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Summary Background Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant. Methods In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0–1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating. Findings Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68–0·88), with a median follow-up of 43·7 months (IQR 37·8–47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52–1·07), with a median follow-up of 39·4 months (IQR 37·0–42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9–not estimable) in the CDKI group and was 45·7 months (95% CI 41·7–not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67–0·89), with a median follow-up of 45·1 months (95% CI 39·2–48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs. Interpretation The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Funding None.

Objective Contemporary management of patients with neuro-oncologic disease requires an understanding of approvals by the US Food and Drug Administration (FDA) related to nervous system tumors. To summarize FDA updates applicable to neuro-oncology practitioners, we sought to review oncology product approvals and Guidances that were pertinent to the field in the past year. Methods Oncology product approvals between January 1, 2020, and December 31, 2020, were reviewed for clinical trial outcomes involving tumors of the nervous system. FDA Guidances relevant to neuro-oncology were also reviewed. Results Five oncology product approvals described outcomes for nervous system tumors in the year 2020. These included the first regulatory approval for neurofibromatosis type 1: selumetinib for children with symptomatic, inoperable plexiform neurofibromas. Additionally, there were 4 regulatory approvals for non-central nervous system (CNS) cancers that described clinical outcomes for patients with brain metastases. These included the approval of tucatinib for metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer including patients with brain metastases, brigatinib for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), and pralsetinib and selpercatinib for RET fusion-positive NSCLC. Finally, two FDA Guidances for Industry, “Cancer Clinical Trial Eligibility Criteria: Brain Metastases” and “Evaluating Cancer Drugs in Patients with Central Nervous System Metastases” were published to facilitate drug development for and inclusion of patients with CNS metastases in clinical trials. Conclusions Despite the challenges of the past year brought on by the COVID-19 pandemic, progress continues to be made in neuro-oncology. These include first-of-their-kind FDA approvals and Guidances that are relevant to the management of patients with nervous system tumors.

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. This was the first new molecular entity evaluated under Project Orbis, an FDA Oncology Center of Excellence initiative, which supports concurrent review of oncology drugs by multiple global health authorities. Approval was based on the HER2CLIMB trial, which randomized patients to receive tucatinib or placebo with trastuzumab and capecitabine. Tucatinib demonstrated efficacy compared with placebo in progression-free survival [PFS; HR: 0.54; 95% confidence interval (CI): 0.42–0.71; P < 0.00001] and overall survival (OS; HR: 0.66; 95% CI, 0.50–0.87; P = 0.00480). Patients with either treated and stable or active brain metastases made up 48% of the study population. PFS in patients with brain metastases confirmed benefit (HR: 0.48; 95% CI, 0.34–0.69; P < 0.00001). The benefit in patients with brain metastases allowed for inclusion of this specific population in the indication. Important safety signals included diarrhea and hepatotoxicity which are listed under Warnings and Precautions. This article summarizes the FDA thought process and data supporting the favorable benefit–risk profile and approval of tucatinib.

Purpose: Restrictive eligibility criteria induce differences between clinical trial and “real-world” treatment populations. Restrictions based on prior therapies are common; minimizing them when appropriate may increase patient participation in clinical trials. Experimental Design: A multi-stakeholder working group developed a conceptual framework to guide evaluation of prevailing practices with respect to using prior treatment as selection criteria for clinical trials. The working group made recommendations to minimize restrictions based on prior therapies within the boundaries of scientific validity, patient centeredness, distributive justice, and beneficence. Recommendations: (i) Patients are eligible for clinical trials regardless of the number or type of prior therapies and without requiring a specific therapy prior to enrollment unless a scientific or clinically based rationale is provided as justification. (ii) Prior therapy (either limits on number and type of prior therapies or requirements for specific therapies before enrollment) could be used to determine eligibility in the following cases: a) the agents being studied target a specific mechanism or pathway that could potentially interact with a prior therapy; b) the study design requires that all patients begin protocol-specified treatment at the same point in the disease trajectory; and c) in randomized clinical studies, if the therapy in the control arm is not appropriate for the patient due to previous therapies received. (iii) Trial designers should consider conducting evaluation separately from the primary endpoint analysis for participants who have received prior therapies. Conclusions: Clinical trial sponsors and regulators should thoughtfully reexamine the use of prior therapy exposure as selection criteria to maximize clinical trial participation. See related commentary by Giantonio, p. 2369

Over the last decade, there has been tremendous progress in the treatment of patients with gynecologic cancers with a changing therapy landscape. This summary provides an overview of U.S. Food and Drug Administration (FDA) approvals for gynecologic cancers from 2010 to 2020, totaling 17 new indications. For each of the approved indications, endpoints, trial design, results, and regulatory considerations are outlined. Among these 17 indications, six received accelerated approval (AA) and 11 received regular approval (RA). As of September 2021, of the six AA, three have subsequently demonstrated clinical benefit resulting in conversion to RA and the remaining three have ongoing clinical trials that have not yet reported results. Approval decisions for these 17 indications were supported by primary efficacy endpoints of progression-free survival (n = 10), objective response rate (n = 6), and overall survival (n = 1) and showed a favorable benefit–risk profile. Among the 17 indications, 15 received priority review and three applications participated in one or more novel Oncology Center of Excellence initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. Current FDA thinking on drug development opportunities and regulatory initiatives currently under way will be discussed.

On April 4, 2019, the FDA approved a supplemental new drug application for palbociclib (IBRANCE), to expand the approved indications in women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant, to include men. Palbociclib was first approved in 2015 for use in combination with letrozole for the treatment of estrogen receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women and subsequently in 2016 in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. The current approval was primarily based on the results of the PALOMA-2 and PALOMA-3 trials and, supported by real-world data from electronic health records and insurance claims. To support the safety evaluation in male patients, data from two phase I studies with palbociclib and safety information from the global safety database, were also reviewed. This article summarizes FDA decision-making and data supporting the approval of palbociclib for the treatment of male patients with HR-positive, HER2-negative advanced or MBC.

Background: Three cyclin dependent kinase 4/6 inhibitors (CDKIs) are approved by the Food and Drug Administration (FDA) for the treatment of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with hormonal therapy. However, the choice of when to initiate CDKI therapy (in the first- or second-line setting, or with aromatase inhibitor or fulvestrant) can be clinically challenging as studies have not directly compared these two approaches, nor have studies determined the benefit of continuation of CDKI therapy with changes in hormonal therapy backbone. Methods: Patient-level data from eight randomized controlled pivotal trials submitted to the FDA for new or supplemental marketing applications were pooled. We performed exploratory analyses of the predictive power of the baseline patient and disease characteristic data to forecast outcomes based on a specific treatment pathway. Variables included were: age, race, ethnicity, country and continent of origin, height, weight, body mass index (BMI), menopause status, estrogen receptor (ER) status, progesterone receptor (PR) status, ECOG performance score, histological type, histological grade, and initial disease stage. Additionally, baseline levels at the time of enrollment of alanine aminotransferase (ALT), albumin, alkaline phosphatase, aspartate aminotransferase (AST), bilirubin, blood urea nitrogen (BUN), calcium, creatinine, hemoglobin, magnesium, potassium, sodium, lymphocytes, neutrophils, platelets, and white blood cells. Statistical and machine learning algorithms were used to build predictive models based on the clinical trial results. Results: The pooled studies included 4580 breast cancer patients. Baseline random survival forest models were constructed for patients that received a CDKI plus hormonal therapy and for patients that received hormonal therapy alone. Preliminary findings for these models produced prediction accuracies of 69.2% for the CDKI model and 70.6% for the hormonal therapy alone model. Median predicted survival times for patients were calculated in both treatment scenarios and used to identify those that were more likely to benefit from initial use of CDKIs and those less likely to benefit. Through further analysis of the patients in each group, we identified patient characteristics that are prognostic of survival. Conclusions: This exploratory analysis utilized clinical trial data to create a model where clinical and disease characteristics are entered to come up with an efficacy prediction. Future efforts will extend this model to predict adverse event development. Citation Format: Jeremy Mason, Yutao Gong, Laleh Amiri-Kordestani, Suparna Wedam, Jennifer J Gao, Harpreet Singh, Richard Pazdur, Peter Kuhn, Gideon Blumenthal, Julia A Beaver. Prediction of CDK inhibitor efficacy in ER+/HER2- breast cancer using machine learning algorithms [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-07.

Summary Background Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are indicated with endocrine therapy as first-line or second-line treatment for hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We aimed to investigate the benefit of adding CDKIs to endocrine therapy in patients whose tumours might have differing degrees of endocrine sensitivity. Methods We pooled individual patient data from all phase 3 randomised breast cancer trials of CDKIs plus endocrine therapy submitted to the US Food and Drug Administration before Jan 1, 2019, in support of marketing applications. Our pooled analysis included all randomly assigned patients in these trials who received at least one dose of CDKI or placebo with endocrine therapy (an aromatase inhibitor [letrozole or anastrazole] or fulvestrant). We did prespecified subgroup analyses in patients with progesterone receptor-negative disease; patients with a disease-free interval of 12 months or less; patients with de-novo metastases, lobular histology, and bone-only disease; patients with visceral metastases; and patients aged up to 40 years. Patients who were not treated, who received tamoxifen as endocrine therapy, or who were treated with an aromatase inhibitor but who had received previous chemotherapy in the metastatic setting (not first-line) were excluded from our pooled analyses. All studies had a primary endpoint of investigator-assessed progression-free survival, defined as time from date of randomisation to the initial date of documented cancer progression or death, whichever occurred first. Median progression-free survival was estimated with Kaplan-Meier methods. Hazard ratios (HR) with 95% CIs for progression-free survival were estimated by means of Cox regression models. Findings The seven studies meeting this study's inclusion criteria were done between Feb 22, 2013, and Nov 3, 2017, with a median duration of follow-up of 19·7 months (IQR 15·9–25·9). 4200 patients were included in the pooled analysis, of whom 1320 received an aromatase inhibitor plus a CDKI, 932 received placebo plus an aromatase inhibitor, 1296 received fulvestrant plus a CDKI, and 652 received fulvestrant plus placebo. Across all seven pooled trials, the difference in estimated median progression-free survival was 8·8 months in favour of CDKI plus endocrine therapy over placebo plus endocrine therapy (range across the trials 6·8–13·3 months; HR 0·59, 95% CI 0·54–0·64). Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population. In first-line aromatase inhibitor-treated patients (n=2252), the median progression-free survival in the CDKI plus aromatase inhibitor group was 28·0 months (95% CI 25·3–29·1) versus 14·9 months (14·0–16·7) in the placebo plus aromatase inhibitor group (difference 13·1 months; range across the trials 13·0–13·3 months; HR 0·55, 95% CI 0·49–0·62). In first-line fulvestrant-treated patients (n=396), the median progression-free survival was 18·6 months (95% CI 14·8–23·5) in the placebo plus fulvestrant group and not estimable (22·4 to not estimable) in the CDKI plus fulvestrant group (difference not estimable; HR 0·58, 95% CI 0·42–0·80). In the patients treated with fulvestrant in the second-line setting and beyond (n=1552), the difference in estimated median progression-free survival between the CDKI plus fulvestrant group and the placebo plus fulvestrant group was 6·9 months in favour of the CDKI group (range across the trials 5·5–7·3 months; HR 0·56, 95% CI 0·49–0·64). Interpretation Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. Funding None.

PURPOSE Many older women will be treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor (AI), given US Food and Drug Administration approval of three agents in this class. The current pooled analysis examines the efficacy and safety of this combination in older women. PATIENTS AND METHODS We pooled data from three randomized controlled studies (N = 1,827) of different CDK4/6 inhibitors in combination with an AI for initial treatment of postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer. The effect of age on progression-free survival was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. RESULTS For patients age 75 years or older (n = 198) who were treated with a CDK4/6 inhibitor and an AI, hazard ratio was 0.49 (95% CI, 0.31 to 0.76) with an estimated median progression-free survival of 31.1 months (95% CI, 20.2 months to not reached) versus 13.7 months (95% CI, 10.9 months to 24.9 months) for those treated with an AI. Incidence of grade 3 to 4 adverse events was 88.8% in patients age 75 years and older and 73.4% in patients younger than age 75 years. Patients age 75 years or older reported a decline in quality-of-life measures using the EQ-5D regardless of treatment with AI alone or with the addition of a CDK4/6 inhibitor. CONCLUSION There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with AI alone for first-line treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer in older women compared with younger patients. Patients older than age 75 years experienced higher rates of toxicity, dose modifications, and a decrease from baseline in quality-of-life measures.

PURPOSE Three cyclin-dependent kinase 4/6 inhibitors (CDKIs) are approved by the US Food and Drug Administration for the treatment of patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced or metastatic breast cancer in combination with hormonal therapy (HT). We hypothesized that on an individual basis, efficacy outcomes and adverse event (AE) development can be predicted using baseline patient and tumor characteristics. METHODS Individual-level data from seven randomized controlled trials submitted to the US Food and Drug Administration for new or supplemental marketing applications of CDKIs were pooled. Progression-free survival (PFS), overall survival (OS), and AE prediction models were developed for specific treatment regimens (HT v HT plus CDKI). An individual's characteristics were used in all models simultaneously to create a group of predicted outcomes that are comparable across treatment settings. RESULTS Accuracy of the PFS and OS prediction models for HT were 66% and 64%, respectively, with the strongest predictors being menopausal status and therapy line. The corresponding AE prediction models resulted in an average area under the curve of 0.613. Accuracy of the PFS and OS prediction models for HT plus CDKI were 62% and 63%, respectively, with the strongest predictors being histologic grade for both. The corresponding AE prediction models resulted in an average area under the curve of 0.639. CONCLUSION This exploratory analysis demonstrated that models of efficacy outcomes and AE development can be developed using baseline patient and tumor characteristics. Comparison of paired models can inform treatment selection for individuals on the basis of the patient's personalized goals and concerns. Although use of CDKIs is standard of care in the first- or second-line setting, this model provides prognostic information that may inform individual treatment decisions.

Background: Cyclin dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as 1st or 2nd line treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival (PFS) of patients in certain clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival (OS) results in patients treated with a CDKI and fulvestrant. Methods: We pooled individual patient data (n=1948) from three phase III randomized breast cancer trials of CDKI in combination with fulvestrant submitted to the US Food and Drug Administration (FDA) in support of marketing applications. All analyzed patients received at least one dose of CDKI or placebo in combination with fulvestrant. The median OS was estimated using Kaplan-Meier (KM) methods, and hazard ratios (HR) with corresponding 95% confidence intervals (CIs) were estimated using Cox regression models. Patients were analyzed collectively, by number of prior lines of systemic endocrine therapy in any disease setting (1st-line or endocrine naive vs. 2nd -line and later), and in various clinicopathologic subgroups of interest. Findings: In all pooled patients (n=1948), the estimated OS HR was 0∙77 (95% CI 0∙68-0∙88), with a median follow-up of 43∙7 months (interquartile range, (IQR): 37∙8, 47∙7) and deaths in 48% of patients. The difference in estimated median OS was 7∙1 months, favoring CDKIs. In patients who were endocrine therapy naive and received CDKIs as 1st -line systemic endocrine therapy (2 trials, n=396), the estimated OS HR was 0∙74 (95% CI 0∙52-1∙07), with a median follow-up of 39∙4 months (IQR: 37∙0, 42∙2) and deaths in 31% of patients. The median OS difference could not be calculated, since median OS was not reached on CDKI arm. In patients who received CDKIs as 2nd-line or later systemic endocrine therapy (3 trials, n=1552), the estimated OS HR was 0∙77 (95% CI 0∙67-0∙89), with a median follow-up of 45∙1 months (IQR: 39∙2, 48∙5) and deaths in 52% of patients. The median OS difference was 7∙0 months, favoring CDKIs. Additional subgroup analyses of OS by progesterone receptor status, site of metastases, breast cancer histology, ECOG performance status, race, and de novo metastatic presentation all favored adding CDKI to fulvestrant. Patients with de novo metastatic disease (n=470, OS HR 0∙91 [95% CI 0∙68-1∙21]) and Asian patients (n=394, OS HR 0∙95 [95% CI 0∙81-1∙60]) appeared to benefit relatively less from the addition of CDKI to fulvestrant. Although the estimated OS HR appeared to favor fulvestrant alone in patients age < 40 [HR 1∙5 (95% CI 0∙75-3∙02)], this result must be interpreted with caution, given the small sample size (n=89) and correspondingly wide confidence interval. Evaluation of other age subgroups showed results in favor of the addition of CDKI to fulvestrant. All results presented are considered exploratory and hypothesis-generating. Interpretation: Addition of CDKIs to fulvestrant appears to confer a consistent overall survival benefit across all pooled patients and within most clinicopathological subgroups of interest. Funding: None. Declaration of Interest: All authors declare no competing interests. Ethical Approval: All patients in the included trials were required to provide informed written consent, and all trials had institutional review board or ethical approval.

Purpose To provide evidence-based consensus recommendations on choice of end points for clinical trials in metastatic breast cancer, with a focus on biologic subtype and line of therapy. Methods The National Cancer Institute Breast Cancer Steering Committee convened a working group of breast medical oncologists, patient advocates, biostatisticians, and liaisons from the Food and Drug Administration to conduct a detailed curated systematic review of the literature, including original reports, reviews, and meta-analyses, to determine the current landscape of therapeutic options, recent clinical trial data, and natural history of four biologic subtypes of breast cancer. Ongoing clinical trials for metastatic breast cancer in each subtype also were reviewed from ClinicalTrials.gov for planned primary end points. External input was obtained from the pharmaceutic/biotechnology industry, real-world clinical data specialists, experts in quality of life and patient-reported outcomes, and combined metrics for assessing magnitude of clinical benefit. Results The literature search yielded 146 publications to inform the recommendations from the working group. Conclusion Recommendations for appropriate end points for metastatic breast cancer clinical trials focus on biologic subtype and line of therapy and the magnitude of absolute and relative gains that would represent meaningful clinical benefit.

Purpose The outcome and proportion of patients with bone-only (BO) metastatic breast cancer (MBC) has not been well described. We sought to describe the differential outcomes of patients with BO MBC in clinical trials and explore whether there was a discrepancy in radiographic reads between investigator and blinded independent central review. Methods We pooled and analyzed data on 10,521 patients from 13 prospective trials submitted for MBC treatment in initial or supplemental New Drug or Biologics License Applications from 2005. Three subsets were evaluated: BO, bone with other metastases (BWO), and no bone metastases (NBM). Early discordance rate and late discordance rate were calculated from 3,733 and 2,813 patients subject to a blinded independent central review, respectively. Results Bone metastases were identified in 49% (range: 42% to 73%) of patients across trials. BO disease was present in 12.5% (range: 4% to 26%), dependent on subtype. Investigator-assessed progression-free survival (PFS) and overall survival (OS) for the pooled trials demonstrated improved outcomes for the BO subgroup compared with other subgroups (BO v BWO PFS hazard ratio [HR], 0.64; 95% CI, 0.591 to 0.696; BO v NBM PFS HR, 0.70; 95% CI, 0.65 to 0.76; BO v BWO OS HR, 0.56; 95% CI, 0.50 to 0.61; BO v NBM OS HR, 0.68; 95% CI, 0.61 to 0.76). The BO subgroup has a higher early discordance rate and lower late discordance rate than the BWO and NBM subgroups. Conclusion To our knowledge, this review is the largest analysis to date of the BO subgroup of MBC and suggests this subgroup may have a distinct natural history. There also seems to be a difference in how the local investigators assessed progression events in the BO subgroup when compared with the other two groups.

On May 3, 2019, the FDA granted regular approval to ado-trastuzumab emtansine (KADCYLA), for the adjuvant treatment of patients with HER2-positive early-breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane-based chemotherapy and trastuzumab-based treatment. Approval was based on data from the KATHERINE trial, which randomized patients to receive ado-trastuzumab emtansine or trastuzumab. At 3 years, the event-free rate for invasive disease-free survival in the ado-trastuzumab emtansine arm was 88.3% [95% confidence interval (CI), 85.8–90.7] compared with 77.0% (95% CI, 73.8–80.7) in the trastuzumab arm, (HR, 0.50; 95% CI, 0.39–0.64; P < 0.0001). Results from secondary endpoints, subgroup analyses, and sensitivity analyses generally supported the primary efficacy endpoint results. Common adverse reactions (>25% and higher incidence in ado-trastuzumab emtansine arm) with ado-trastuzumab emtansine were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. Ado-trastuzumab emtansine is the first drug approved for the treatment of patients with residual disease after neoadjuvant treatment and surgery. This article summarizes the FDA review and the data supporting the approval of ado-trastuzumab emtansine as a component of treatment for patients with HER2-positive EBC with residual disease.

1055 JJG, JC, TMP contributed equally. JAB, LAK contributed equally. Background: Cyclin dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first or secondline treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival of patients in certain clinicopathologic subgroups, and results showed a consistent benefit from the addition of a CDKI to endocrine therapy. Here, we report the pooled overall survival (OS) results in patients treated with a CDKI plus fulvestrant. Methods: We pooled individual patient data (n=1948) from three phase III randomized breast cancer trials of a CDKI plus fulvestrant submitted to the FDA in support of marketing applications. All analyzed patients received at least one dose of a CDKI or placebo, plus fulvestrant. The median OS was estimated using Kaplan-Meier (KM) methods, and hazard ratios (HR) with corresponding 95% confidence intervals (CIs) were estimated using Cox regression models. Results: Results of OS analyses, including all pooled patients, patients treated in the first-line setting, and patients treated in the second line and later settings, are summarized in the table below. Additional subgroup analyses of OS by progesterone receptor status, site of metastases, breast cancer histology, ECOG performance status, race, and de novo metastatic presentation all favored adding a CDKI to fulvestrant. In patients age < 40, the estimated OS HR favored fulvestrant alone, but this subgroup had a small sample size (n=89), so this result must be interpreted with caution. All results are considered exploratory and hypothesis-generating. Conclusions: Addition of CDKIs to fulvestrant appears to confer a consistent survival benefit across all pooled patients and within most clinicopathological subgroups of interest.[Table: see text]

On February 19, 2016, the FDA approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, AstraZeneca) for the treatment of women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2:1) to receive palbociclib plus fulvestrant (n = 347) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator-assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 months vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% confidence interval (CI), 0.36–0.59; P < 0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (>20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. Clin Cancer Res; 22(20); 4968–72. ©2016 AACR.

On September 30, 2013, the FDA granted accelerated approval to pertuzumab (Perjecta; Genentech, Inc.) for use in combination with trastuzumab and docetaxel as neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. The approval was based in part on a randomized multicenter trial in the indicated population that allocated 417 patients to neoadjuvant treatment with trastuzumab–docetaxel (TD), pertuzumab–trastuzumab–docetaxel (PTD), pertuzumab–trastuzumab, or pertuzumab–docetaxel. PTD was administered preoperatively every 3 weeks for four cycles. Following surgery patients received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide every 3 weeks and trastuzumab every 3 weeks to complete 1 year of therapy. The pathologic complete response rates by the FDA-preferred definition [absence of invasive cancer in the breast and lymph nodes (ypT0/is ypN0)] were 39.3% and 21.5% in the PTD and the TD arms, respectively (P = 0.0063). The most common adverse reactions with PTD were alopecia, diarrhea, nausea, and neutropenia. This approval was based on the totality of evidence, particularly improved survival in the metastatic breast cancer trial, and a fully accrued confirmatory trial. Clin Cancer Res; 20(21); 5359–64. ©2014 AACR.

Background: With recent FDA approvals of inhibitors of Cyclin Dependent Kinases 4 and 6 (CDK 4/6) in combination with endocrine therapy for the treatment of postmenopausal women with hormone-receptor positive metastatic breast cancer (MBC), an increasing number of older adults will be treated with this class of agents. An improved understanding of the safety and efficacy of CDK 4/6 inhibitors in this population is important to inform clinical decision making for the treatment of older patients. Methods: Data from two prospective randomized controlled studies (n=1334) of different CDK 4/6 inhibitors in combination with an aromatase inhibitor for the initial treatment of postmenopausal patients with hormone-receptor positive MBC were pooled and analyzed. The effect of age on progression free survival (PFS) was explored using Kaplan Meier (KM) estimates and a Cox-proportional hazard model. Safety analysis included adverse events up to 30 days after last administration of drug based on standardized adverse event datasets. Results: Age was balanced between the two studies, and between treatment arms within each study. The median age of women was 62 (range 23-91). Of the 1334 total patients, 42% were ≥65, and 24% were ≥ 70. For patients ≥70 who were treated with a CDK4/6 inhibitor in combination with an aromatase inhibitor, the estimated PFS was not reached (95% CI: 25.1months, NR) vs an estimated 18 months (95% CI: 13.8, 31.3) for those treated only with an aromatase inhibitor. For patients Safety was evaluated in the 778 patients who received at least one dose of CDK4/6 inhibitor. Adverse Events by Age in Patients Treated with a CDK4/6 Inhibitor Patients < 65 yearsPatients≥65 yearsPatients≥70 years N=447N=331N=187 n (%)n (%)n (%)Grade 1-2 Adverse Events437 (98)324 (98)185 (99)Grade 3-4 Adverse Events340 (76)276 (83)159 (85)Serious Adverse Events72 (16)88 (27)50 (27)Adverse Events Leading to Discontinuation35 (8)56 (17)38 (20)Adverse Events leading to dose reduction and/or interruption323 (72)253 (76)147 (79)Selected Adverse Events Neutropenia (all grades)341 (76)256 (77)150 (80)Grade 3-4 neutropenia292 (65)228 (69)134 (72)Infections (all grades)190 (43)165 (50)100 (53)Hepatotoxicty (all grades)79 (18)51 (15)34 (18)Grade 3-4 hepatotoxicity32 (7)16 (5)12 (6)Fatigue (all grades)195 (44)153 (46)89 (48)Grade 3 fatigue11 (2)11 (3)7 (4) Conclusions: This exploratory analysis suggests the use of a CDK4/6 inhibitor in combination with an aromatase inhibitor for the first line treatment of HR+ MBC in older women results in similar efficacy benefit as seen in younger women. Although incidence and severity of Grade 1-4 adverse reactions appeared similar between age groups, greater serious adverse events and discontinuations occurred in patients ≥65. The inclusion of greater numbers of patients ≥70, in clinical trials will further inform clinicians about the safety and efficacy of CDK4/6 inhibitors in older adults. Citation Format: Singh H, Howie LJ, Bloomquist E, Wedam S, Amiri-Kordestani L, Tang S, Sridhara R, Ibrahim A, Goldberg K, McKee A, Beaver JA, Pazdur R. A U.S. food and drug administration pooled analysis of outcomes of older women with hormone-receptor positive metastatic breast cancer treated with a CDK4/6 inhibitor as initial endocrine based therapy [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-06.

Background: A reduction in mammographic density(MD) has been associated with the reduction in breast cancer risk among those taking tamoxifen. Aromatase inhibitors (AIs) show promise for breast cancer prevention in postmenopausal women. We are conducting a phase II trial of exemestane in women at increased risk for breast cancer. The primary endpoint for this study is change in MD. Methods: Subjects were screened and enrolled at two sites: Center for Cancer Research, National Cancer Institute and Lombardi Comprehensive Cancer Center, Georgetown University Hospital. Eligible participants are at increased risk for breast cancer by virtue of: Gail model risk ≥1. 7% over 5 years; high risk pathological lesion (e.g. lobular neoplasia, ductal carcinoma in situ); known BRCA1/2 deleterious mutation or prior stage I/II breast cancer at least 2 years from breast cancer treatment and not treated with AIs. Women were excluded if AP spine T-score was Results:For the 22 subjects included in this analysis 15 were eligible due to a high risk pathological lesion, 4 by Gail Model and 3 by prior breast cancers. 18 had film screen mammograms at baseline and 12 months, 4 had film screen mammograms at baseline and digital mammogram at 12 months. Mammographic density declined 7% (p=0.0006, 95% CI −11% to −3%) at one year. The change in MD ranged from −26% to +14% and the standard deviation was 9%. In regard to the four subjects who had film screen mammograms at baseline and digital at follow up, the baseline percent dense areas were slightly higher than average but this did not reach statistical significance (p=0.32 by the Wilcoxon rank sum test). The 12 month MD comparison was similar to the 18 subjects with film images (p=0.90). Conclusions: Exemestane use was associated with a statistically significant decrease in MD at one year. Prior evaluations of AI therapy in high risk women have not shown a significant decline in MD, however time on treatment was shorter and other third generation AIs were used. Although the number of subjects is small, MD did not differ significantly between film screen and digital mammograms. We will further evaluate change in MD in the entire cohort at 1 and 2 years and between film screen and digital mammography. Phase III trials are on-going to evaluate the effect of exemestane on breast cancer prevention. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-07-03.

Purpose Vascular endothelial growth factor (VEGF) is a potent molecule that mediates tumor angiogenesis primarily through VEGF receptor 2 (VEGFR2). Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, was administered to previously untreated patients to evaluate parameters of angiogenesis. Patients and Methods Twenty-one patients with inflammatory and locally advanced breast cancer were treated with bevacizumab for cycle 1 (15 mg/kg on day 1) followed by six cycles of bevacizumab with doxorubicin (50 mg/m2) and docetaxel (75 mg/m2) every 3 weeks. After locoregional therapy, patients received eight cycles of bevacizumab alone, and hormonal therapy when indicated. Tumor biopsies and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were obtained at baseline, and after cycles 1, 4, and 7. Results A median decrease of 66.7% in phosphorylated VEGFR2 (Y951) in tumor cells (P = .004) and median increase of 128.9% in tumor apoptosis (P = .0008) were seen after bevacizumab alone. These changes persisted with the addition of chemotherapy. There were no significant changes in microvessel density or VEGF-A expression. On DCE-MRI, parameters reflecting reduced angiogenesis, a median decrease of 34.4% in the inflow transfer rate constant (P = .003), 15.0% in the backflow extravascular- extracellular rate constant (P = .0007) and 14.3% in extravascular-extracellular volume fraction (P = .002) were seen after bevacizumab alone. Conclusion Bevacizumab has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells.

Purpose Ixabepilone (BMS-247550) is an epothilone B analog that stabilizes microtubules and has antitumor activity in taxane-refractory patients in phase I studies. In a phase II trial, we evaluated the efficacy and safety of ixabepilone in women with metastatic and locally advanced breast cancer. Patients and Methods Breast cancer patients with measurable disease who had paclitaxel and/or docetaxel as prior neoadjuvant, adjuvant, or metastatic therapy were treated with ixabepilone at 6 mg/m2/d intravenously on days 1 through 5 every 3 weeks. Levels of glutamate (glu) -terminated and acetylated α-tubulin, markers of microtubule stabilization, were detected by Western blot and by immunohistochemistry in a subset of matched pre- and post-treatment tumor biopsies. Results Thirty-seven patients received 153 cycles of ixabepilone. The best responses were a complete response in one patient (3%), partial responses in seven patients (19%), and stable disease in 13 patients (35%). Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). Two patients were removed from study because of prolonged grade 2 or 3 neurotoxicity, and three patients were removed from study for other grade 3 and 4 nonhematologic toxicities. Compared with baseline levels, levels of both glu-terminated and acetylated α-tubulin were increased in tumor biopsies performed after ixabepilone therapy. Conclusion An objective response was seen in 22% of the patients in a population who had been previously treated with a taxane. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Microtubule stabilization occurred in tumor biopsies after treatment with ixabepilone.

1073 Background: There is significant heterogeneity in the natural history of MBC. Several recent randomized CT have yielded statistically significant advantages for the experimental arm, but neither led to regulatory approval nor practice change. Formal guidance for industry on CT endpoints provided by the US FDA in 2007 was not disease-specific. Patient-focused drug development is mandated by Prescription Drug User Fee Act V. Our WG sought to create specific consensus on endpoints for MBC CT focusing on subtype and line of therapy, with sensitivity to various stakeholders. Methods: A WG composed of medical oncologists, statisticians, advocates, FDA and NCI liaisons performed a systematic literature review of MBC natural history, CT endpoints by subtype (HR+/HER2-, HR+/HER+, HR-/HER2-, HR-/HER2+), and line of therapy (n = 146 papers). External expertise was obtained on industry perspectives, big data and real world evidence (RWE), and patient reported outcomes (PROs). WG members voted anonymously on statements and positions generated from deliberation. Results: The WG reached consensus on definitions relevant to contemporary CT endpoints. WG recommendations on the appropriate choice of OS or PFS are sensitive to expected post progression survival (PPS), and proportional and absolute gains. Currently, for HR-/HER2- MBC, OS is preferred as the optimal primary endpoint regardless of line of therapy; PFS is preferred in settings where expected PPS is longer. Toxicity can outweigh modest gains in PFS; scant data exist to gauge how patients value PFS gain vs toxicity. Where new agents may prolong PFS without impacting OS, exploring/validating graphic approaches that capture grade and timing of toxicity and PROs is warranted. An overview of WG Consensus Statements will be presented in detail. Conclusions: CT design for MBC should be sensitive to natural history (PPS), availability of other effective agents, PROs and toxicity burden. As unique subtypes (e.g. AR+) and novel therapies (e.g. immunotherapy) emerge, reassessment of relevant benchmarks is indicated. Rigorous big data approaches providing insights from RWE may inform CT endpoints in the future.

Neoadjuvant therapy has become prevalent for many tumor types including breast cancer, especially for locally advanced disease. Although a survival advantage has not been shown, such an approach offers the oppurtunity to monitor treatment response and possibly perform more conservative surgical therapy. Given similar survival outcomes to adjuvant therapy and the potential for breast conservation, neoadjuvant therapy is being used more commonly for operable breast tumors.

To retrospectively compare three dynamic contrast material-enhanced magnetic resonance (MR) imaging (dynamic MR imaging) analytic methods to determine the parameter or combination of parameters most strongly associated with changes in tumor microvasculature during treatment with bevacizumab alone and bevacizumab plus chemotherapy in patients with inflammatory or locally advanced breast cancer.This study was conducted in accordance with the institutional review board of the National Cancer Institute and was compliant with the Privacy Act of 1974. Informed consent was obtained from all patients. Patients with inflammatory or locally advanced breast cancer were treated with one cycle of bevacizumab alone (cycle 1) followed by six cycles of combination bevacizumab and chemotherapy (cycles 2-7). Serial dynamic MR images were obtained, and the kinetic parameters measured by using three dynamic analytic MR methods (heuristic, Brix, and general kinetic models) and two region-of-interest strategies were compared by using two-sided statistical tests. A P value of .01 was required for significance.In 19 patients, with use of a whole-tumor region of interest, the authors observed a significant decrease in the median values of three parameters measured from baseline to cycle 1: forward transfer rate constant (Ktrans) (-34% relative change, P=.003), backflow compartmental rate constant extravascular and extracellular to plasma (Kep) (-15% relative change, P.001), and integrated area under the gadolinium concentration curve (IAUGC) at 180 seconds (-23% relative change, P=.009). A trend toward differences in the heuristic slope of the washout curve between responders and nonresponders to therapy was observed after cycle 1 (bevacizumab alone, P=.02). The median relative change in slope of the wash-in curve from baseline to cycle 4 was significantly different between responders and nonresponders (P=.009).The dynamic contrast-enhanced MR parameters Ktrans, Kep, and IAUGC at 180 seconds appear to have the strongest association with early physiologic response to bevacizumab. Clinical trial registration no. NCT00016549

Abstract #5086 Background: The aromatase inhibitors (AIs) show promise for breast cancer prevention in postmenopausal women. However these agents have been shown to decrease bone mineral density in women with breast cancer. Exemestane, a steroidal aromatase inhibitor, may be more bone sparing than the non-steroidal aromatase inhibitors. Methods: We conducted a phase II trial of exemestane in postmenopausal women at increased risk of breast cancer to assess the effect on anterior-posterior (AP) spine and total hip bone mineral density (BMD). Eligible participants are at increased risk for breast cancer by virtue of: Gail model risk > 1.7% over 5 years; high risk pathological lesion (e.g. lobular neoplasia, ductal carcinoma in situ); known BRCA1/2 deleterious mutation or prior stage I/II breast cancer at least 2 years from breast cancer treatment and not treated with AIs. Women were required to undergo DEXA scan of the AP spine and hip at baseline and were excluded if AP spine T-score was ≤-2.5. AP spine measurements were done twice at each time point and the results averaged. Study participants receive exemestane 25 mg, calcium carbonate 1200 mg and vitamin D 400 IU daily for two years. We report the results of a planned interim safety analysis assessing one year change in bone density in the first 18 subjects. Student's t-test was used to determine relative change from baseline in AP spine and total hip BMD. Results: To date, 30 women have enrolled in the trial and 21 have completed 1 year of exemestane. Three women discontinued agent after an average of 3 months due to joint pain. For the 21 included in this analysis 15 were eligible due to a high risk pathological lesion, 4 by Gail Model and 2 by prior breast cancers. The average change in AP spine BMD from baseline to 1 year (N= 21) is –1.3 %, range -10.0 to +7.0% (p=0.20 for the null hypothesis of zero overall change; 95% C.I. for the mean -3.2% to +0.7%). Average AP spine T score is -0.28 at baseline and -0.45 at one year. Change in total hip BMD is -1.4%, range -7.5% to 5.9% (p=0.058, 95% C.I. -2.8% to +0.1%). Average total hip T score is -0.05 at baseline and -0.17 at one year. Conclusions: These preliminary data suggest that exemestane 25 mg/day for one year with concurrent calcium and vitamin D has acceptable effects on bone density in postmenopausal high risk women, although there were wide ranges in effects. The observed average reduction in BMD is less than the reported effect in treatment studies of women with invasive breast cancer. Studies are in progress to determine whether exemestane use by postmenopausal women is effective in reducing the risk of invasive breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5086.

611 Background: Levels of serum vascular cell adhesion molecule (sVCAM-1), a potential surrogate marker for angiogenesis, are elevated in breast cancer. This study aims to assess changes in sVCAM-1...

545 Background: The epothilones are nontaxane microtubule stabilizers which have shown promising activity in 1- and 3-hour infusions every 3 weeks. Grade 3 neuropathy was reported in 12–37% of brea...

578 Background: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer associated with vascular and lymphatic invasion. Previously untreated IBC patients received bevacizumab (BV), a recombinant humanized monoclonal antibody to VEGF, to evaluate endothelial cell proliferation (CD31/Ki67), tumor cell proliferation (Ki67), tumor microvessel density (MVD), VEGF, and vascular permeability (k21) on dynamic contrast enhanced MRI (dMRI). Methods: Treatment consisted of BV alone for cycle (C) 1 (15mg/m2 on day 1) followed by six cycles of BV (15mg/m2) with doxorubicin (50mg/m2) and docetaxel (75mg/m2) q3wk and G-CSF in C2–7. Following mastectomy and radiation, BV was given for eight more cycles with hormonal therapy for ER+ pts. Tumor core biopsies and dMRI were obtained at baseline, after C1, 4, 7. Results: Sixteen pts enrolled received 125 cycles of treatment. Pts: Stage III 87.5% and IV 12.5%, ER+ 38%, Her2 positive 12.5%. Post-chemo, thirteen pts (3 too early to evaluate): 8PRs, 1PR unconfirm...

584 Introduction: We compared three models of DCE-MRI analysis to determine which parameter or combination would best predict clinical response after bevacizumab (BV) alone or BV and chemotherapy (...