First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis.

BACKGROUND: Guidelines recommend atezolizumab plus nab-paclitaxel (A + nP) for first-line treatment of unresectable, locally advanced, or metastatic triple-negative breast cancer expressing programmed death-ligand 1 (PD-L1) on tumor-infiltrating immune cells (IC), based on IMpassion130. We report the final overall survival (OS) and safety of that study as per the prespecified analysis plan. PATIENTS AND METHODS: Patients were randomized to nP 100 mg/m2 (days 1, 8, and 15 of a 28-day cycle) with atezolizumab 840 mg (A + nP) or placebo (P + nP; days 1 and 15), until progression or unacceptable toxicity. Coprimary endpoints were progression-free survival [intention-to-treat (ITT) and PD-L1 IC-positive populations] and OS (tested hierarchically in the ITT population and, if significant, in the PD-L1 IC-positive population). RESULTS: Each arm comprised 451 patients; 666 (73.8%) had died by the final OS analysis cut-off (median follow-up, 18.8 months; interquartile range, 8.9-34.7 months). Median OS in the ITT population was 21.0 months [95% confidence interval (CI), 19.0-23.4 months] with A + nP, and 18.7 months (95% CI, 16.9-20.8 months) with P + nP [stratified hazard ratio (HR), 0.87; 95% CI, 0.75-1.02; P = 0.077]. Exploratory analysis in the PD-L1 IC-positive population showed a median OS of 25.4 months (95% CI, 19.6-30.7 months) with A + nP (n = 185) and 17.9 months (95% CI, 13.6-20.3 months) with P + nP (n = 184; stratified HR, 0.67; 95% CI, 0.53-0.86). Safety outcomes were consistent with previous analyses and the known toxicity profiles of each agent. Immune-mediated adverse events of special interest were reported in 58.7% and 41.6% of patients treated with A + nP and P + nP, respectively. CONCLUSION: Although the OS benefit in the ITT population was not statistically significant, precluding formal testing, clinically meaningful OS benefit was observed with A + nP in PD-L1 IC-positive patients, consistent with prior interim analyses. This combination remained safe and tolerable with longer follow-up.

Patient-reported outcomes from the phase III IMpassion130 trial of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancer.

BACKGROUND: Metastatic triple-negative breast cancer (mTNBC) is incurable. A key treatment goal is providing palliation while maintaining patients' health-related quality of life (HRQoL). IMpassion130 demonstrated progression-free survival benefit with atezolizumab + nab-paclitaxel (A + nP) versus placebo + nab-paclitaxel (Pl + nP) in first-line treatment of mTNBC patients with programmed death-ligand 1 positive (PD-L1+) tumors. We report data on patient-reported outcomes (PROs), which capture patient perspectives of treatment. PATIENTS AND METHODS: Patients with untreated advanced or mTNBC received atezolizumab (840 mg) or placebo every 2 weeks in combination with nab-paclitaxel (100 mg/m2) on days 1, 8, and 15 of each 28-day cycle until progression or intolerance. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and its Breast Cancer Module (QLQ-BR23) on day 1 of each cycle, at end of treatment, and every 4 weeks during 1 year of follow-up. Time-to-deterioration (TTD) in HRQoL (first ≥10-point decrease from baseline lasting two cycles) was a secondary end point. Exploratory end points included TTD in functioning and mean and mean change from baseline scores in HRQoL, functioning, and disease- and treatment-related symptoms. RESULTS: Baseline completion of PROs was 92% (QLQ-C30) and 89% (QLQ-BR23) and remained >80% through cycle 20 in intent-to-treat (ITT) and PD-L1+ patients. No differences between arms in median TTD in PD-L1+ patients were observed for HRQoL {hazard ratio (HR) 0.94 [95% confidence interval (CI) 0.69-1.28]} or physical [HR 1.02 (95% CI 0.76-1.37)] or role [HR 0.77 (95% CI 0.57-1.04)] functioning. Mean baseline scores for A + nP versus Pl + nP for HRQoL (67.5 versus 65.0) and physical (82.8 versus 79.4) and role (73.7 versus 71.7) functioning were comparable between arms and throughout the course of treatment, with no clinically meaningful (≥10 point) changes from baseline until patients discontinued treatment. No differences in clinically meaningful worsening in treatment symptoms (fatigue, diarrhea, or nausea/vomiting) were observed between arms. Results in ITT patients were similar. CONCLUSIONS: A + nP as first-line treatment for mTNBC delayed progression without compromising patients' day-to-day functioning or HRQoL or worsening treatment symptoms. CLINICALTRIAL. GOV IDENTIFIER: NCT02425891.

Early effects of metformin in women with polycystic ovary syndrome: a prospective randomized, double-blind, placebo-controlled trial.

CONTEXT: Metformin is successfully used in the treatment of cycle disorders and anovulation in women with polycystic ovary syndrome (PCOS). No data of the exact point and the impact of insulin resistance (IR) on metformin's efficacy exist. OBJECTIVE: The objective of the study was to evaluate the early potential effects of metformin treatment, their time of onset, and the role of IR on metformin's efficacy. DESIGN: This was a prospective randomized, double-blind, placebo-controlled trial. SETTING: The study was conducted at the University of Heidelberg, Heidelberg, Germany. PATIENTS: The patient population was 45 oligo-/anovulatory PCOS women with typical ovaries. INTERVENTIONS: Women were stratified for IR (32 of 13) and then randomly allocated to receive either metformin (n = 22) or placebo (n = 23) and were assessed before and every 4 wk within a treatment period of 12 wk. MAIN OUTCOME MEASURES: Menstrual disturbance and markers of insulin metabolism were measured. RESULTS: The main outcome criterion menstrual disturbance was successfully improved in the metformin-treated group, depending on IR (12 of 15 vs. three of 17), whereas women without IR (four of seven vs. four of six) had no significant amelioration of their menstrual irregularities (P < 0.05). Estradiol levels increased continuously only in the treatment group (P < 0.005), indicating an improvement of ovulatory function. Sixty-seven percent of metformin-treated women had at least one ovulation, compared with only 45% in the placebo group, shown by biphasic body temperature curves. Insulin sensitivity improved within 4 wk after beginning of metformin as shown by an increased area under the curve glucose to insulin ratio, compared with baseline (P < 0.005). CONCLUSIONS: IR is a baseline predictor of clinical efficacy in metformin treatment in PCOS women measured by improved menstrual cyclicity and ovulatory function.