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Background: Pembrolizumab showed durable antitumour activity and manageable safety in metastatic triple-negative breast cancer in the single-arm KEYNOTE-012 and KEYNOTE-086 trials. In this study, we compared pembrolizumab with chemotherapy for second-line or third-line treatment of patients with metastatic triple-negative breast cancer.Methods: KEYNOTE-119 was a randomised, open-label, phase 3 trial done at 150 medical centres (academic medical centres, community cancer centres, and community hospitals) in 31 countries. Patients aged 18 years or older, with centrally confirmed metastatic triple-negative breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, who had received one or two previous systemic treatments for metastatic disease, had progression on their most recent therapy, and had previous treatment with an anthracycline or taxane were eligible. Patients were randomly assigned (1:1) using a block method (block size of four) and an interactive voice-response system with integrated web-response to receive intravenous pembrolizumab 200 mg once every 3 weeks for 35 cycles (pembrolizumab group), or to single-drug chemotherapy per investigator's choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrolment cap for each; chemotherapy group). Randomisation was stratified by PD-L1 tumour status (positive [combined positive score (CPS) ≥1] vs negative [CPS <1]) and history of previous neoadjuvant or adjuvant treatment versus de-novo metastatic disease at initial diagnosis. Primary endpoints were overall survival in participants with a PD-L1 combined positive score (CPS) of 10 or more, those with a CPS of 1 or more, and all participants; superiority of pembrolizumab versus chemotherapy was tested in all participants only if shown in those with a CPS of one or more. The primary endpoint was analysed in the intention-to-treat population; safety was analysed in the all-subjects-as-treated population. This Article describes the final analysis of the trial, which is now completed. This trial is registered with ClinicalTrials.gov, number NCT02555657.Findings: From Nov 25, 2015, to April 11, 2017, 1098 participants were assessed for eligibility and 622 (57%) were randomly assigned to receive either pembrolizumab (312 [50%]) or chemotherapy (310 [50%]). Median study follow-up was 31·4 months (IQR 27·8-34·4) for the pembrolizumab group and 31·5 months (27·8-34·6) for the chemotherapy group. Median overall survival in patients with a PD-L1 CPS of 10 or more was 12·7 months (95% CI 9·9-16·3) for the pembrolizumab group and 11·6 months (8·3-13·7) for the chemotherapy group (hazard ratio [HR] 0·78 [95% CI 0·57-1·06]; log-rank p=0·057). In participants with a CPS of 1 or more, median overall survival was 10·7 months (9·3-12·5) for the pembrolizumab group and 10·2 months (7·9-12·6) for the chemotherapy group (HR 0·86 [95% CI 0·69-1·06]; log-rank p=0·073). In the overall population, median overall survival was 9·9 months (95% CI 8·3-11·4) for the pembrolizumab group and 10·8 months (9·1-12·6) for the chemotherapy group (HR 0·97 [95% CI 0·82-1·15]). The most common grade 3-4 treatment-related adverse events were anaemia (three [1%] patients in the pembrolizumab group vs ten [3%] in the chemotherapy group), decreased white blood cells (one [<1%] vs 14 [5%]), decreased neutrophil count (one [<1%] vs 29 [10%]), and neutropenia (0 vs 39 [13%]). 61 (20%) patients in the pembrolizumab group and 58 (20%) patients in the chemotherapy group had serious adverse events. Three (<1%) of 601 participants had treatment-related adverse events that led to death (one [<1%] in the pembrolizumab group due to circulatory collapse; two [1%] in the chemotherapy group, one [<1%] due to pancytopenia and sepsis and one [<1%] haemothorax).Interpretation: Pembrolizumab did not significantly improve overall survival in patients with previously treated metastatic triple-negative breast cancer versus chemotherapy. These findings might inform future research of pembrolizumab monotherapy for selected subpopulations of patients, specifically those with PD-L1-enriched tumours, and inform a combinatorial approach for the treatment of patients with metastatic triple-negative breast cancer.Funding: Merck Sharp & Dohme. [ABSTRACT FROM AUTHOR]

Purpose: Human epidermal growth factor receptor 2 (HER2)-directed therapy improves local control among women with HER2-positive breast cancer. This retrospective analysis evaluates the safety and efficacy of radiation therapy (RT) among patients receiving adjuvant trastuzumab emtansine (T-DM1) or paclitaxel (T) plus trastuzumab (H) in the ATEMPT (Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab) trial; Translational Breast Cancer Research Consortium (TBCRC) 033.Methods and Materials: Patients with stage I HER2-positive breast cancer were randomized 3:1 to receive adjuvant T-DM1 or TH after mastectomy or breast-conserving surgery (BCS). Breast RT was required after BCS and permitted after mastectomy. Patients receiving T-DM1 began RT after 12 weeks of therapy and received RT concurrently with T-DM1. Patients receiving TH began RT after paclitaxel, but concurrent with trastuzumab. RT records were retrospectively reviewed to determine details of radiation delivery and acute RT-related toxicity.Results: Protocol therapy was initiated by 497 patients. Among the 299 BCS patients, 289 received whole breast RT (WBRT) and 10 partial breast. Among WBRT patients, 40.2% in the T-DM1 arm and 41.5% of TH patients received hypofractionated (≥2.5 Gy/fraction) RT. Eight mastectomy patients received RT, all conventional fractionation. Skin toxicity (grade ≥2) was seen in 33.9% of patients in the T-DM1 arm and 23.2% in the TH arm (P = .11). In conventionally fractionated WBRT patients, 44.7% had a grade ≥2 skin toxicity compared with 17.9% of patients receiving hypofractionation (P < .001). Five patients experienced pneumonitis after RT (T-DM1: n = 4, 1.0%; TH: n = 1, 0.9%). Three-year invasive disease-free survival was 97.8% for T-DM1 (95% confidence interval, 96.3-99.3) and 93.4% for TH (95% confidence interval, 88.7-98.2). Among the 18 invasive disease-free survival events, 7 were isolated locoregional recurrences (2, T-DM1; 5, TH).Conclusions: RT was well-tolerated when given concurrently with either T-DM1 or TH. Among BCS patients, hypofractionation resulted in lower grade ≥2 acute skin toxicity even with concurrent anti-HER2 therapy. Although follow-up was short, local recurrences were uncommon, attesting to the efficacy of HER2-directed therapy combined with RT. [ABSTRACT FROM AUTHOR]

Purpose: Patients with triple-negative breast cancer (TNBC) experience higher local-regional recurrence rates than those with luminal or HER2-positive tumors. This prospective, phase 1B trial was designed to assess the safety and to establish the maximum tolerated dose (MTD) of cisplatin with radiation therapy for women with early-stage TNBC.Methods and Materials: Eligible patients had stage II or III TNBC. Cisplatin was initiated at 10 mg/m2 intravenously once weekly during radiation and then escalated in a 3 + 3 design by 10 mg/m2 at each dose level until 40 mg/m2, or the MTD, was reached. Patients undergoing breast-conserving therapy (BCT) or mastectomy were accrued in separate parallel cohorts during dose escalation, followed by a 10-patient expansion at the MTD.Results: During 2013 to 2018, 55 patients were accrued. Four patients developed dose-limiting toxicity. In the BCT cohort, 1 patient receiving 40 mg/m2 developed tinnitus resulting in a cisplatin delay; therefore, this was the BCT cohort MTD. In the mastectomy cohort, 1 patient receiving 20 mg/m2 developed a grade 3 urinary infection, and 2 additional patients had dose-limiting toxicities at 40 mg/m2 (grade 3 neutropenia and grade 2 tinnitus), both resulting in cisplatin delay. Thus, 30 mg/m2 was the mastectomy cohort MTD. Median follow-up was 48.5 months. Three-year disease-free survival was 74.7% for the BCT cohort and 64.4% for the mastectomy cohort.Conclusions: Adjuvant radiation therapy with concurrent cisplatin is feasible with a recommended phase 2 dose of 30 mg/m2 and 40 mg/m2 intravenously weekly in mastectomy and BCT cohorts, respectively. [ABSTRACT FROM AUTHOR]

Background: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer.Methods: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30).Findings: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths.Interpretation: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing.Funding: Pfizer. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy in combination with chemotherapy has shown promising efficacy across many different tumour types. We report the prespecified second interim overall survival analysis of the phase 3 IMpassion130 study assessing the efficacy and safety of atezolizumab plus nab-paclitaxel in patients with unresectable, locally advanced or metastatic triple-negative breast cancer.Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 246 academic centres and community oncology practices in 41 countries, patients aged 18 years or older, with previously untreated, histologically documented, locally advanced or metastatic triple-negative breast cancer, and Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomly assigned (1:1) using a permuted block method (block size of four) and an interactive voice-web response system. Randomisation was stratified by previous taxane use, liver metastases, and PD-L1 expression on tumour-infiltrating immune cells. Patients received atezolizumab 840 mg or matching placebo intravenously on day 1 and day 15 of every 28-day cycle and nab-paclitaxel 100 mg/m2 of body surface area intravenously on days 1, 8, and 15 until progression or unacceptable toxicity. Investigators, patients, and the funder were masked to treatment assignment. Coprimary endpoints were investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1 and overall survival, assessed in the intention-to-treat population and in patients with PD-L1 immune cell-positive tumours (tumours with ≥1% PD-L1 expression). The final progression-free survival results were previously reported at the first interim overall survival analysis. The prespecified statistical testing hierarchy meant that overall survival in the subgroup of PD-L1 immune cell-positive patients could only be formally tested if overall survival was significantly different between the treatment groups in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02425891.Findings: Between June 23, 2015, and May 24, 2017, 902 patients were enrolled, of whom 451 were randomly assigned to receive atezolizumab plus nab-paclitaxel and 451 were assigned to receive placebo plus nab-paclitaxel (the intention-to-treat population). Six patients from each group did not receive treatment. At the second interim analysis (data cutoff Jan 2, 2019), median follow-up was 18·5 months (IQR 9·6-22·8) in the atezolizumab group and 17·5 months (8·4-22·4) in the placebo group. Median overall survival in the intention-to-treat patients was 21·0 months (95% CI 19·0-22·6) with atezolizumab and 18·7 months (16·9-20·3) with placebo (stratified hazard ratio [HR] 0·86, 95% CI 0·72-1·02, p=0·078). In the exploratory overall survival analysis in patients with PD-L1 immune cell-positive tumours, median overall survival was 25·0 months (95% CI 19·6-30·7) with atezolizumab versus 18·0 months (13·6-20·1) with placebo (stratified HR 0·71, 0·54-0·94]). As of Sept 3, 2018 (the date up to which updated safety data were available), the most common grade 3-4 adverse events were neutropenia (38 [8%] of 453 patients in the atezolizumab group vs 36 [8%] of 437 patients in the placebo group), peripheral neuropathy (25 [6%] vs 12 [3%]), decreased neutrophil count (22 [5%] vs 16 [4%]), and fatigue (17 [4%] vs 15 [3%]). Treatment-related deaths occurred in two (<1%) patients in the atezolizumab group (autoimmune hepatitis related to atezolizumab [n=1] and septic shock related to nab-paclitaxel [n=1]) and one (<1%) patient in the placebo group (hepatic failure). No new treatment-related deaths have been reported since the primary clinical data cutoff date (April 17, 2018).Interpretation: Consistent with the first interim analysis, this second interim overall survival analysis of IMpassion130 indicates no significant difference in overall survival between the treatment groups in the intention-to-treat population but suggests a clinically meaningful overall survival benefit with atezolizumab plus nab-paclitaxel in patients with PD-L1 immune cell-positive disease. However, this positive result could not be formally tested due to the prespecified statistical testing hierarchy. For patients with PD-L1 immune cell-positive metastatic triple-negative breast cancer, atezolizumab plus nab-paclitaxel is an important therapeutic option in a disease with high unmet need.Funding: F Hoffmann-La Roche and Genentech. [ABSTRACT FROM AUTHOR]

Objectives: Data from the Intergroup Exemestane Study (IES) suggest that switching to the aromatase inhibitor, exemestane, after 2 to 3 years of tamoxifen therapy prolongs disease-free survival versus continuing on tamoxifen therapy. We sought to evaluate the cost-effectiveness of this management strategy. Methods: A Markov model was developed to predict patients' transitions across various health states based on treatment strategy (continuing tamoxifen vs. switching to exemestane), breast cancer status (no recurrence, local or distant recurrence, contralateral breast cancer), and other related health events (osteoporosis, endometrial cancer, death). Rates of disease-related events (recurrence and contralateral breast cancer) were estimated using data from the IES. Survival and lifetime medical-care costs by type of disease-related event were estimated using SEER-Medicare data. The model was used to estimate direct costs (in 2004 USdollars), life expectancy, quality-adjusted life-years (QALYs), and incremental cost-effectiveness. Results: Switching to exemestane versus continuing tamoxifen therapy was associated with increased disease-free survival (181 vs. 172 months), QALYs (12.21 vs. 11.89), and net discounted lifetime costs of cancer care ($12,124 vs. $7724 per patient). The incremental cost-effectiveness ratio of exemestane was $20,100 per QALY gained (95% confidence interval: $12,100, $59,000). Sensitivity analyses showed that results were robust to plausible variations in recurrence rates, costs, and utilities. Conclusions: Switching postmenopausal early-stage breast cancer patients to exemestane after 2 to 3 years of tamoxifen appears to be a cost-effective treatment strategy versus completing a 5-year course of tamoxifen. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and feasibility of concurrent radiation therapy and paclitaxel-based adjuvant chemotherapy, given either weekly or every 3 weeks, after adjuvant doxorubicin and cyclophosphamide (AC). Methods and Materials: After definitive breast surgery and AC chemotherapy, 40 patients with operable Stage II or III breast cancer received protocol-based treatment with concurrent paclitaxel and radiation therapy. Paclitaxel was evaluated on 2 schedules, with treatment given either weekly × 12 weeks (60 mg/m2), or every 3 weeks × 4 cycles (135–175 mg/m2). Radiation fields and schedules were determined by the patient’s surgery and pathology. The tolerability of concurrent therapy was evaluated in cohorts of 8 patients as a phase I study. Results: Weekly paclitaxel treatment at 60 mg/m2 per week with concurrent radiation led to dose-limiting toxicity in 4 of 16 patients (25%), including 3 who developed pneumonitis (either Grade 2 [1 patient] or Grade 3 [2 patients]) requiring steroids. Efforts to eliminate this toxicity in combination with weekly paclitaxel through treatment scheduling and CT-based radiotherapy simulation were not successful. By contrast, dose-limiting toxicity was not encountered among patients receiving concurrent radiation with paclitaxel given every 3 weeks at 135–175 mg/m2. However, Grade 2 radiation pneumonitis not requiring steroid therapy was seen in 2 of 24 patients (8%) treated in such a fashion. Excessive radiation dermatitis was not observed with either paclitaxel schedule. Conclusions: Concurrent treatment with weekly paclitaxel and radiation therapy is not feasible after adjuvant AC chemotherapy for early-stage breast cancer. Concurrent treatment using a less frequent paclitaxel dosing schedule may be possible, but caution is warranted in light of the apparent possibility of pulmonary injury. [Copyright &y& Elsevier]