The phase Ib KEYNOTE-173 study was conducted to assess the safety and preliminary antitumor activity of neoadjuvant chemotherapy plus pembrolizumab in high-risk, early-stage, non-metastatic ...triple-negative breast cancer (TNBC).
Six pembrolizumab plus chemotherapy regimens were evaluated (cohorts A–F). All cohorts received a pembrolizumab 200-mg run-in dose (cycle 1), then eight cycles of pembrolizumab in combination with a taxane with or without carboplatin for 12 weeks, and then doxorubicin and cyclophosphamide for an additional 12 weeks before surgery. Primary end points were safety and recommended phase II dose (RP2D); secondary end points were pathological complete response (pCR) rate, objective response rate, and event-free and overall survival. Exploratory end points were the relationship between outcome and potential biomarkers, such as tumor programmed death ligand 1 (PD-L1) expression (combined positive score) and stromal tumor-infiltrating lymphocyte levels (sTILs).
Sixty patients were enrolled between 18 February 2016, and 28 February 2017. Dose-limiting toxicities occurred in 22 patients, most commonly febrile neutropenia (n = 10 across cohorts). Four cohorts (B, C, D, F) did not meet the RP2D threshold; two cohorts did (A, E). The most common grade ≥3 treatment-related adverse event was neutropenia (73%). Immune-mediated adverse events and infusion reactions occurred in 18 patients (30%) and were grade ≥3 in six patients (10%). The pCR rate (ypT0/Tis ypN0) across all cohorts was 60% (range 49%–71%). Twelve-month event-free and overall survival rates ranged from 80% to 100% across cohorts (100% for four cohorts). Higher pre-treatment PD-L1 combined positive score, and pre- and on-treatment sTILs were significantly associated with higher pCR rates (P = 0.0127, 0.0059, and 0.0085, respectively).
Combination neoadjuvant chemotherapy and pembrolizumab for high-risk, early-stage TNBC showed manageable toxicity and promising antitumor activity. In an exploratory analysis, the pCR rate showed a positive correlation with tumor PD-L1 expression and sTIL levels.
ClinicalTrials.gov identifier: NCT02622074.
•Neoadjuvant pembrolizumab + chemotherapy showed no unexpected safety findings in patients with high-risk, early-stage TNBC.•Two chemotherapy regimens met the RP2D threshold: nab-paclitaxel 125 mg/m2 qw; paclitaxel 80 mg/m2 qw + carboplatin AUC5 q3w.•pCR rate (ypT0/Tis ypN0) across all cohorts was 60% and 12-month EFS and OS rates ranged from 80% to 100% across cohorts.•pCR rate showed positive correlation with tumor PD-L1 expression and stromal tumor-infiltrating lymphocyte levels.
In the OlympiAD study, olaparib was shown to improve progression-free survival compared with chemotherapy treatment of physician’s choice (TPC) in patients with a germline BRCA1 and/or BRCA2 mutation ...(BRCAm) and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). We now report the planned final overall survival (OS) results, and describe the most common adverse events (AEs) to better understand olaparib tolerability in this population.
OlympiAD, a Phase III, randomized, controlled, open-label study (NCT02000622), enrolled patients with a germline BRCAm and HER2-negative mBC who had received ≤2 lines of chemotherapy for mBC. Patients were randomized to olaparib tablets (300mg bid) or predeclared TPC (capecitabine, vinorelbine, or eribulin). OS and safety were secondary end points.
A total of 205 patients were randomized to olaparib and 97 to TPC. At 64% data maturity, median OS was 19.3months with olaparib versus 17.1months with TPC (HR 0.90, 95% CI 0.66–1.23; P = 0.513); median follow-up was 25.3 and 26.3months, respectively. HR for OS with olaparib versus TPC in prespecified subgroups were: prior chemotherapy for mBC no (first-line setting): 0.51, 95% CI 0.29–0.90; yes (second/third-line): 1.13, 0.79–1.64; receptor status (triple negative: 0.93, 0.62–1.43; hormone receptor positive: 0.86, 0.55–1.36); prior platinum (yes: 0.83, 0.49–1.45; no: 0.91, 0.64–1.33). Adverse events during olaparib treatment were generally low grade and manageable by supportive treatment or dose modification. There was a low rate of treatment discontinuation (4.9%), and the risk of developing anemia did not increase with extended olaparib exposure.
While there was no statistically significant improvement in OS with olaparib compared to TPC, there was the possibility of meaningful OS benefit among patients who had not received chemotherapy for metastatic disease. Olaparib was generally well-tolerated, with no evidence of cumulative toxicity during extended exposure.
•This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing metastatic breast cancer.•It covers diagnosis, staging, risk assessment, treatment, disease monitoring, ...palliative care and the patient perspective.•ESMO-MCBS and ESCAT scores are given to describe the levels of evidence for treatment choices.•The authors comprise an international expert group, with recommendations based on available evidence and expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach.
Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit ...of adjuvant chemotherapy in these patients remains unclear.
We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival.
The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval CI, 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group.
After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).
Nanoscale catalysis depends on spatial and surface arrangements of atoms. The synthesis of core/shell nanoparticles by synthetic approaches, the characterization of the core/shell nanostructures in ...terms of the relative core/shell compositions, and the demonstration of the electrocatalytic activities for fuel cell reactions (see figure), as reported in this Communication, have important implications to the design of desired nanoscale catalysts.
This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast ...cancer (ABC) with or without visceral metastases.
Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N=521) and postmenopausal women untreated for ABC (PALOMA-2; N=666) were randomized 2:1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement.
Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2months with palbociclib plus fulvestrant versus 3.4months with placebo plus fulvestrant hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35–0.61, and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3months, HR 0.53; 95% CI 0.36–0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3months with palbociclib plus letrozole versus 12.9months with placebo plus letrozole (HR 0.63; 95% CI 0.47–0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8months with placebo plus letrozole (HR 0.50; 95% CI 0.36–0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC.
Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy.
NCT01942135, NCT01740427
The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor-positive, human ...epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We report the results of a prespecified analysis of overall survival.
We randomly assigned patients with hormone-receptor-positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety.
Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval CI, 28.8 to 40.0) in the palbociclib-fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo-fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo-fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib-fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo-fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib-fulvestrant group, as compared with 8.8 months in the placebo-fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up.
Among patients with hormone-receptor-positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib-fulvestrant resulted in longer overall survival than treatment with placebo-fulvestrant. The differences in overall survival in the entire trial group were not significant. (Funded by Pfizer; PALOMA-3 ClinicalTrials.gov number, NCT01942135 .).
Abstract
Background
The phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in ...patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2− ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population.
Methods
Postmenopausal patients with HR+/HER2− ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of neoadjuvant ET) was assessed by Cox proportional hazards model and Kaplan–Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615).
Results
At data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50–0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed.
Conclusions
This analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2− ABC.
The CORDEX-CORE initiative was developed with the aim of producing homogeneous regional climate model (RCM) projections over domains world wide. In its first phase, two RCMs were run at 0.22° ...resolution downscaling 3 global climate models (GCMs) from the CMIP5 program for 9 CORDEX domains and two climate scenarios, the RCP2.6 and RCP8.5. The CORDEX-CORE simulations along with the CMIP5 GCM ensemble and the most recently produced CMIP6 GCM ensemble are analyzed, with focus on several temperature, heat, wet and dry hazard indicators for present day and mid-century and far future time slices. The CORDEX-CORE ensemble shows a better performance than the driving GCMs for several hazard indices due to its higher spatial resolution. For the far future time slice the 3 ensembles project an increase in all temperature and heat indices analyzed under the RCP8.5 scenario. The largest increases are always shown by the CMIP6 ensemble, except for Tx > 35 °C, for which the CORDEX-CORE projects higher warming. Extreme wet and flood prone maxima are projected to increase by the RCM ensemble over the la Plata basin in South America, the Congo basin in Africa, east North America, north east Europe, India and Indochina, regions where a better performance is obtained, whereas the GCM ensembles show small or negligible signals. Compound hazard hotspots based on heat, drought and wet indicators are detected in each continent worldwide in region like Central America, the Amazon, the Mediterranean, South Africa and Australia, where a linear relation is shown between the heatwave and drought change signal, and region like Arabian peninsula, the central and south east Africa region (SEAF), the north west America (NWN), south east Asia, India, China and central and northern European regions (WCE, NEU) where the same linear relation is found for extreme precipitation and HW increases. Although still limited, the CORDEX-CORE initiative was able to produce high resolution climate projections with almost global coverage and can provide an important resource for impact assessment and climate service activities.
The phase III CLEOPATRA study demonstrated that combining pertuzumab with trastuzumab plus docetaxel significantly improves progression-free and overall survival in previously untreated HER2-positive ...metastatic breast cancer. Here, we report health-related quality-of-life (HRQoL) results from CLEOPATRA.
Participants were randomly assigned to pertuzumab or placebo, each given with trastuzumab plus docetaxel every 3 weeks. Pertuzumab and trastuzumab were administered until progression and six or more docetaxel cycles were recommended. Time from randomization to a ≥5-point decrease in Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) of the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire was analyzed as a prespecified secondary end point. A post hoc exploratory analysis investigated time to ≥2-point deterioration in Breast Cancer Subscale (BCS) score.
Time to ≥5-point decline in TOI-PFB did not differ significantly between the pertuzumab and placebo arms hazard ratio (HR), 0.97; P = 0.7161. The median times to TOI-PFB deterioration were 18.4 and 18.3 weeks, respectively (approximately six cycles). The mean TOI-PFB declined slightly until week 18 and recovered thereafter. Pertuzumab increased time until BCS deterioration versus placebo (median 26.7 versus 18.3 weeks; HR, 0.77; P = 0.0061).
Combining pertuzumab with trastuzumab and docetaxel had no adverse impact on HRQoL and may prolong time to worsening of breast cancer-specific symptoms.
PDF
