{"product_id":"ribociclib-plus-hormone-therapy-improves-outcomes-in-early-breast-cancer-results-from-the-natalee-trial","title":"Ribociclib Plus Hormone Therapy Improves Outcomes in Early Breast Cancer: Results from the NATALEE Trial","description":"\u003cp\u003eA large international trial studied 5,101 patients with hormone receptor (HR)–positive, HER2-negative early breast cancer. In this trial, adding the targeted drug ribociclib to standard endocrine (hormone) therapy significantly improved invasive disease–free survival. At 3 years, 90.4% of patients taking ribociclib plus an aromatase inhibitor remained free of invasive disease, recurrence, or death. This compared with 87.1% of those taking an aromatase inhibitor alone. This was a 25.2% relative reduction in risk (hazard ratio 0.75; 95% CI, 0.62 to 0.91; P=0.003). Secondary measures, including distant disease–free survival and recurrence-free survival, also favored the ribociclib combination. The 3-year ribociclib regimen at a 400-mg starting dose did not produce any new safety signals, though neutropenia and liver-related events were more common with ribociclib.\u003c\/p\u003e\n\n\u003ch1\u003eRibociclib Plus Hormone Therapy Improves Outcomes in Early Breast Cancer: Results from the NATALEE Trial\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#methods\"\u003eHow the Study Was Conducted\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#patients\"\u003eWho Participated in the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#findings\"\u003eKey Findings: What the Study Showed\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#subgroups\"\u003eResults in Different Patient Groups\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#safety\"\u003eSafety and Side Effects\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#implications\"\u003eWhat This Means for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Next Steps\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn a trial of 5,101 patients with HR-positive, HER2-negative stage II or III early breast cancer, adding ribociclib to an aromatase inhibitor improved invasive disease-free survival.\u003c\/li\u003e\n\u003cli\u003eAt 3 years, 90.4% of patients on ribociclib plus an aromatase inhibitor remained free of invasive disease, recurrence, or death, versus 87.1% on an aromatase inhibitor alone.\u003c\/li\u003e\n\u003cli\u003eThe relative risk reduction was 25.2%, with an absolute benefit of about 3 percentage points at 3 years.\u003c\/li\u003e\n\u003cli\u003eNeutropenia and liver-related events were more common with ribociclib; the 3-year regimen at a 400-mg starting dose did not produce new safety signals.\u003c\/li\u003e\n\u003cli\u003eOverall survival data are not yet mature; longer follow-up is needed to determine if ribociclib improves overall survival in early breast cancer.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eHormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer is the most common subtype of breast cancer. It accounts for 70 to 75% of all breast cancer cases. The majority of patients with this subtype are diagnosed at an early stage (stage I to III).\u003c\/p\u003e\n\n\u003cp\u003eEarly breast cancer is treated with the goal of curing the disease. Standard treatment for HR-positive, HER2-negative early breast cancer includes surgery, with or without radiation therapy or chemotherapy. This is followed by adjuvant endocrine therapy (hormone therapy) for 5 to 10 years.\u003c\/p\u003e\n\n\u003cp\u003eAdjuvant endocrine therapy improves outcomes for these patients. However, recurrence (the cancer coming back) still occurs in a significant number of patients. Recurrence happens in 27 to 37% of patients with stage II disease and in 46 to 57% of patients with stage III disease. Recurrence can occur up to 20 years after the initial diagnosis.\u003c\/p\u003e\n\n\u003cp\u003eA class of drugs called cyclin-dependent kinase 4 and 6 (CDK4\/6) inhibitors has shown significant benefits in advanced breast cancer. These drugs include ribociclib, palbociclib, and abemaciclib. In patients with HR-positive, HER2-negative advanced breast cancer, these drugs improved progression-free survival (the time before the cancer worsened).\u003c\/p\u003e\n\n\u003cp\u003eRibociclib and abemaciclib also showed a significant overall survival benefit in the same patient population with advanced disease. However, results in early breast cancer have been mixed.\u003c\/p\u003e\n\n\u003cp\u003eIn the PENELOPE-B and PALLAS trials, palbociclib plus endocrine therapy did not show a significant invasive disease–free survival benefit. In contrast, the monarchE trial showed a significant invasive disease–free survival benefit after 2 years of adjuvant therapy with abemaciclib. These results led to approval of abemaciclib by international health authorities for HR-positive, HER2-negative early breast cancer in patients with node-positive disease at high risk for recurrence.\u003c\/p\u003e\n\n\u003cp\u003eThe established benefit of ribociclib in advanced breast cancer prompted its investigation in early breast cancer. The NATALEE trial is a phase 3 trial comparing ribociclib plus endocrine therapy with endocrine therapy alone. The trial was designed to test CDK4\/6 inhibition in a broad population of patients with stage II or III HR-positive, HER2-negative early breast cancer.\u003c\/p\u003e\n\n\u003ch2 id=\"methods\"\u003eHow the Study Was Conducted\u003c\/h2\u003e\n\n\u003cp\u003eThe NATALEE trial was an international, open-label, randomized, phase 3 trial. \"Open-label\" means that both patients and doctors knew which treatment was being given. \"Randomized\" means that patients were assigned to treatment groups by chance.\u003c\/p\u003e\n\n\u003cp\u003eThe trial planned to enroll 5,000 patients. Approximately 2,000 patients (about 40%) were expected to have stage II disease.\u003c\/p\u003e\n\n\u003cp\u003ePatients were randomly assigned in a 1:1 ratio to one of two treatment groups:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eRibociclib plus NSAI group:\u003c\/strong\u003e Ribociclib at a dose of 400 mg taken by mouth once daily for 21 consecutive days, followed by 7 days off, for a complete cycle of 28 days. This was given for 36 months (3 years). Patients also received a nonsteroidal aromatase inhibitor (NSAI) — either letrozole at 2.5 mg once daily or anastrozole at 1 mg once daily — on a continuous schedule for 60 months (5 years).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eNSAI alone group:\u003c\/strong\u003e An NSAI (letrozole or anastrozole) alone at the same doses for 60 months.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003ePatients in the ribociclib–NSAI group were expected to continue receiving the NSAI after completing the 36 months of ribociclib treatment. They were considered to be receiving trial treatment during this time. Additional NSAI treatment beyond 60 months was at the discretion of the treating physician and was not considered part of the trial treatment.\u003c\/p\u003e\n\n\u003cp\u003eMen and premenopausal women in both groups also received goserelin for gonadal suppression. Goserelin was given at a dose of 3.6 mg injected under the skin once every 28 days.\u003c\/p\u003e\n\n\u003cp\u003eEligible patients were men or premenopausal or postmenopausal women who were 18 years of age or older. All patients had histologically confirmed HR-positive, HER2-negative early breast cancer according to local assessment. Patients were required to have stage II or III disease based on anatomical stage according to the American Joint Committee on Cancer Staging Manual, Eighth Edition.\u003c\/p\u003e\n\n\u003cp\u003eThe anatomical stage was derived using tumor–node–metastasis (TNM) staging. For patients who had not received adjuvant or neoadjuvant treatment, staging was determined at the time of surgery. For patients who had received adjuvant or neoadjuvant treatment, the \"worst stage\" was derived using TNM staging at diagnosis and at the time of surgery.\u003c\/p\u003e\n\n\u003cp\u003eAll patients with stage III or IIB disease were allowed to participate regardless of nodal status. Patients with stage IIA disease were eligible if they had at least one lymph node involved. Patients with stage IIA disease and no nodal involvement were eligible if they had a grade 2 tumor with a Ki-67 proliferation index of at least 20%. Patients with stage IIA disease and no nodal involvement were also eligible if they were considered to be in a high genomic risk group. Patients with stage IIA disease with no nodal involvement and grade 3 tumors were also eligible.\u003c\/p\u003e\n\n\u003cp\u003eHigh genomic risk was defined as an Oncotype DX Breast Recurrence Score of 26 or higher. High genomic risk was also defined as a result categorized as high risk on the Prosigna PAM50, MammaPrint, or EndoPredict assay.\u003c\/p\u003e\n\n\u003cp\u003ePatients could have received any adjuvant or neoadjuvant endocrine therapy for up to 12 months before randomization. Patients were ineligible if they had received a previous CDK4\/6 inhibitor or if they had clinically significant, uncontrolled heart disease, cardiac repolarization abnormalities, or both.\u003c\/p\u003e\n\n\u003cp\u003eRandomization was stratified according to several factors:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eAnatomical stage (II or III)\u003c\/li\u003e\n\u003cli\u003eMenopausal status (premenopausal women and men, or postmenopausal women)\u003c\/li\u003e\n\u003cli\u003ePrevious adjuvant or neoadjuvant chemotherapy (yes or no)\u003c\/li\u003e\n\u003cli\u003eGeographic location (North America, Western Europe, Oceania, or rest of the world)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe primary end point was invasive disease–free survival. This was defined according to standardized definitions for efficacy end points (STEEP) criteria, version 1.0, as assessed by the investigator. Secondary end points included distant disease–free survival, recurrence-free survival, overall survival, safety, quality of life, and pharmacokinetics. Distant recurrence–free survival was an exploratory end point.\u003c\/p\u003e\n\n\u003cp\u003eAdverse events were monitored for 36 months beginning at the time of randomization. Serious adverse events were monitored throughout the trial. Events were graded according to the Common Terminology Criteria for Adverse Events, version 4.03.\u003c\/p\u003e\n\n\u003cp\u003eThe trial was funded by Novartis and overseen in collaboration with Translational Research in Oncology (TRIO). The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The trial protocol was approved by an institutional review board or independent ethics committee at each site. All patients provided written informed consent.\u003c\/p\u003e\n\n\u003cp\u003eAn independent data monitoring committee assessed efficacy and safety data. Representatives of the sponsor designed the trial and confirmed the accuracy of the data. Two professional medical writers, funded by the sponsor, provided editorial assistance.\u003c\/p\u003e\n\n\u003cp\u003eFor the statistical analysis, the trial was designed to provide approximately 85% power to detect a hazard ratio of 0.76 for invasive disease, recurrence, or death. This required 500 events. The analysis used a stratified log-rank test. This report is based on the protocol-specified second interim efficacy analysis, performed after 426 events had occurred. A prespecified stopping boundary of a one-sided P-value threshold of 0.0128 was used to conclude that ribociclib plus an NSAI was significantly superior to an NSAI alone. The two-sided stopping boundary (P-value threshold, 0.0256) is reported.\u003c\/p\u003e\n\n\u003cp\u003eAll end points were evaluated using the Kaplan–Meier method. Hazard ratios were estimated using a stratified Cox proportional-hazards model. All reported 95% confidence intervals are two-sided. The efficacy analyses were performed in the intention-to-treat population, which included all patients who had undergone randomization. The safety analyses were performed in the safety population, which included all patients who had undergone randomization and had received at least one dose of trial treatment.\u003c\/p\u003e\n\n\u003ch2 id=\"patients\"\u003eWho Participated in the Study\u003c\/h2\u003e\n\n\u003cp\u003eFrom January 10, 2019, to April 20, 2021, a total of 5,101 patients were randomly assigned. Of these, 2,549 patients received ribociclib plus an NSAI, and 2,552 patients received an NSAI alone.\u003c\/p\u003e\n\n\u003cp\u003eDemographic and baseline clinical characteristics were well balanced between the two groups. The median age was 52 years (range, 24 to 90 years).\u003c\/p\u003e\n\n\u003cp\u003eRegarding menopausal status:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003ePremenopausal women: 2,238 patients (43.9%)\u003c\/li\u003e\n\u003cli\u003ePostmenopausal women: 2,843 patients (55.7%)\u003c\/li\u003e\n\u003cli\u003eMen: 20 patients (0.4%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eRegarding race, the majority of patients (73.4%) were White, 13.2% were Asian, and 1.7% were Black.\u003c\/p\u003e\n\n\u003cp\u003eRegarding anatomical stage:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eStage I: 14 patients (0.3%)\u003c\/li\u003e\n\u003cli\u003eStage IIA: 1,000 patients (19.6%)\u003c\/li\u003e\n\u003cli\u003eStage IIB: 1,045 patients (20.5%)\u003c\/li\u003e\n\u003cli\u003eStage III: 3,040 patients (59.6%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eRegarding nodal status at diagnosis:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eNX (not assessed): 536 patients (10.5%)\u003c\/li\u003e\n\u003cli\u003eN0 (no nodal involvement): 1,431 patients (28.1%)\u003c\/li\u003e\n\u003cli\u003eN1 (1 to 3 axillary lymph nodes): 2,099 patients (41.1%)\u003c\/li\u003e\n\u003cli\u003eN2 or N3 (4 or more axillary lymph nodes): 950 patients (18.6%)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eRegarding previous endocrine therapy, 3,625 patients (71.1%) had received it. This included ovarian function–suppression therapy in 1,290 patients (25.3%), aromatase inhibitors in 3,193 patients (62.6%), and antiestrogen therapy in 685 patients (13.4%).\u003c\/p\u003e\n\n\u003cp\u003eRegarding previous neoadjuvant or adjuvant chemotherapy, 4,494 patients (88.1%) had received it. This included neoadjuvant chemotherapy in 2,180 patients (42.7%) and adjuvant chemotherapy in 2,443 patients (47.9%).\u003c\/p\u003e\n\n\u003cp\u003eAt the time of data cutoff, 1,984 patients (77.8%) in the ribociclib–NSAI group were either still receiving ribociclib plus an NSAI or were continuing to receive an NSAI. In the NSAI group, 1,826 patients (71.6%) were still receiving an NSAI.\u003c\/p\u003e\n\n\u003cp\u003eOverall, 515 patients (20.2%) completed the planned 3 years of treatment with ribociclib. In the ribociclib–NSAI group, 1,147 patients (45.0%) were continuing to receive ribociclib, and 1,449 patients (56.8%) had completed at least 2 years of treatment with ribociclib plus an NSAI.\u003c\/p\u003e\n\n\u003cp\u003eThe median duration of follow-up from randomization to the data cutoff was 34 months (minimum, 21 months). The median duration of exposure to trial treatment was 30 months in the ribociclib–NSAI group and 30 months in the NSAI group. In the ribociclib–NSAI group, the median duration of exposure to ribociclib alone was 27 months.\u003c\/p\u003e\n\n\u003ch2 id=\"findings\"\u003eKey Findings: What the Study Showed\u003c\/h2\u003e\n\n\u003cp\u003eThe second interim efficacy analysis for invasive disease–free survival was performed after 426 patients had experienced invasive disease, recurrence, or death. This included 189 patients (7.4%) in the ribociclib–NSAI group and 237 patients (9.3%) in the NSAI group. The median duration of follow-up from randomization to the last completed recurrence assessment was 28 months.\u003c\/p\u003e\n\n\u003cp\u003eThe risk of invasive disease, recurrence, or death was significantly lower — by 25.2% — with the addition of ribociclib to NSAI compared with NSAI alone. This means that patients who received ribociclib plus an NSAI had a 25.2% lower relative risk of their cancer returning or of dying compared with patients who received an NSAI alone.\u003c\/p\u003e\n\n\u003cp\u003eKaplan–Meier estimates of invasive disease–free survival at 3 years were:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e90.4%\u003c\/strong\u003e with ribociclib plus an NSAI\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e87.1%\u003c\/strong\u003e with an NSAI alone\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe hazard ratio for invasive disease, recurrence, or death was 0.75 (95% confidence interval [CI], 0.62 to 0.91). The two-sided P value was 0.003, which crossed the prespecified stopping boundary (P-value threshold of 0.0256). This means the result was statistically significant — there is less than a 0.3% probability that this result occurred by chance alone.\u003c\/p\u003e\n\n\u003cp\u003eDistant recurrences were the most commonly reported type of event in the analysis of invasive disease–free survival. Distant recurrence occurred in 120 patients (4.7%) in the ribociclib–NSAI group and in 170 patients (6.7%) in the NSAI group. The most frequent sites of disease recurrence were bone and liver in each group.\u003c\/p\u003e\n\n\u003cp\u003eSeveral secondary efficacy end points also showed a consistent benefit with ribociclib:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eDistant disease–free survival at 3 years:\u003c\/strong\u003e 90.8% with ribociclib plus an NSAI versus 88.6% with an NSAI alone (hazard ratio for distant disease or death, 0.74; 95% CI, 0.60 to 0.91).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eRecurrence-free survival at 3 years:\u003c\/strong\u003e 91.7% with ribociclib plus an NSAI versus 88.6% with an NSAI alone (hazard ratio for disease recurrence or death, 0.72; 95% CI, 0.58 to 0.88).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eOverall survival:\u003c\/strong\u003e The median duration of follow-up for overall survival was 30 months. At the time of data cutoff, 61 of 2,549 patients (2.4%) in the ribociclib–NSAI group and 73 of 2,552 patients (2.9%) in the NSAI group had died (hazard ratio for death, 0.76; 95% CI, 0.54 to 1.07).\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eDistant recurrence–free survival (exploratory end point):\u003c\/strong\u003e Also improved with ribociclib plus an NSAI compared with an NSAI alone (hazard ratio for distant recurrence or death, 0.72; 95% CI, 0.58 to 0.89).\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"subgroups\"\u003eResults in Different Patient Groups\u003c\/h2\u003e\n\n\u003cp\u003eAn analysis of invasive disease–free survival was performed across prespecified subgroups. At 3 years, the absolute invasive disease–free survival benefit with ribociclib and NSAI was:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e3.0 percentage points\u003c\/strong\u003e among patients with stage II disease\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e3.2 percentage points\u003c\/strong\u003e among patients with stage III disease\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThis means that the benefit was consistent across both stage II and stage III disease. The absolute benefit — the actual difference in the percentage of patients who remained free of invasive disease — was approximately 3 percentage points in both groups.\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eSafety and Side Effects\u003c\/h2\u003e\n\n\u003cp\u003eThe safety analyses included 2,524 patients in the ribociclib–NSAI group and 2,444 patients in the NSAI group.\u003c\/p\u003e\n\n\u003cp\u003eAt least one adverse event occurred in 2,470 patients (97.9%) in the ribociclib–NSAI group and in 2,128 patients (87.1%) in the NSAI group. Serious adverse events were reported in 336 patients (13.3%) in the ribociclib–NSAI group and in 242 patients (9.9%) in the NSAI group.\u003c\/p\u003e\n\n\u003cp\u003eAdverse events that led to early discontinuation of ribociclib were reported in 477 patients (18.9%). Adverse events that led to early discontinuation of both ribociclib and the NSAI occurred in 83 patients (3.3%). The percentages of patients who discontinued the NSAI for any cause or because of adverse events were similar in the two groups.\u003c\/p\u003e\n\n\u003cp\u003eThe most common adverse events of any grade were:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eNeutropenia\u003c\/strong\u003e (low levels of a type of white blood cell called neutrophils): 62.1% in the ribociclib–NSAI group versus 4.5% in the NSAI group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eArthralgia\u003c\/strong\u003e (joint pain): 36.5% in the ribociclib–NSAI group versus 42.5% in the NSAI group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLiver-related events:\u003c\/strong\u003e 25.4% in the ribociclib–NSAI group versus 10.6% in the NSAI group\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThese events were also the most common events of grade 3 or higher. The most frequent event of grade 3 or higher was neutropenia, occurring in 43.8% of patients in the ribociclib–NSAI group and in 0.8% of patients in the NSAI group.\u003c\/p\u003e\n\n\u003cp\u003eThe most common adverse events of any grade that led to discontinuation of any trial treatment were:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eLiver-related events:\u003c\/strong\u003e 8.9% in the ribociclib–NSAI group versus 0.1% in the NSAI group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eArthralgia:\u003c\/strong\u003e 1.3% in the ribociclib–NSAI group versus 1.9% in the NSAI group\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eMost discontinuations of ribociclib occurred early during treatment, with a median time to ribociclib discontinuation of 4 months. The incidence of NSAI-related events leading to discontinuation of treatment was similar in the two treatment groups.\u003c\/p\u003e\n\n\u003cp\u003eDose reductions of ribociclib occurred in 554 patients (21.9%).\u003c\/p\u003e\n\n\u003cp\u003eDeaths without disease progression or recurrence occurred in 19 patients in the ribociclib–NSAI group and in 13 patients in the NSAI group. Deaths during treatment or within 30 days after the last dose of trial treatment occurred in 17 patients (0.7%) in the ribociclib–NSAI group and in 9 patients (0.4%) in the NSAI group. Among these deaths, 10 (0.4%) occurred within 30 days after the last dose of ribociclib.\u003c\/p\u003e\n\n\u003cp\u003eThe 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals. This means that the side effects seen in this trial were consistent with what was already known about ribociclib from previous studies.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eWhat This Means for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThis study shows that adding ribociclib to standard hormone therapy significantly improves outcomes for patients with HR-positive, HER2-negative stage II or III early breast cancer. The benefit was seen across multiple measures, including invasive disease–free survival, distant disease–free survival, and recurrence-free survival.\u003c\/p\u003e\n\n\u003cp\u003eThe absolute benefit at 3 years was approximately 3 percentage points. This means that for every 100 patients treated with ribociclib plus an NSAI instead of an NSAI alone, about 3 more patients remained free of invasive disease, recurrence, or death at 3 years. While this number may sound small, it represents a meaningful improvement in a disease where preventing recurrence is critically important.\u003c\/p\u003e\n\n\u003cp\u003eThe relative risk reduction was 25.2%. This means that the risk of invasive disease, recurrence, or death was about one-quarter lower for patients who received ribociclib plus an NSAI. This was compared with those who received an NSAI alone.\u003c\/p\u003e\n\n\u003cp\u003eIt is important to note that the overall survival data are not yet mature. At the time of this analysis, there was a trend toward improved overall survival with ribociclib (hazard ratio 0.76), but this did not reach statistical significance (95% CI, 0.54 to 1.07). Longer follow-up is needed to determine whether ribociclib improves overall survival in early breast cancer.\u003c\/p\u003e\n\n\u003cp\u003eThe safety profile of ribociclib in this trial was consistent with what has been seen in previous studies. The most common side effect was neutropenia, which occurred in 62.1% of patients taking ribociclib. Neutropenia is a low level of neutrophils, a type of white blood cell that helps fight infection. Grade 3 or higher neutropenia occurred in 43.8% of patients taking ribociclib. Liver-related events were also more common with ribociclib, occurring in 25.4% of patients.\u003c\/p\u003e\n\n\u003cp\u003eMost patients who discontinued ribociclib did so early in treatment, with a median time to discontinuation of 4 months. This suggests that if patients tolerate the first few months of ribociclib, they are likely to continue treatment.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Study\u003c\/h2\u003e\n\n\u003cp\u003eThis report is based on a prespecified interim analysis, not the final analysis. Interim analyses are conducted before all planned data have been collected. The results may change with longer follow-up.\u003c\/p\u003e\n\n\u003cp\u003eThe median duration of follow-up was 34 months from randomization to the data cutoff. This is a relatively short follow-up period for early breast cancer, where recurrence can occur up to 20 years after diagnosis. Longer follow-up is needed to fully understand the long-term benefits of ribociclib.\u003c\/p\u003e\n\n\u003cp\u003eThe overall survival data are not yet mature. At the time of this analysis, 61 patients (2.4%) in the ribociclib–NSAI group and 73 patients (2.9%) in the NSAI group had died. The hazard ratio for death was 0.76 (95% CI, 0.54 to 1.07), which did not reach statistical significance. This means the study cannot yet conclude whether ribociclib improves overall survival in early breast cancer.\u003c\/p\u003e\n\n\u003cp\u003eThe trial was open-label, meaning that both patients and doctors knew which treatment was being given. This could potentially influence how side effects are reported or how patients feel. However, the primary end point of invasive disease–free survival is an objective measure that is less likely to be affected by this limitation.\u003c\/p\u003e\n\n\u003cp\u003eThe widths of the confidence intervals have not been adjusted for multiplicity. This means they may not be used in place of hypothesis testing for secondary end points.\u003c\/p\u003e\n\n\u003cp\u003eThe study population was predominantly White (73.4%). This may limit how well the results apply to other racial and ethnic groups.\u003c\/p\u003e\n\n\u003cp\u003eThe trial did not include patients with stage I disease, except for a small number (14 patients, 0.3%) who were enrolled. The results may not apply to patients with stage I breast cancer.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Next Steps\u003c\/h2\u003e\n\n\u003cp\u003eBased on the results of this trial, ribociclib plus an NSAI significantly improved invasive disease–free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. This represents a potential new treatment option for this patient population.\u003c\/p\u003e\n\n\u003cp\u003ePatients with HR-positive, HER2-negative stage II or III early breast cancer should discuss with their healthcare provider whether adding ribociclib to their hormone therapy is appropriate for them. This discussion should include the potential benefits of reduced recurrence risk and the potential side effects, particularly neutropenia and liver-related events.\u003c\/p\u003e\n\n\u003cp\u003ePatients taking ribociclib should be monitored for side effects, including:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003eBlood counts:\u003c\/strong\u003e Regular blood tests to check for neutropenia and other blood cell changes.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLiver function:\u003c\/strong\u003e Regular blood tests to check for liver-related side effects.\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eJoint pain:\u003c\/strong\u003e Report any new or worsening joint pain to your healthcare provider.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eMost patients who discontinued ribociclib did so early in treatment, with a median time to discontinuation of 4 months. Patients who tolerate the first few months of ribociclib are likely to continue treatment. If side effects occur, dose reductions may be possible. In this trial, dose reductions of ribociclib occurred in 554 patients (21.9%).\u003c\/p\u003e\n\n\u003cp\u003eThe trial is ongoing, and longer follow-up is needed to determine whether ribociclib improves overall survival in early breast cancer. Patients and healthcare providers should stay informed about updated results as they become available.\u003c\/p\u003e\n\n\u003cp\u003eThe monarchE trial previously led to approval of abemaciclib for this indication in patients with node-positive disease at high risk for recurrence. The NATALEE trial may expand the population of patients who can benefit from CDK4\/6 inhibitors in early breast cancer.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat did the NATALEE trial find about adding ribociclib to hormone therapy for early breast cancer?\u003c\/h3\u003e\n\u003cp\u003eIn a trial of 5,101 patients with HR-positive, HER2-negative stage II or III early breast cancer, adding ribociclib to an aromatase inhibitor improved invasive disease-free survival. At 3 years, 90.4% of patients on ribociclib plus an aromatase inhibitor remained free of invasive disease, recurrence, or death, compared with 87.1% on an aromatase inhibitor alone. This was a 25.2% relative reduction in risk.\u003c\/p\u003e\n\u003ch3\u003eWho was eligible to join the NATALEE trial?\u003c\/h3\u003e\n\u003cp\u003eEligible patients were adults with histologically confirmed HR-positive, HER2-negative early breast cancer, stage II or III. Those with stage IIA needed at least one positive lymph node, or specific high-risk features like grade 2 tumor with Ki-67 of at least 20%, high genomic risk, or grade 3 tumor. Patients who had received a prior CDK4\/6 inhibitor or had significant uncontrolled heart disease were not eligible.\u003c\/p\u003e\n\u003ch3\u003eWhat does a 25.2% relative risk reduction mean for me?\u003c\/h3\u003e\n\u003cp\u003eIt means the risk of invasive disease, recurrence, or death was about one-quarter lower for patients who received ribociclib plus an aromatase inhibitor compared with those who received an aromatase inhibitor alone. In absolute terms, about 3 more patients out of every 100 remained free of invasive disease, recurrence, or death at 3 years.\u003c\/p\u003e\n\u003ch3\u003eWhat side effects were more common with ribociclib in the NATALEE trial?\u003c\/h3\u003e\n\u003cp\u003eNeutropenia (low white blood cell counts) occurred in 62.1% of patients on ribociclib plus an aromatase inhibitor versus 4.5% on an aromatase inhibitor alone. Liver-related events occurred in 25.4% versus 10.6%. Joint pain was common in both groups. The 3-year ribociclib regimen at a 400-mg starting dose did not produce any new safety signals.\u003c\/p\u003e\n\u003ch3\u003eHow long do patients take ribociclib, and what if side effects occur?\u003c\/h3\u003e\n\u003cp\u003eIn the trial, ribociclib 400 mg was taken once daily for 21 days followed by 7 days off, for 36 months (3 years). The aromatase inhibitor was continued for 60 months (5 years). If side effects occur, dose reductions may be possible; in the trial, 21.9% of patients had a ribociclib dose reduction. Most discontinuations happened early, with a median time to stopping of 4 months.\u003c\/p\u003e\n\u003ch3\u003eDoes ribociclib improve overall survival in early breast cancer?\u003c\/h3\u003e\n\u003cp\u003eThe overall survival data are not yet mature. At the time of this analysis, 2.4% of patients on ribociclib plus an aromatase inhibitor and 2.9% on an aromatase inhibitor alone had died. The hazard ratio for death was 0.76, but this did not reach statistical significance. Longer follow-up is needed to determine whether ribociclib improves overall survival in early breast cancer.\u003c\/p\u003e\n\u003ch3\u003eWhat should I discuss with my healthcare provider about adding ribociclib?\u003c\/h3\u003e\n\u003cp\u003ePatients with HR-positive, HER2-negative stage II or III early breast cancer should discuss with their healthcare provider whether adding ribociclib to their hormone therapy is appropriate. This discussion should include the potential benefit of reduced recurrence risk and the potential side effects, particularly neutropenia and liver-related events. Monitoring includes regular blood tests for blood counts and liver function.\u003c\/p\u003e\n\u003ch3\u003eI have stage II HR-positive, HER2-negative early breast cancer — should I get a second opinion before adding ribociclib to my hormone therapy?\u003c\/h3\u003e\n\u003cp\u003eAdding ribociclib to an aromatase inhibitor improved invasive disease–free survival at 3 years (90.4% versus 87.1%), a 25.2% relative reduction in risk, with about a 3 percentage point absolute benefit in both stage II and stage III disease. Overall survival data are not yet mature. Because the decision involves weighing this benefit against neutropenia (62.1%) and liver-related events (25.4%), an independent review of your stage, pathology, and hormone therapy plan can help clarify whether the combination is appropriate for you. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Ribociclib plus Endocrine Therapy in Early Breast Cancer NEJM 2024\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e D. Slamon, O. Lipatov, Z. Nowecki, N. McAndrew, B. Kukielka-Budny, D. Stroyakovskiy, D.A. Yardley, C.-S. Huang, P.A. Fasching, J. Crown, A. Bardia, S. Chia, S.-A. Im, M. Ruiz-Borrego, S. Loi, B. Xu, S. Hurvitz, C. Barrios, M. Untch, R. Moroose, F. Visco, K. Afenjar, R. Fresco, I. Severin, Y. Ji, F. Ghaznawi, Z. Li, J.P. Zarate, A. Chakravartty, T. Taran, and G. Hortobagyi\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e New England Journal of Medicine, 2024;390:1080-1091\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1056\/NEJMoa2305488\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c\/strong\u003e Novartis\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eClinicalTrials.gov number:\u003c\/strong\u003e NCT03701334 (NATALEE trial)\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47919020474524,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"url":"https:\/\/diagnosticdetectives.com\/it\/products\/ribociclib-plus-hormone-therapy-improves-outcomes-in-early-breast-cancer-results-from-the-natalee-trial","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}