2 — BRCA1 185 del AG,4153delA — 1. Аll mutations belonged to the group of founder mutations in the ethnic group of Ashkenazi Jews and the geographical group of Baltic-Black Sea region

Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial

Background Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. Methods In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0–2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. Findings Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637–0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83–20·99) in the fulvestrant group versus 13·8 months (11·99–16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Interpretation Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients

Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first‑line treatment of ER+/HER2− advanced breast cancer (PALOMA‑1, TRIO‑18)

Purpose Palbociclib is a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, approved in combination with endocrine therapy for the treatment of women and men with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer (HR+/HER2− ABC). In the phase 2, open-label, PALOMA-1 trial, palbociclib plus letrozole signifcantly prolonged progression-free survival (PFS) versus letrozole alone (hazard ratio, 0.488; 95% CI 0.319‒0.748; P=0.0004; median PFS, 20.2 vs 10.2 months, respectively) in postmenopausal women with estrogen receptor–positive (ER+)/HER2− ABC. Here, we present the fnal overall survival (OS) and updated safety results. Methods Postmenopausal women with ER+/HER2− ABC were randomized 1:1 to receive either palbociclib (125 mg/day, 3/1 schedule) plus letrozole (2.5 mg/day, continuous) or letrozole alone (2.5 mg/day, continuous). The primary endpoint was investigator-assessed PFS; secondary endpoints included OS and safety. Results A total of 165 patients were randomized. At the data cutof date of December 30, 2016 (median duration of follow-up, 64.7 months), the stratifed hazard ratio for OS was 0.897 (95% CI 0.623–1.294; P=0.281); median OS in the palbociclib plus letrozole and letrozole alone arms was 37.5 and 34.5 months, respectively. The median time from randomization to frst subsequent chemotherapy use was longer with palbociclib plus letrozole than letrozole alone (26.7 and 17.7 months, respectively). The most frequently reported adverse event in the palbociclib plus letrozole arm was neutropenia (any grade, 75%; grade 3 or 4, 59%). Conclusions Palbociclib plus letrozole treatment led to a numerical but not statistically signifcant improvement in median OS. Pfzer Inc (NCT00721409

Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation

Aim: MERiDiAN evaluated plasma vascular endothelial growth factor-A (pVEGF-A) prospectively as a predictive biomarker for bevacizumab efficacy in metastatic breast cancer (mBC). Methods: In this double-blind placebo-controlled randomised phase III trial, eligible patients had HER2-negative mBC previously untreated with chemotherapy. pVEGF-A was measured before randomisation to paclitaxel 90 mg/m2 on days 1, 8 and 15 with either placebo or bevacizumab 10 mg/kg on days 1 and 15, repeated every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal. Stratification factors were baseline pVEGF-A, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary endpoints were investigator-assessed progression-free survival (PFS) in the intent-to-treat and pVEGF-Ahigh populations. Results: Of 481 patients randomised (242 placeboepaclitaxel; 239 bevacizumabepaclitaxel), 471 received study treatment. The stratified PFS hazard ratio was 0.68 (99% confidence interval, 0.51e0.91; log-rank p Z 0.0007) in the intent-to-treat population (median 8.8 months with placeboepaclitaxel versus 11.0 months with bevacizumabepaclitaxel) and 0.64 (96% con-fidence interval, 0.47e0.88; log-rank p Z 0.0038) in the pVEGF-Ahigh subgroup. The PFS treatment-by-VEGF-A interaction p value (secondary end-point) was 0.4619. Bevacizumab was associated with increased incidences of bleeding (all grades: 45% versus 27% with placebo), neutropenia (all grades: 39% versus 29%; grade 3: 25% versus 13%) and hypertension (all grades: 31% versus 13%; grade 3: 11% versus 4%). Conclusion: The significant PFS improvement with bevacizumab is consistent with previous placebo-controlled first-line trials in mBC. Results do not support using baseline pVEGF-A to identify patients benefitting most from bevacizumab. Clinical trials registration: ClinicalTrials.gov NCT01663727

Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study

Purpose: Some targeted anticancer agents are associated with serious ventricular tachyarrhythmias, which may be predicted by electrocardiographic evaluation of drug-related QT prolongation. We studied the effects of nintedanib (BIBF 1120; an oral, triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors) on the QT interval in patients with renal cell carcinoma (RCC) participating in an open-label phase II trial. Methods: Treatment-naïve, adult patients with unresectable/metastatic, clear cell RCC received nintedanib 200 mg twice daily. QT intervals were evaluated at baseline (day −1), on day 1 (after the first dose), and on day 15 (steady state) by 12-lead electrocardiograms (ECGs) performed in triplicate. Pharmacokinetic sampling was also undertaken. Results: Among 64 evaluable patients, the upper limits of the 2-sided 90 % confidence intervals for the adjusted mean time-matched changes in QTcF interval (corrected for heart rate by Fridericia’s method) from baseline to day 1 and 15 (primary ECG endpoint) were well below the regulatory threshold of 10 ms at all times. No relationship between nintedanib exposure and change from baseline in QTcF was seen. Nintedanib was generally well tolerated with no drug-related cardiovascular adverse events. Conclusion: Nintedanib administered at 200 mg twice daily was not associated with clinically relevant QT prolongation