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. 2025 Oct 17;10(11):105858. doi: 10.1016/j.esmoop.2025.105858

Adjuvant ribociclib plus nonsteroidal aromatase inhibitor therapy in patients with HR-positive/HER2-negative early breast cancer: 5-year follow-up of NATALEE efficacy outcomes and updated overall survival☆

J Crown 1,∗, D Stroyakovskii 2, DA Yardley 3, C-S Huang 4, PA Fasching 5, A Bardia 6,7, S Chia 8, S-A Im 9, M Martin 10, B Xu 11, CH Barrios 12, M Untch 13, R Moroose 14, SA Hurvitz 15, GN Hortobagyi 16, DJ Slamon 6, F Visco 17, G Spera 18, JP Zarate 19, D Halligan 20, Z Li 19, S Loi 21
PMCID: PMC12684762  PMID: 41320342

Abstract

Background

At the primary efficacy analysis of the NATALEE phase III trial, ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) demonstrated a statistically significant improvement in invasive disease-free survival (iDFS) versus NSAI alone in patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC). Continued follow-up of efficacy outcomes is important in assessing the durability of treatment benefit. We report 5-year estimates of efficacy outcomes, including an udpated analysis of overall survival (OS).

Patients and methods

Eligible patients included pre/postmenopausal women and men with HR-positive/HER2-negative EBC and anatomic stage IIA (N1 or N0 with high-risk factors), IIB, or III disease. Patients were randomized 1 : 1 to ribociclib 400 mg/day (3 weeks on/1 week off for 3 years) + NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 5 years) or NSAI alone. Premenopausal women and men received goserelin. The primary endpoint was iDFS, and secondary/exploratory endpoints included distant disease-free survival, recurrence-free survival, distant recurrence-free survival, and OS.

Results

With a median iDFS follow-up of 55.4 months, ribociclib + NSAI demonstrated persistent iDFS benefit versus NSAI alone [hazard ratio 0.716, 95% confidence interval (CI) 0.618-0.829, nominal one-sided log-rank P < 0.0001]. Absolute iDFS improvement between treatment arms increased from the 3- (Δ2.7%) to the 5-year (Δ4.5%) time points. Persistent benefit over time was also observed across subgroups [including N0 patients (hazard ratio 0.606, 95% CI 0.372-0.986)] and secondary/exploratory endpoints. As OS continues to mature, numerical improvement in favor of ribociclib was observed (hazard ratio 0.800, 95% CI 0.637-1.003, nominal one-sided log-rank P = 0.026).

Conclusions

This prespecified 5-year follow-up of efficacy outcomes from NATALEE demonstrated that ribociclib + NSAI continued to reduce the risk of recurrence beyond the 3-year treatment window, supporting its use as adjuvant therapy in patients with HR-positive/HER2-negative EBC. An ongoing positive trend for improved OS in favor of ribociclib + NSAI was observed.

Key words: ribociclib, CDK4/6 inhibitor, HR positive/HER2 negative, early breast cancer, NATALEE

Highlights

  • •

    This prespecified analysis assessed 5-year efficacy outcomes of the NATALEE trial (median iDFS follow-up of 55.4 months).

  • •

    Persistent iDFS benefit was observed with ribociclib + NSAI versus NSAI alone (hazard ratio 0.716, 95% CI 0.618-0.829).

  • •

    iDFS benefit with ribociclib was observed across subgroups, including in node-0 disease (hazard ratio 0.606, 95% CI 0.372-0.986).

  • •

    A positive trend for OS in favor of ribociclib continues to emerge (hazard ratio 0.800, 95% CI 0.637-1.003, nominal one-sided P = 0.026).

  • •

    No new safety signals for causes of deaths or secondary primary malignancies were identified with this updated analysis.

Introduction

Despite advances in systemic adjuvant chemotherapy and endocrine treatment, between one-third and one-half of patients diagnosed with early-stage hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer (EBC) will develop metastatic recurrence, a condition associated with poor long-term survival.1,2 Patients with EBC undergo multimodal therapies with curative intent3; nonetheless, the indolent yet persistent nature of HR-positive/HER2-negative disease confers a sustained risk of recurrence.1,4,5 In contrast to the triple-negative and HER2-positive variants of the disease, HR-positive/HER2-negative EBC has a long natural history, leading to an underestimate of recurrence risk in studies with short follow-up.1 Furthermore, in comparison to other subtypes, progress in treating HR-positive/HER2-negative EBC has been relatively slow, with previous novel therapies being introduced nearly 20 years ago (i.e. aromatase inhibitors).6, 7, 8, 9 Approximately 30% of patients with HR-positive/HER2-negative EBC are expected to experience a recurrence 5 years after initiation of adjuvant endocrine therapy (ET).4 For patients at high clinical risk, additional therapies in the adjuvant setting may further reduce undetectable residual disease and help mitigate some of the long-term risk of relapse.

Ribociclib in combination with a nonsteroidal aromatase inhibitor (NSAI) is indicated as adjuvant treatment for patients with stage II and III HR-positive/HER2-negative EBC at high risk of recurrence.10,11 At the primary efficacy analysis of the NATALEE phase III trial, ribociclib + NSAI demonstrated statistically significant improvement in invasive disease-free survival (iDFS) versus NSAI alone [median iDFS follow-up, 27.7 months; hazard ratio 0.75, 95% confidence interval (CI) 0.62-0.91, two-sided P = 0.003].12 Continued follow-up in an exploratory 4-year landmark analysis found sustained benefit after all patients were off ribociclib (median iDFS follow-up, 44.2 months; hazard ratio 0.72, 95% CI 0.61-0.84), with the treatment and control curves further separating.13

Extended follow-up of efficacy outcomes is important in assessing the durability of treatment benefit. At this prespecified analysis of NATALEE, we report 5-year estimates of iDFS, including updates of distant disease-free survival (DDFS), distant relapse-free survival (DRFS), relapse-free survival (RFS), and overall survival (OS).

Patients and methods

Study design and population

NATALEE (NCT03701334) is an open-label, multicenter, randomized, phase III trial that investigated the efficacy and safety of ribociclib with NSAI as adjuvant treatment in patients with stage II or III HR-positive/HER2-negative EBC. NATALEE study design and methods have been previously described.12,14 Briefly, pre- or postmenopausal women and men were randomized 1 : 1 to ribociclib 400 mg/day (3 weeks on/1 week off for 36 months) + NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone. Premenopausal women and men also received goserelin 3.6 mg every 28 days. All patients with stage III or IIB disease, including node (N) negative [based on the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, eighth edition], were eligible. Patients with stage IIA disease were eligible if they had N1 involvement or N0 disease with either grade 3 histology, grade 2 histology with Ki-67 ≥20%, or grade 2 histology with high genomic risk. Prior ET was allowed if initiated ≤12 months before randomization.

The study protocol and amendments were approved by each ethical and institutional review board in compliance with the Declaration of Helsinki. All patients provided written informed consent.

Endpoints

This prespecified time-triggered analysis (data cut-off: 28 May 2025) assessed efficacy outcomes ∼2 years after the final iDFS analysis (data cut-off: 21 July 2023). Patients assessed for efficacy included those who completed study treatments, those still on treatment, and those who discontinued treatments for any reason. Patients who discontinued the study treatment early because of withdrawal of consent or loss to follow-up were censored at the time of discontinuation. Patients who discontinued study treatment for other reasons [adverse event (AE), patient/physician decision, protocol deviation, etc.] were not censored at the time of discontinuation but were followed up until an iDFS event occurred (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105858). Extended follow-up of iDFS (primary endpoint), DDFS (secondary endpoint), DRFS (exploratory endpoint), RFS (secondary endpoint), and OS (secondary endpoint) was assessed. AEs during the ribociclib treatment period (randomization up to 36 months) were previously analyzed and reported.13 With all patients off ribociclib treatment for a median of 2 years, AEs were not reassessed at this 5-year time point. Key safety events (secondary primary malignancies, deaths) were continuously monitored and are reported.

Statistical analyses

Survival functions of efficacy outcomes were estimated using the Kaplan–Meier method, and results are descriptive. The Cox proportional hazards model was used to estimate the hazard ratios and 95% CIs. Comparison of survival between treatment arms was generated by stratified log-rank test (one-sided P value, informational and not pre-planned). Analyses were conducted using SAS (version 9.4; SAS Institute, Cary, NC).

Results

Patients

At this 5-year analysis, all patients in the ribociclib + NSAI arm (n = 2549) were off ribociclib for a median of 2 years, and 1600 (62.8%) completed the 3-year ribociclib treatment regimen (Figure 1). In the ribociclib + NSAI arm, 36.5% of patients completed 5 years of NSAI treatment versus 34.4% in the NSAI-alone arm, and 27.1% had NSAI treatment ongoing versus 23.7% in the NSAI-alone arm. The percentage of patients who discontinued NSAI treatment was similar across arms (ribociclib + NSAI, 35.5%; NSAI alone, 37.6%). Patient baseline demographics and clinical characteristics are shown in Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2025.105858.

Figure 1.

Figure 1

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Patient disposition. NSAI, nonsteroidal aromatase inhibitor; RIB, ribociclib. aTotal count includes two patients randomized to the NSAI-alone arm who were given one dose each of ribociclib in error. They are accounted for in the RIB discontinuation box as ‘protocol deviation’ and ‘other’. bPatients were required to discontinue ribociclib treatment if ribociclib dosing was interrupted for >28 days due to ribociclib-related adverse events. cThe NATALEE protocol required patients who discontinued NSAI treatment to also discontinue ribociclib treatment (if on ribociclib treatment). Patients who discontinued RIB treatment early could continue to receive their NSAI treatment.

Efficacy

With a median iDFS follow-up of 55.4 months, 317 patients (12.4% of the full analysis set) experienced an iDFS event in the ribociclib + NSAI arm versus 407 (15.9%) in the NSAI-alone arm, and 1892 (74.2%) were ongoing in the trial without an event versus 1703 (66.7%) in the NSAI-alone arm (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2025.105858). In the ribociclib + NSAI arm, 340 (13.3%) patients were censored [NSAI alone, 442 (17.3%)] for loss to follow-up [ribociclib + NSAI, 34 (1.3%); NSAI alone, 37 (1.4%)] and withdrawal of consent [ribociclib + NSAI, 306 (12.0%); NSAI alone, 405 (15.9%)]. An imbalance of censored patients was observed for those who withdrew consent at randomization [ribociclib + NSAI, 84 (3.3%); NSAI alone, 201 (7.9%)], with similar rates of withdrawal across 0- to 60-month time points. Baseline prognostic factors in patients who withdrew consent were similar in both treatment arms (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2025.105858). iDFS sensitivity analyses accounting for different censoring assessments were consistent with the outcomes in the intention-to-treat population (Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2025.105858).

At this 5-year landmark, ribociclib continues to demonstrate a durable iDFS benefit (hazard ratio 0.716, 95% CI 0.618-0.829, nominal P < 0.0001) (Figure 2). Absolute iDFS benefit with ribociclib increased from the 3-year (Δ 2.7%) to the 5-year analysis (4.5%), with nonoverlapping 95% CIs between treatment and control arms at each landmark time point. iDFS benefit was seen regardless of nodal status (N0: hazard ratio 0.606, 95% CI 0.372-0.986; N1-3: hazard ratio 0.737, 95% CI 0.631-0.860; Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2025.105858), stage (stage II: hazard ratio 0.660, 95% CI 0.493-0.884; stage III: hazard ratio 0.730, 95% CI 0.615-0.865; Supplementary Figure S2), prior chemotherapy (yes versus no), and menopausal status (Figure 3). Ribociclib + NSAI also demonstrated continued benefit in DDFS (hazard ratio 0.709, 95% CI 0.608-0.827; Figure 4A), DRFS (hazard ratio 0.699, 95% CI 0.594-0.824; Figure 4B), and RFS (hazard ratio 0.700, 95% CI 0.598-0.820; Figure 4C) versus NSAI alone, with fewer distant recurrences in patients receiving ribociclib + NSAI [207 (8.1%)] compared with NSAI alone [290 (11.4%)] (Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2025.105858).

Figure 2.

Figure 2

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Kaplan–Meier survival curve of iDFS in the ITT population. CI, confidence interval; IDFS, invasive disease-free survival; ITT, intention to treat; NSAI, nonsteroidal aromatase inhibitor; RIB, ribociclib. aThe difference between percentages does not equal 2.7 due to rounding.

Figure 3.

Figure 3

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Subgroup analysis of iDFS. AJCC, American Joint Committee on Cancer; CI, confidence interval; CT, chemotherapy; ET, endocrine therapy; iDFS, invasive disease-free survival; ITT, intent to treat; N, node; NSAI, nonsteroidal aromatase inhibitor; RIB, ribociclib. aIncludes neoadjuvant and adjuvant chemotherapy. bNodal status classification according to AJCC staging. Nodal status is from the most advanced stage derived per surgical specimen or at diagnosis. cFrom archival tumor tissue.

Figure 4.

Figure 4

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Kaplan-Meier survival curves. Kaplan–Meier survival curves of DDFS (A), DRFS (B), and RFS (C) in the ITT population. CI, confidence interval; DDFS, distant disease-free survival; DRFS, distant recurrence-free survival; ITT, intention to treat; NSAI, nonsteroidal aromatase inhibitor; RIB, ribociclib; RFS, recurrence-free survival.

At data cut-off, 300 patients had died, 137 (5.4%) in the ribociclib + NSAI arm and 163 (6.7%) in the NSAI-alone arm. Deaths related to breast cancer occurred in 101 patients (4.0%) in the ribociclib + NSAI arm and 133 (5.4%) in the NSAI-alone arm (Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2025.105858). As OS data matured, a positive trend favoring ribociclib + NSAI continued to be observed (hazard ratio 0.800, 95% CI 0.637-1.003, nominal P = 0.026; Figure 5; Supplementary Figure S4, available at https://doi.org/10.1016/j.esmoop.2025.105858). More patients were living with metastatic disease in the NSAI-alone arm [169 (6.9%)] versus the ribociclib + NSAI arm [114 (4.5%)] (Supplementary Figure S4, available at https://doi.org/10.1016/j.esmoop.2025.105858).

Figure 5.

Figure 5

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Kaplan–Meier survival curve of OS in the ITT population. CI, confidence interval; ITT, intention to treat; NSAI, nonsteroidal aromatase inhibitor; OS, overall survival; RIB, ribociclib.

Safety

At this 5-year analysis, no new safety signals (secondary primary malignancies, causes of death) were identified (median safety follow-up, 58.4 months). The proportion of patients who developed secondary primary malignancies was similar between the two arms [ribociclib + NSAI: 67 patients (2.7%); NSAI alone: 74 (3.0%)]. With 12.9 months of additional follow-up, five new deaths due to AEs occurred since the prior 4-year analysis. These deaths were not considered related to study treatment and occurred in three patients in the ribociclib + NSAI arm (brain hemorrhage, myocardial infarction, gastric adenocarcinoma) and two in the NSAI-alone arm (rectal adenocarcinoma, aortic aneurysm rupture).

Discussion

While advances in therapeutics treating stage I-III breast cancer have improved outcomes in patients with estrogen receptor-positive tumors, late relapses are still observed, and considerable importance is placed on evaluating the long-term benefits of adjuvant treatments for this patient population.6,15 In the patient population eligible for NATALEE, real-world studies have demonstrated a considerable risk of recurrence within 5 years and beyond.16 At this 5-year follow-up of the NATALEE study, adjuvant ribociclib + NSAI demonstrated durable iDFS, DDFS, DRFS, and RFS benefit versus NSAI alone, with a 28% relative reduction in the risk of recurrence or death. With all patients off ribociclib treatment for a median of 2 years, increasing absolute iDFS benefit was observed at the 3- (2.7%) and 5-year (4.5%) time points.

In NATALEE, patients were censored from the study at the time of discontinuation only in the instances of withdrawal of consent or loss to follow-up. An imbalance of censoring at randomization was observed, with balanced numbers thereafter throughout the study. Baseline disease characteristics of the patients who withdrew consent at randomization were similar to those of patients who remained in the study, suggesting no prognostic differences. Sensitivity analyses at this 5-year time point assessing the durability of the iDFS result under various event and censoring patterns found no meaningful difference in efficacy outcomes versus the intention-to-treat analysis. Similar results were also found in sensitivity analyses conducted by the United States Food and Drug Administration at the final iDFS readout of NATALEE.17 These analyses imputed various iDFS data scenarios for patients censored at randomization for withdrawal of consent. Taken together, these assessments further support the robustness of the iDFS benefit observed with adjuvant ribociclib + NSAI.

To date, two cyclin-dependent kinase (CDK) 4/6 inhibitors have demonstrated significant iDFS benefit in the adjuvant setting, with varying eligibility criteria in their respective phase III trials.12,18 NATALEE investigated adjuvant ribociclib in patients with stage I-III HR-positive/HER2-negative EBC with node-positive or node-negative disease.12 Patients with stage IIA N0 disease were included only if exhibiting additional high-risk features [T3, T4, T2 (grade 3, or grade 2 with Ki-67 ≥20%, or grade 2 with high genomic risk)].12 The monarchE trial investigated adjuvant abemaciclib in a more restricted patient population. Eligibility criteria included high-risk node-positive (N1-3) HR-positive/HER2-negative EBC, and patients with N1 disease were included only if they exhibited additional high-risk features (grade 3, tumor size ≥5 cm, Ki-67 ≥20%).18 Real-world studies have found that patients with high-risk N0 disease demonstrate a similar risk of recurrence as those with N1 disease.16,19 At this 5-year follow-up of NATALEE, sustained iDFS benefit with ribociclib + NSAI was observed across subgroups, demonstrating consistent benefit across a broad population of patients, including those with high-risk N0 disease. With a median of 2 years off ribociclib treatment, ribociclib continues to demonstrate persistent benefit in patients with high-risk N0 disease, with an updated hazard ratio and 95% CIs that are <1 (hazard ratio 0.606, 95% CI 0.372-0.986). The strength of these data reaffirms the benefit of ribociclib as the only approved CDK4/6 inhibitor to address an unmet need in high-risk N0 disease in addition to node-positive disease.10,11,20,21

With a median safety follow-up of 58.4 months, no new safety signals (secondary primary malignancies, causes of death) were observed. At this data cut-off, a similar percentage of patients in both treatment arms completed 5 years of NSAI therapy (ribociclib + NSAI, 36.5%; NSAI alone, 34.4%), demonstrating that the addition of ribociclib treatment did not impact the patient’s ability to complete 5 years of ET. Discontinuation of ribociclib treatment did not impact NSAI completion rates.

Given the long natural history of HR-positive/HER2-negative EBC, iDFS and DDFS are accepted surrogate endpoints for OS while awaiting the prolonged follow-up necessary for sufficient OS data to mature.22,23 Nonetheless, continued follow-up assessing OS outcomes is critical for understanding the benefit of adjuvant treatments. This is of particular interest for CDK4/6 inhibitors, which represent the most recent addition to adjuvant treatment for patients with HR-positive/HER2-negative EBC, and for which preliminary OS data with longer follow-up are beginning to become available.13,24,25 With 56.5 months of follow-up, a positive trend with ribociclib treatment continues to emerge (hazard ratio 0.800, 95% CI 0.637-1.003, nominal one-sided P = 0.026). Additional OS follow-up is planned.

Conclusion

This 5-year follow-up of efficacy outcomes from NATALEE demonstrated persistent iDFS, DDFS, DRFS, and RFS benefit over time in patients with stage II/III HR-positive/HER2-negative EBC treated with ribociclib + NSAI versus NSAI alone, providing further assurance of benefit beyond the 3-year treatment period. These data strengthen support for ribociclib use in patients with EBC at high risk of recurrence, including those with high-risk N0 disease. A continued numerical trend for improved OS in favor of ribociclib + NSAI was observed.

Acknowledgements

We thank the patients who participated in the trial and their families and caregivers, the members of the independent data monitoring committee, the members of the trial steering committee, the staff members who assisted with the trial at each site, and Anjeza Petersen, PhD, William Ho, PhD, and Tara Wabbersen, PhD, of Nucleus Global for medical writing assistance. Ribociclib was discovered by Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals.

Funding

This work was supported by Novartis Pharmaceuticals Corporation (no grant number).

Disclosure

JC reports personal fees from Pierre Fabre and Immunocore; personal fees and other from Novartis, AstraZeneca, and Regeneron; other from MSD Oncology, Pfizer, Roche, Oncoassure, and Akkure, outside the submitted work; in addition, JC has a patent pending: WO2020011770 (A1)—A method of predicting response to treatment in cancer patients. DAY reports grants from Ambrx, Amgen, AstraZeneca, BioMarin, Biothera Pharmaceuticals, Clovis Pharma, Dana Farber Cancer Institute, Lilly, Roche/Genentech, G1 Therapeutics, Gilead Therapeutics, Incyte, Innocrin Pharmaceuticals, MacroGenics, MedImmune, Medivation, Merck, Merrimack Pharmaceuticals, Nektar Therapeutics, Novartis, NSABP, Polyphor, Stemline Therapeutics, and UT Southwestern; nonfinancial support from AstraZeneca, G1 Therapeutics, Gilead Sciences, Immunomedics, Integra Connect, Novartis, Sanofi Aventis, and Stemline Therapeutics, outside the submitted work. CSH reports grants, personal fees, and nonfinancial support from Novartis, Daiichi Sankyo, AstraZeneca, EirGenix, Eli Lilly, Pfizer, Roche, and Novartis; grants and nonfinancial support from MSD; grants from OBI Pharma, Seagen, and Aston Sci; grants and personal fees from Gilead, outside the submitted work. PAF reports personal fees from Novartis; grants and personal fees from Pfizer, personal fees from Daiichi Sankyo, AstraZeneca, Eisai, and MSD; grants from Biontech and Cepheid; personal fees from Lilly, Seagen, Roche, Agendia, Gilead, Mylan, Menarini, Veracyte, and GuardantHealth, during the conduct of the study; and Translational Research in Oncology (TRIO). AB reports grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Mersana, and Innocrin; grants and personal fees from Biothernostics Inc.; personal fees from Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Spectrum Pharma, Taiho, Sanofi, Daiichi Pharma, and Puma, outside the submitted work. SC reports grants and personal fees from Novartis, Pfizer, Hoffman LaRoche, Eli Lilly, Merck, and AstraZeneca, outside the submitted work. SAI reports grants and personal fees from AstraZeneca, Pfizer, Eisai, Daiichi Sankyo, and Roche; personal fees from Novartis, GSK, MSD, Bertis, Idience, and Lilly; grants from Daewoong Pharm and Boryung Pharm, outside the submitted work. MM reports personal fees from Lilly, Pfizer, and AstraZeneca; grants and personal fees from Novartis and Roche-Genentech; personal fees from GSK, Pharmamar, Taiho Oncology, and Menarini, outside the submitted work. BX reports personal fees from Novartis and AstraZeneca, outside the submitted work. CHB reports grants from Pfizer, Pharma Mar, Polyphor, Henlius Biotech, Shanghai, Merck KGaA, Millennium, LEO Pharma, ImClone Systems, Exelixis, Medivation, Asana Biosciences, AB Science, Abraxis Biosciences, Daiichi Sankyo, BMS, BioMarin, Astellas Pharma, AbbVie, Merck (MSD), Merrimack, Mylan, Taiho Pharmaceutical, Sanofi, GSK, Roche/Genentech, Lilly, Boehringer Ingelheim, Novartis, AstraZeneca, Amgen, and Pfizer; personal fees from Boehringer Ingelheim, Sanofi, Lilly, Zodiac, AstraZeneca, MSD, Bayer, Eisai, Roche/Genentech, Pfizer, Novartis, and GSK; other from MedSIR and Thummi; personal fees and other from Daiichi Sankyo; grants from Nektar, Polyphor, Seagen, Janssen, OBI Pharma, Novocure, Celgene, Aveo Oncology, Takeda, TRIO, PPD, Syneos Health, ICON, IQVIA, Parexel, Nuvisan, PSI, Gilead, and Servier, outside the submitted work. MU reports personal fees from AstraZeneca, Amgen, Daiichi Sankyo, Lilly, Roche, Pfizer, MSD Oncology, Seagen, Pierre Fabre, Sanofi Aventis, Myriad, Gilead, Novartis, Menarini Stemline, and Genzyme, during the conduct of the study. RM reports personal fees from Gilead, Lilly, and Johnson & Johnson, outside the submitted work. SAH reports grants from Ambrx, Amgen, Arvinas, AstraZeneca, Bayer, Celcuity, Cytomx, Daiichi Sankyo, Dantari, Dignitana, Genentech/Roche, G1-Therapeutics, Gilead, Greenwich Life Sciences Inc, GSK, Immunomedics, Eli Lilly, LOXO, Macrogenics, Novartis, OBI Pharma, Orinove, Orum, Pfizer, Phoenix Molecular Designs, Ltd., Pieris, PUMA, Radius, Samumed, Sanofi, Seagen, and Zymeworks; other from Alliance Foundation, QuantumLeap (I-SPY), and InClin/Atossa, outside the submitted work. GNH reports grants and personal fees from Novartis, during the conduct of the study. DJS reports nonfinancial support and other from BioMarin; grants, nonfinancial support, and other from Pfizer; grants, personal fees, and nonfinancial support from Novartis; personal fees from Eli Lilly; other from Amgen, Seattle Genetics, 1200 Pharma, and TORL BioTherapeutics, outside the submitted work. JPZ, DH, and ZL report employment and stock ownership from Novartis. SL reports grants from Novartis, Bristol Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, AstraZeneca, and Seattle Genetics; other from Seattle Genetics, Novartis, Bristol Myers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, Gilead Therapeutics, Roche/Genentech, Novartis, GlaxoSmithKline, AstraZeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Daiichi Sankyo, Merck, Amunix, Tallac Therapeutics, Eli Lilly, Bristol Myers Squibb, and Aduro Biotech, outside the submitted work; and supported by the National Breast Cancer Foundation of Australia Endowed Chair and the Breast Cancer Research Foundation, New York. All other authors have declared no conflicts of interest.

Data sharing

Novartis is committed to sharing with qualified external researchers access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided are anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

Supplementary data

Supplementary Figures and Tables
mmc1.pdf (650.9KB, pdf)

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