Prognostic Factors and Survival Outcomes of Patients With Early HER2+ Breast Cancer Treated With Trastuzumab in a Brazilian Public Reference Center: A Real-World Study.

PURPOSE: Trastuzumab was introduced into the Brazilian public health care service for early breast cancer (BC) in 2012. This study describes the survival outcomes and prognostic factors related to early HER2+ BC treatment in a Brazilian reference cancer center. PATIENTS AND METHODS: This were a retrospective, single-center, observational study of early HER2+ BC patients treated with trastuzumab in the (neo)adjuvant setting between 2012 and 2018 at Hospital Pérola Byington. Demographic, clinical, disease-free survival (DFS) and overall survival (OS) data were evaluated. Multivariate analysis was performed to assess independent prognostic factors. RESULTS: One hundred seventy-six and 353 patients treated in the neoadjuvant and adjuvant setting were included, respectively. The 3- and 5-year OS rates were 79% and 56% for the neoadjuvant group and 97% and 92% for the adjuvant group, respectively. Node positivity at diagnosis predicted poor OS for both groups. In the neoadjuvant group, stage III disease at diagnosis, delayed surgery, and lack of pathological complete response (pCR) predicted poor prognosis. The 3- and 5-year DFS rates were 67% and 46% in the neoadjuvant group and 91% and 86% in the adjuvant group, respectively. Histological grade 2, stage III disease at diagnosis, and lack of pCR predicted poor DFS for the neoadjuvant group. For the adjuvant group, node positivity at diagnosis predicted poor DFS. CONCLUSION: Our results reveal multiple clinical parameters affecting survival outcomes according to the treatment setting. Patients treated with neoadjuvant therapy have a poor prognosis since they present with more advanced disease, indicating the importance of early diagnosis and optimized treatment.

Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.

BACKGROUND: An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. METHODS: This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. FINDINGS: Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group. INTERPRETATION: Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. FUNDING: Daiichi Sankyo and AstraZeneca.

nextMONARCH Phase 2 randomized clinical trial: overall survival analysis of abemaciclib monotherapy or in combination with tamoxifen in patients with endocrine-refractory HR + , HER2- metastatic breast cancer.

PURPOSE: Resistance to endocrine therapy poses a major clinical challenge for patients with hormone receptor-positive (HR +), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). We present the preplanned 24-month final overall survival (OS) results, alongside updated progression-free survival (PFS), and objective response rate (ORR) results. METHODS: nextMONARCH is an open-label, controlled, randomized, Phase 2 study of abemaciclib alone or in combination with tamoxifen in women with endocrine-refractory HR + , HER2- MBC previously treated with chemotherapy. Patients were randomized 1:1:1 to: abemaciclib 150 mg and tamoxifen 20 mg (A + T), abemaciclib 150 mg (A-150), or abemaciclib 200 mg and prophylactic loperamide (A-200). OS was the main prespecified secondary endpoint. PFS, ORR, and safety at 24 months were compared to previously reported primary analysis results. RESULTS: Of the 234 patients enrolled, 12 were receiving study treatment at data cutoff (28Jun2019). Median follow-up was 27.2 months. Median OS was 24.2 months in the A + T arm, 20.8 months in A-150, and 17.0 months in A-200 (A + T versus A-200: HR 0.62; 95%CI [0.40, 0.97], P = 0.03 and A-150 versus A-200: HR 0.96; 95%CI [0.64, 1.44], P = 0.83). PFS and ORR results at 24 months were consistent with the primary analysis. The safety profile corresponded with previous reports. CONCLUSION: The addition of tamoxifen to abemaciclib demonstrated greater OS benefit than monotherapy. This study confirmed the single-agent activity of abemaciclib in heavily pretreated women with endocrine-refractory HR + , HER2- MBC, as well as the previously reported primary PFS and ORR results, with no new safety signals observed. Trial Registration ClinicalTrials.gov Identifier: NCT02747004.

Treatment With Adjuvant Abemaciclib Plus Endocrine Therapy in Patients With High-risk Early Breast Cancer Who Received Neoadjuvant Chemotherapy: A Prespecified Analysis of the monarchE Randomized Clinical Trial.

Importance: Patients selected to receive neoadjuvant chemotherapy (NAC) are usually those at higher risk of relapse, and there is a need to find better therapeutic options for these patients. Objective: To determine the efficacy and safety outcomes for patients with hormone receptor (HR)-positive, ERBB2 (formerly HER2)-, high-risk early breast cancer enrolled in the randomized clinical trial monarchE who received NAC. Design, Setting, and Participants: The monarchE randomized clinical trial was a multicenter, phase 3, open-label study that evaluated adjuvant treatment with abemaciclib plus endocrine therapy (ET) compared with ET alone in patients with HR+, ERBB2-, and node-positive early breast cancer who were at high risk of recurrence. Patients were recruited between July 2017 and August 2019 from 603 sites in 38 countries. This subgroup analysis was performed with primary outcome data, with a cutoff date of July 8, 2020. Intervention: Enrolled patients were randomized (1:1) to receive standard of care ET for at least 5 years with or without treatment with abemaciclib (150 mg, twice daily) for 2 years (treatment period) or until criteria were met for discontinuation. Main Outcomes and Measures: Prior chemotherapy (NAC vs adjuvant vs none) was a stratification factor in monarchE, and and a prespecified exploratory analysis included outcomes in patients who received NAC. The data presented in this article are from the primary outcome analysis (395 invasive disease-free survival [IDFS] events; cutoff date, July 8, 2020; median follow-up 19 months [IQR, 15.6-23.9 months]). Invasive disease-free survival (the primary end point of monarchE) and distant relapse-free survival (DRFS) were evaluated using the Cox proportional hazard model and Kaplan-Meier method. Results: Of the 5637 patients (mean [SD] age, 49.9 [10.6] years; 2046 women [99.5%]; 462 Asian [22.8%], 54 Black [2.7%], and 1473 White participants [70.8%]) enrolled in monarchE, 2056 (37%) received treatment with NAC. In this subgroup, treatment with abemaciclib and ET demonstrated clinically meaningful benefit in IDFS (hazard ratio, 0.61; 95% CI, 0.47-0.80) and DRFS (hazard ratio, 0.61; 95% CI, 0.46-0.81), which corresponded with an absolute improvement of 6.6% in 2-year IDFS rates and 6.7% in 2-year DRFS rates. A consistent treatment benefit was observed across subgroups of pathological breast tumor size or number of positive lymph nodes at surgery. Conclusions and Relevance: In the randomized clinical trial monarchE, treatment with adjuvant abemaciclib combined with ET demonstrated a clinically meaningful improvement in IDFS and DRFS for patients with HR+, ERBB2-, node-positive, high-risk early breast cancer who received NAC before trial enrollment. Trial Registration: ClinicalTrials.gov Identifier: NCT03155997.

Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer.

BACKGROUND: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety. RESULTS: Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5. CONCLUSIONS: Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).

Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study.

PURPOSE: Balstilimab (antiprogrammed death-1) and zalifrelimab (anticytotoxic T-lymphocyte-associated antigen-4) are two new checkpoint inhibitors emerging as promising investigational agents for the treatment of advanced cervical cancer. This phase II trial (ClinicalTrials.gov identifier: NCT03495882) evaluated the combination of balstilimab plus zalifrelimab in patients with recurrent and/or metastatic cervical cancer who relapsed after prior platinum-based therapy. PATIENTS AND METHODS: Patients were intravenously dosed with balstilimab 3 mg/kg once every 2 weeks and zalifrelimab 1 mg/kg once every 6 weeks, for up to 24 months. The primary end point was objective response rate (ORR, RECIST version 1.1, assessed by independent central review). Secondary end points included duration of response, safety and tolerability, and survival. RESULTS: In total, 155 women (median age, 50 years [range, 24-76 years]) were enrolled and treated with balstilimab plus zalifrelimab; 125 patients had measurable disease at baseline and one prior line of platinum-based therapy in the advanced setting, and these patients constituted the efficacy-evaluable population. The median follow-up was 21 months. The confirmed ORR was 25.6% (95% CI, 18.8 to 33.9), including 10 complete responders and 22 partial responders, with median duration of response not reached (86.5%, 75.5%, and 64.2% at 6, 9, and 12 months, respectively). The ORRs were 32.8% and 9.1% in patients with programmed death ligand-1-positive and programmed death ligand-1-negative tumors, respectively. For patients with squamous cell carcinoma, the ORR was 32.6%. The overall disease control rate was 52% (95% CI, 43.3 to 60.6). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated adverse events. CONCLUSION: Promising and durable clinical activity, with favorable tolerability, was seen in this largest trial to date evaluating dual programmed death-1/cytotoxic T-lymphocyte-associated antigen-4 blockade in patients with recurrent and/or metastatic cervical cancer. Further investigation of the balstilimab and zalifrelimab combination in this setting is continuing.

A Long-Term Extension Study of Bevacizumab in Patients With Solid Tumors.

BACKGROUND: Bevacizumab has been studied in numerous clinical trials in multiple types of cancer; however, patients may receive bevacizumab over an extended period of time. This study assessed the long-term safety and tolerability of bevacizumab among patients with solid tumors. MATERIALS AND METHODS: Patients enrolled in a Roche/Genentech-sponsored trial who had derived benefit from bevacizumab therapy as monotherapy or in combination with anticancer drugs were eligible for continuation of bevacizumab in this long-term extension (LTE) study. The primary endpoints were the incidence of adverse events (AEs) of Common Terminology Criteria for AEs (CTCAE) grade ≥3 related to bevacizumab treatment, serious AEs (SAEs), and deaths. RESULTS: Ninety-five patients with the following cancer types were enrolled in the LTE: ovarian cancer or peritoneal carcinoma (n = 41), non-small cell lung cancer (n = 16), glioblastoma multiforme (n = 14), breast cancer (n = 11), colorectal cancer (n = 7), or renal cell carcinoma (n = 6). The median (range) duration of bevacizumab treatment was 15.6 (0.0-81.0) months during the LTE and 57.5 (16.4-134.9) months overall (parent trial + LTE), with three patients receiving bevacizumab for >10 years. Overall, 17 patients (17.9%) experienced SAEs, and 21 (22.1%) had a bevacizumab-related AE of CTCAE grade ≥3 (proteinuria and hypertension were the most common). Four patients died: three from disease progression and one from an AE considered unrelated to bevacizumab. CONCLUSION: The safety outcomes observed support the tolerability of long-term bevacizumab in patients with various solid tumors, with a median extended treatment duration of almost 5 years overall and >10 years in some individual patients. ClinicalTrials.gov identifier: NCT01588184. IMPLICATIONS FOR PRACTICE: In this long-term extension study of patients with solid tumors, the median duration of bevacizumab treatment (including parent trials) was just under 5 years, with a long-term exposure in some patients of 7 to >10 years. Grade ≥3 adverse events related to bevacizumab were consistent with the established safety profile, with proteinuria and hypertension being the most common. Patients received bevacizumab over an extended period of time (beyond the length of most clinical trials), and the overall safety outcomes observed support the tolerability of long-term bevacizumab treatment in patients with solid tumors, with clinical benefit achieved over an extended period.

FLABRA, frontline approach for BRCA testing in an ovarian cancer population: a Latin America epidemiologic study.

Aim: FLABRA evaluated the prevalence of BRCA mutations, genetic counseling and management approaches in patients with ovarian cancer in Latin America. Patients & methods: Patients with ovarian cancer from six Latin-American countries were enrolled. Tumor samples were tested for BRCA mutations (BRCAmut). In cases with BRCAmut, blood samples were analyzed to determine germline versus somatic mutations. Medical records were reviewed for counseling approach and treatment plan. Results: From 472 patients enrolled, 406 samples yielded conclusive results: 282 were BRCA wild-type (BRCAwt), 115 were BRCAmut and nine were variants of uncertain significance. In total, 110/115 were tested for germline mutations (77 germline and 33 somatic). Conclusion: Tumor testing to identify mutations in BRCA1/2 in ovarian cancer can help optimize treatment choices, meaning fewer patients require germline testing and genetic counseling, a scant resource in Latin America. Clinical trial registration: NCT02984423 (ClinicalTrials.gov).

Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: Updated Results of ALTERNATIVE.

PURPOSE: Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. This updated article reflects minor numerical corrections in some secondary efficacy analyses that resulted from programming errors and that do not change the major conclusions of the study. METHODS: Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) plus TRAS plus AI, TRAS plus AI, or LAP plus AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP plus TRAS plus AI versus TRAS plus AI. Secondary end points were PFS (comparison of other arms), overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), and safety. RESULTS: Three hundred fifty-five patients were included in this analysis: LAP plus TRAS plus AI (n = 120), TRAS plus AI (n = 117), and LAP plus AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP plus TRAS plus AI versus TRAS plus AI (median PFS, 11 v 5.6 months; hazard ratio, 0.62 [95% CI, 0.45 to 0.88]; P = .0063). A consistent PFS benefit was observed in predefined subgroups. ORR, CBR, and OS also favored LAP plus TRAS plus AI. The median PFS with LAP plus AI versus TRAS plus AI was 8.3 versus 5.6 months (hazard ratio, 0.85 [95% CI, 0.62 to 1.17]; P = .3159). Common adverse events (AEs; ≥ 15%) with LAP plus TRAS plus AI, TRAS plus AI, and LAP plus AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the 3 groups, and AEs leading to discontinuation were lower with LAP plus TRAS plus AI. CONCLUSION: Dual HER2 blockade with LAP plus TRAS plus AI showed superior PFS benefit versus TRAS plus AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.

nextMONARCH: Abemaciclib Monotherapy or Combined With Tamoxifen for Metastatic Breast Cancer.

BACKGROUND: Abemaciclib is a selective cyclin-dependent kinase 4 and 6 inhibitor administered continuously for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Abemaciclib is associated with dose-dependent early-onset diarrhea. nextMONARCH evaluated abemaciclib monotherapy (with or without prophylactic loperamide) and combined with tamoxifen for endocrine refractory metastatic breast cancer (MBC) after chemotherapy. PATIENTS AND METHODS: nextMONARCH is an open-label, controlled, randomized, phase II study of women with endocrine-refractory HR+, HER2- MBC previously treated with chemotherapy. Patients received abemaciclib 150 mg plus tamoxifen 20 mg (A+T), abemaciclib 150 mg every 12 hours (A-150), or abemaciclib 200 mg plus prophylactic loperamide (A-200). The primary objective was progression-free survival (PFS). PFS analyses tested superiority of A+T to A-200 and informal noninferiority of A-150 to A-200. The secondary objectives included the objective response rate (ORR), safety, and pharmacokinetics. RESULTS: The median PFS was 9.1 months for A+T versus 7.4 months for A-200 (hazard ratio, 0.815; 95% confidence interval, 0.556-1.193; P = .293). The A-200 PFS was comparable to that with A-150 at 6.5 months (hazard ratio, 1.045; 95% confidence interval, 0.711-1.535; P = .811). The ORR was 34.6%, 24.1%, and 32.5% for A+T, A-150, and A-200, respectively. No new safety signals were identified. The incidence and severity of diarrhea (62.3%; grade 3, 7.8%) with A-200 was similar to that with A-150 (67.1%; grade 3, 3.8%). The pharmacokinetics were comparable to previous observations. CONCLUSIONS: The addition of tamoxifen to abemaciclib did not significantly improve PFS or ORR compared with abemaciclib monotherapy but confirmed the single-agent activity of abemaciclib in heavily pretreated HR+, HER2- MBC. Dose reductions and antidiarrheal medication generally managed diarrhea while maintaining efficacy.

MONARCH plus: abemaciclib plus endocrine therapy in women with HR+/HER2- advanced breast cancer: the multinational randomized phase III study.

AIM: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. METHODS: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. RESULTS: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346-0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm (p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240-0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm (p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). CONCLUSION: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population.Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial.

BACKGROUND: Preferred neoadjuvant regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. IMpassion031 compared efficacy and safety of atezolizumab versus placebo combined with nab-paclitaxel followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC. METHODS: This double-blind, randomised, phase 3 study enrolled patients in 75 academic and community sites in 13 countries. Patients aged 18 years or older with previously untreated stage II-III histologically documented TNBC were randomly assigned (1:1) to receive chemotherapy plus intravenous atezolizumab at 840 mg or placebo every 2 weeks. Chemotherapy comprised of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks, which was then followed by surgery. Stratification was by clinical breast cancer stage and programmed cell death ligand 1 (PD-L1) status. Co-primary endpoints were pathological complete response in all-randomised (ie, all randomly assigned patients in the intention-to-treat population) and PD-L1-positive (ie, patients with PD-L1-expressing tumour infiltrating immune cells covering ≥1% of tumour area) populations. This study is registered with ClinicalTrials.gov (NCT03197935), Eudra (CT2016-004734-22), and the Japan Pharmaceutical Information Center (JapicCTI-173630), and is ongoing. FINDINGS: Between July 7, 2017, and Sept 24, 2019, 455 patients were recruited and assessed for eligibility. Of the 333 eligible patients, 165 were randomly assigned to receive atezolizumab plus chemotherapy and 168 to placebo plus chemotherapy. At data cutoff (April 3, 2020), median follow-up was 20·6 months (IQR 8·7-24·9) in the atezolizumab plus chemotherapy group and 19·8 months (8·1-24·5) in the placebo plus chemotherapy group. Pathological complete response was documented in 95 (58%, 95% CI 50-65) patients in the atezolizumab plus chemotherapy group and 69 (41%, 34-49) patients in the placebo plus chemotherapy group (rate difference 17%, 95% CI 6-27; one-sided p=0·0044 [significance boundary 0·0184]). In the PD-L1-positive population, pathological complete response was documented in 53 (69%, 95% CI 57-79) of 77 patients in the atezolizumab plus chemotherapy group versus 37 (49%, 38-61) of 75 patients in the placebo plus chemotherapy group (rate difference 20%, 95% CI 4-35; one-sided p=0·021 [significance boundary 0·0184]). In the neoadjuvant phase, grade 3-4 adverse events were balanced and treatment-related serious adverse events occurred in 37 (23%) and 26 (16%) patients, with one patient per group experiencing an unrelated grade 5 adverse event (traffic accident in the atezolizumab plus chemotherapy group and pneumonia in the placebo plus chemotherapy group). INTERPRETATION: In patients with early-stage TNBC, neoadjuvant treatment with atezolizumab in combination with nab-paclitaxel and anthracycline-based chemotherapy significantly improved pathological complete response rates with an acceptable safety profile. FUNDING: F Hoffmann-La Roche/Genentech.

Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE).

PURPOSE: Many patients with HR+, HER2- early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2- advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting. METHODS: This open-label, phase III study included patients with HR+, HER2-, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse-free survival, overall survival, and safety. RESULTS: At a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone (P = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib. CONCLUSION: Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2- node-positive EBC at high risk of early recurrence.

Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer. METHOD: In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154. FINDINGS: Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness. INTERPRETATION: Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer. FUNDING: Amgen.

Subcutaneous vs Intravenous Trastuzumab for Patients With ERBB2-Positive Early Breast Cancer: Final Analysis of the HannaH Phase 3 Randomized Clinical Trial.

IMPORTANCE: Confirmation of long-term comparability between subcutaneous and intravenous trastuzumab is essential. OBJECTIVE: To evaluate efficacy and safety of subcutaneous trastuzumab compared with that of intravenous trastuzumab for patients with ERBB2 (HER2)-positive early breast cancer after 6 years' follow-up in the HannaH (Enhanced Treatment With Neoadjuvant Herceptin) trial. DESIGN, SETTING, AND PARTICIPANTS: Open-label, prospective, multicenter, international, neoadjuvant-adjuvant, randomized, phase 3 noninferiority clinical trial (primary end points: pathologic complete response and serum trough concentration predose cycle 8) conducted for 596 patients with ERBB2-positive early breast cancer enrolled from October 19, 2009, to December 1, 2010. INTERVENTIONS: Eligible patients received 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of fluorouracil, 500 mg/m2, epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) with either fixed-dose subcutaneous trastuzumab, 600 mg, or intravenous trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in the neoadjuvant setting. Patients received an additional 10 cycles of subcutaneous trastuzumab or intravenous trastuzumab (according to their initial randomization) after surgery in the adjuvant setting to complete 1 year of anti-ERBB2 therapy. MAIN OUTCOMES AND MEASURES: Event-free and overall survival rates were calculated using the Kaplan-Meier method. Hazard ratios were estimated by Cox proportional hazards regression. Adverse events and serious adverse events were graded per standard criteria. RESULTS: In total, 294 women (mean [SD] age, 50.3 [11.1] years) treated with subcutaneous trastuzumab and 297 women (mean [SD] age, 49.5 [10.8] years) treated with intravenous trastuzumab were included in respective intention-to-treat populations. Six-year event-free survival rates (65% in both study groups; hazard ratio, 0.98; 95% CI, 0.74-1.29) and overall survival rates (84% in both study groups; hazard ratio, 0.94; 95% CI, 0.61-1.45) were similar between the subcutaneous and intravenous trastuzumab groups. Patients achieving a total pathologic complete response had longer event-free survival and higher 6-year overall survival rates than those with residual disease. Incidence of adverse events (290 of 297 [97.6%] vs 282 of 298 [94.6%]), grade 3 or higher adverse events (158 of 297 [53.2%] vs 160 of 298 [53.7%]), cardiac events (44 of 297 [14.8%] vs 42 of 298 [14.1%]), and serious adverse events (65 of 297 [21.9%] vs 45 of 298 [15.1%]) was comparable between the subcutaneous and intravenous trastuzumab treatment groups. CONCLUSIONS AND RELEVANCE: This final analysis of the HannaH trial further confirms the comparable efficacy and safety of subcutaneous and intravenous trastuzumab and highlights the suitability of subcutaneous trastuzumab as an alternative route of administration for patients with ERBB2-positive early breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00950300.

Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial).

BACKGROUND: Single-agent paclitaxel and vinorelbine are recommended treatments for advanced breast cancer (ABC) non-responsive to hormone therapy and without visceral crisis. This phase II trial compared first-line oral vinorelbine versus weekly paclitaxel for ABC. METHODS: Eligible female patients had measurable locally recurrent/metastatic estrogen receptor-positive HER2-negative breast cancer and had received prior endocrine therapy (any setting) but no chemotherapy for ABC. Patients were stratified by prior taxane and visceral metastases and randomized to either oral vinorelbine 80 mg/m2 (first cycle at 60 mg/m2, escalated to 80 mg/m2 in the absence of grade 3/4 toxicity) or intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR; confirmed complete or partial response, or stable disease for ≥6 weeks). RESULTS: The 131 randomized patients had received a median of 2 prior endocrine therapies; >70% had prior (neo)adjuvant chemotherapy and 79% visceral metastases. DCR was 75.8% (95% confidence interval: 63.6-85.5%) with vinorelbine and 75.4% (63.1-85.2%) with paclitaxel. The most common grade 3/4 adverse events were neutropenia (52%), fatigue (11%), and vomiting (5%) with vinorelbine, and neutropenia (17%), dyspnea (6%), hypertension (6%), and peripheral sensory neuropathy (5%) with paclitaxel. Grade 2 alopecia occurred in 2% of vinorelbine-treated and 34% of paclitaxel-treated patients. Neither arm showed relevant global health status changes. CONCLUSION: Oral vinorelbine and paclitaxel demonstrated similar DCRs (∼75%). Safety profiles differed and, together with administration route and convenience, may influence treatment choice (EudraCT number, 2012-003530-16).

Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer.

BACKGROUND: Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup). RESULTS: Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel. CONCLUSIONS: Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).

First-Line Trastuzumab Plus an Aromatase Inhibitor, With or Without Pertuzumab, in Human Epidermal Growth Factor Receptor 2-Positive and Hormone Receptor-Positive Metastatic or Locally Advanced Breast Cancer (PERTAIN): A Randomized, Open-Label Phase II Trial.

PURPOSE: To assess pertuzumab plus trastuzumab and an aromatase inhibitor (AI) in patients with human epidermal growth factor receptor 2 (HER2)-positive and hormone receptor-positive metastatic/locally advanced breast cancer (MBC/LABC). PATIENTS AND METHODS: The PERTAIN trial (NCT01491737) is an ongoing randomized, open-label, multicenter-80 sites and eight countries-phase II trial. Patients have HER2-positive, hormone receptor-positive MBC/LABC and no prior systemic therapy with the exception of endocrine. Random assignment was 1:1 to intravenous pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) plus trastuzumab (8 mg/kg followed by 6 mg/kg every 3 weeks), and oral anastrozole (1 mg every day) or letrozole (2.5 mg every day), or trastuzumab and an AI. Induction intravenous docetaxel every 3 weeks or paclitaxel every week could be administered for 18 to 24 weeks at the investigator's discretion (decided before but given after random assignment). Primary end point was progression-free survival (PFS). Patients were stratified by whether they received induction chemotherapy and their time since adjuvant hormone therapy. RESULTS: One hundred twenty-nine patients were randomly assigned per arm (February 2012 to October 2014; intent-to-treat populations); 75 in one arm and 71 in the other were chosen to receive induction chemotherapy. Stratified median PFS was 18.89 months (95% CI, 14.09 to 27.66 months) in the pertuzumab plus trastuzumab arm and 15.80 months (95% CI, 11.04 to 18.56 months) in the trastuzumab arm (stratified hazard ratio, 0.65; 95% CI, 0.48 to 0.89; P = .0070). Serious adverse events (AEs) were reported for 42 (33.1%) of 127 and 24 (19.4%) of 124 patients in the safety populations of the pertuzumab plus trastuzumab and trastuzumab arms, respectively. Rates of grade ≥ 3 AEs were 64 (50.4%) of 127 and 48 (38.7%) of 124, respectively. There were no deaths as a result of AEs. CONCLUSION: PERTAIN met its primary PFS end point. Pertuzumab plus trastuzumab and an AI is effective for the treatment of HER2-positive MBC/LABC. The safety profile was consistent with previous trials of pertuzumab plus trastuzumab.

Everolimus Plus Endocrine Therapy for Postmenopausal Women With Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: A Clinical Trial.

Importance: Cotargeting the mammalian target of rapamycin pathway and estrogen receptor may prevent or delay endocrine resistance in patients receiving first-line treatment for advanced breast cancer. Objective: To investigate the combination of everolimus plus endocrine therapy in first-line and second-line treatment settings for postmenopausal women with estrogen receptor-positive, human epidermal growth receptor 2-negative advanced breast cancer. Design, Setting, and Participants: In the multicenter, open-label, single-arm, phase 2 BOLERO-4 (Breast Cancer Trials of Oral Everolimus) clinical trial, 245 patients were screened for eligibility; 202 were enrolled between March 7, 2013, and December 17, 2014. A median follow-up of 29.5 months had been achieved by the data cutoff date (December 17, 2016). Interventions: Patients received first-line treatment with everolimus, 10 mg/d, plus letrozole, 2.5 mg/d. Second-line treatment with everolimus, 10 mg/d, plus exemestane, 25 mg/d, was offered at the investigator's discretion upon initial disease progression. Main Outcomes and Measures: The primary end point was investigator-assessed progression-free survival in the first-line setting per Response Evaluation Criteria in Solid Tumors, version 1.0. Safety was assessed in patients who received at least 1 dose of study medication and at least 1 postbaseline safety assessment. Results: A total of 202 women treated in the first-line setting had a median age of 64.0 years (interquartile range, 58.0-70.0 years) with metastatic (194 [96.0%]) or locally advanced (8 [4.0%]) breast cancer. Median progression-free survival was 22.0 months (95% CI, 18.1-25.1 months) with everolimus and letrozole. Median overall survival was not reached; 24-month estimated overall survival rate was 78.7% (95% CI, 72.1%-83.9%). Fifty patients started second-line treatment; median progression-free survival was 3.7 months (95% CI, 1.9-7.4 months). No new safety signals were observed. In the first-line setting, the most common all-grade adverse event was stomatitis (139 [68.8%]); the most common grade 3 to 4 adverse event was anemia (21 [10.4%]). In the second-line setting, the most common adverse events were stomatitis and decreased weight (10 [20.0%] each); the most common grade 3 to 4 adverse event was hypertension (5 [10.0%]). There were 50 (24.8%) deaths overall during the study; 40 were due to study indication (breast cancer). Conclusions and Relevance: The results of this trial add to the existing body of evidence suggesting that everolimus plus endocrine therapy is a good first-line treatment option for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Trial Registration: clinicaltrials.gov Identifier: NCT01698918.

Ribociclib with letrozole vs letrozole alone in elderly patients with hormone receptor-positive, HER2-negative breast cancer in the randomized MONALEESA-2 trial.

PURPOSE: Determine the efficacy and safety of first-line ribociclib plus letrozole in elderly patients with HR+, HER2- advanced breast cancer. METHODS: 668 postmenopausal women with HR+, HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021); 295 patients were aged ≥ 65 years. Patients were randomized to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation. The primary endpoint was PFS, which was evaluated in elderly (≥ 65 years) and younger (< 65 years) patients. Secondary endpoints included response rates and safety. RESULTS: Ribociclib plus letrozole significantly improved PFS vs placebo plus letrozole in elderly (hazard ratio: 0.608; 95% CI 0.394-0.937) and younger patients (hazard ratio: 0.523; 95% CI 0.378-0.723). Overall response rates were numerically higher in the ribociclib vs placebo arm, regardless of age. Ribociclib plus letrozole was well tolerated in elderly patients, with the safety profile similar to the overall study population. Nausea, vomiting, alopecia, and diarrhea were > 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm in both subgroups; most events were grade 1/2. In elderly patients, grade 1/2 anemia and fatigue were > 10% more frequent in the ribociclib plus letrozole vs placebo plus letrozole arm and discontinuation rates were similar in both arms. CONCLUSIONS: Addition of ribociclib to letrozole is a valid therapeutic option for elderly patients with HR+, HER2- advanced breast cancer in the first-line setting.