On January 17, 2025, the FDA approved datopotamab deruxtecan-dlnk (DATROWAY; Dato-DXd), a Trop-2-directed antibody and topoisomerase inhibitor conjugate, for the treatment of adults with unresectable or metastatic, hormone receptor-positive, HER2-negative breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. Approval was based on results from TROPION-Breast01 (TB01), a multicenter, randomized, open-label trial comparing Dato-DXd with investigator's choice of chemotherapy (ICC). The trial was designed with dual primary endpoints: progression-free survival assessed by blinded independent central review according to RECIST v1.1 and overall survival (OS). TB01 demonstrated a 2-month improvement in median progression-free survival for Dato-DXd compared with ICC (6.9 vs. 4.9 months, respectively; stratified HR, 0.63; 95% confidence interval, 0.52-0.76; P < 0.0001). The OS endpoint was not met; at the final analysis of OS, the median OS was 18.6 months in the Dato-DXd arm and 18.3 months in the ICC arm (HR, 1.01; 95% confidence interval, 0.83-1.22). Although there was no OS improvement, Dato-DXd was also not associated with a clear trend toward potential detriment compared with ICC. The most commonly reported adverse reactions (≥20%) with Dato-DXd were stomatitis, nausea, fatigue, alopecia, constipation, dry eye, keratitis, and vomiting. Overall, the favorable benefit-risk profile for Dato-DXd supported its approval for the intended indication.

1055 Background: Cyclin-dependent kinase 4/6 inhibitors (CDKI) are FDA-approved for use in combination with aromatase inhibitors (AI) for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced or metastatic breast cancer (MBC) as initial (1L) endocrine-based therapy. We have previously reported the pooled analyses of the benefit in progression-free survival of adding CDKI to AI, and here report the pooled overall survival (OS) results for adults treated with CDKI + AI for 1L HR+/HER2- MBC. Methods: We pooled individual patient data (N=2252) from 4 randomized trials (MONALEESA-2 & 7, MONARCH-3, PALOMA-2) of a CDKI (abemaciclib, palbociclib, ribociclib) or placebo + AI in adults with 1L HR+/HER2- MBC. OS was defined as time from randomization to death from any cause and was a key secondary endpoint in all 4 trials. Not all 4 trials reached OS statistical significance, but all OS hazard ratios of the individual trials were <1. The median OS was estimated using Kaplan-Meier methods, and hazard ratios with 95% confidence intervals (CI) were estimated using Cox regression models. Analyses were prespecified, with patients analyzed collectively and by various clinicopathological subgroups of interest. Results: Overall results in all patients and various clinicopathologic subgroups of interest are shown (Table). Conclusions: In this descriptive exploratory pooled analysis, the addition of a CDKI to AI suggested an association with an OS benefit for this class of drugs used as a component of 1L endocrine-based therapy for adults with HR+/HER2- MBC. Additional research is needed to determine which subgroup of patients may benefit more or less of the addition of a CDKI to AI. n # Events CDKI/n (%) # Events Placebo/n (%) HR (95% CI) All 2252 716/1320 (54) 550/932 (59) 0.81 (0.73, 0.91) PR negative 273 84/155 (54) 89/118 (75) 0.51 (0.38, 0.70) De Novo 752 233/450 (52) 173/302 (57) 0.82 (0.67, 1.00) Lobular Histology 144 72/97 (74) 34/47 (72) 0.99 (0.66, 1.50) Bone-Only 493 142/284 (50) 115/209 (55) 0.74 (0.58, 0.95) Liver/Lung Mets 1111 365/639 (57) 291/472 (62) 0.81 (0.70, 0.95) Age <40 193 40/106 (38) 44/87 (51) 0.78 (0.51, 1.21) Age >70 403 159/247 (64) 106/156 (68) 0.86 (0.67, 1.09) ECOG 1 851 305/499 (61) 239/352 (68) 0.78 (0.66, 0.93) White 1594 529/919 (58) 407/675 (60) 0.88 (0.77, 1.00) Asian 438 113/269 (42) 89/169 (53) 0.59 (0.45, 0.78) Black or African American 43 14/25 (56) 11/18 (61) 0.80 (0.36, 1.76) Additional clinicopathologic subgroup analyses conducted with results not shown.

Background: The standard of care treatment for patients (pts) with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer is a CDK 4/6 inhibitor (CDKI, abemaciclib, palbociclib, ribociclib) added to endocrine therapy (ET). Patients with liver or lung metastases may have a worse prognosis and derive different amounts of benefit from the addition of a CDKI. This pooled analysis examines whether patients with only lung (LuOM) or liver (LiOM) metastases may respond differently to CDKI-based treatment. Methodology: We pooled individual patient data from 7 randomized trials of CDKI+ET for patients with HR+, HER2-negative MBC submitted to the FDA before January 1, 2024, in support of marketing applications. The primary endpoint was investigator-assessed progression-free survival (PFS), and overall survival (OS) was a key secondary endpoint in all 7 trials. The analyses included all pts who received at least 1 dose of CDKI/placebo (PBO) with ET (aromatase inhibitor [AI] anastrozole or letrozole, or fulvestrant [F]). Using descriptive statistics, we performed a prespecified exploratory subgroup analyses in patients with LiOM or LuOM. Pts with bone-only disease, pleural lesions/effusion, ascites, other visceral metastasis, only nodal disease, and both lung and liver metastases were excluded. Analyses were performed in subgroups of pts treated with CDKI+AI only and pts with CDKI+F only. OS analyses were only performed on pts treated with CDKI+F based on data available at the time of this analysis. Median (med) PFS and OS were estimated using Kaplan-Meier (K-M) methods. Hazard ratios (HR) with 95% confidence intervals (CIs) for PFS and OS were estimated using Cox regression models. for PFS and OS were estimated using Cox regression models. Findings: Seven trials were used for PFS analyses (n=4200) and 1582 pts met inclusion criteria for the LiOM (n=651) and LuOM (n=931). Key baseline demographic and prognostic factors appeared similar between the subgroups. Accuracy of site of metastases and treatment allocation were limited to information captured in trials and datasets. LuOM PFS: 389 pts received CDKI+AI, 248 pts received PBO+AI, 197 pts received CDKI+F, and 97 pts received PBO+F. Med PFS was 25.3 mo (21.6-28.1) for CDKI+ET vs 15.2 mo (13.5-19.2) for PBO+ET (HR 0.64, 95% CI 0.53-0.78). Med PFS for CDKI+AI was 27.8 mo (23.1-31.1) vs 16.7 mo (13.8-24.2) for PBO+AI (HR 0.60, 95% CI 0.47-0.76). Med PFS for CDKI+F was 19.6 mo (13.8-not estimable [NE]) vs 14 mo (11.1-8.7) for PBO+F (HR 0.72, 95% CI 0.51-1.00). LiOM PFS: 142 pts received CDKI+AI, 141 pts received PBO+AI, 234 pts received CDKI+F, and 134 pts received PBO+F. Med PFS was 11.2 mo (9.4-13.1) for CDKI+ET vs 5.6 mo (3.6-7.0) for PBO+ET (HR 0.59, 95% CI 0.49-0.72). Med PFS for CDKI+AI was 13.1 mo (10.4-14.9) vs 9.4 mo (5.6-11.2) for PBO+AI (HR 0.63, 95% CI 0.47-0.84). Med PFS for CDKI+F was 9.4 mo (7.6 -12.9) vs 3.4 mo (2.0-5.4) for PBO+F (HR 0.51, 95% CI 0.40-0.65). Three trials were used for OS analyses (n=1948). CDKI+F OS (n=662): 431 pts received CDKI+F (197 LuOM and 234 LiOM) and 231 pts received PBO+F (97 LuOM and 134 LiOM). In LiOM, med OS was 31.8 mo (28.0-36.5) for CDKI+F vs 25.3 mo (21.9-31.8) for PBO+F (HR 0.77, 95% CI 0.59-1.01). In LuOM, med OS was 48.2 mo (41.5- NE) for CDKI+F vs 51.6 mo (36.3-NE) for PBO+F (HR 0.90, 95% CI 0.61-1.31), although these results should be interpreted with caution due to the high level of censoring after 3 years and limited follow up. KM curve of LuOM suggested non-proportional hazards; a restricted mean survival time analysis showed a difference at 54.4 mo of 0.98 mo (SE 2.2). Conclusion: Prior results show that pts with liver/lung metastases benefit from the addition of CDKI to ET. This pooled analysis suggests there may be differences in amount of benefit with adding CDKI to ET based on the site of the metastasis and the choice of ET. Further research is needed to understand which subgroup of pts with lung metastases may benefit more or less from adding CDKI to ET. Citation Format: Raissa Kentsa, Hee-Koung Joeng, Melanie Royce, Suparna Wedam, Mirat Shah, Preeti Narayan, Xin Gao, Joyce Cheng, Mallorie Fiero, Shenghui Tang, Christy Osgood, Richard Pazdur, Paul Kluetz, Jennifer Gao, Laleh Amiri-Kordestani. Efficacy of cyclin-dependent kinase 4/6 inhibitor + endocrine therapy in patients w/ hormone receptor-positive, HER2-negative advanced or metastatic breast cancer w/ liver or lung only metastases: a US Food & Drug Administration pooled analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-09-19.

On December 14, 2022, the FDA approved revisions to the United States Prescribing Information (USPI) for capecitabine that revised existing indications and dosage regimens, added new indications and their recommended dosage regimens, revised safety information, updated the description of the risk of capecitabine in patients with dihydropyrimidine dehydrogenase deficiency, and edited other sections of the USPI to conform with FDA's current labeling guidance. These supplements were reviewed and approved under Project Renewal, a public health initiative established by the FDA's Oncology Center of Excellence that aims to update the prescribing information of certain older oncology drugs to ensure information is clinically meaningful and scientifically up to date. This article summarizes the FDA approach that supported revisions to the capecitabine USPI within the context of Project Renewal.

PURPOSE The US Food and Drug Administration approved abemaciclib in combination with endocrine therapy (ET) for the adjuvant treatment of adult patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative, node-positive, early breast cancer (EBC) at high risk of recurrence and a Ki-67 score ≥ 20%. PATIENTS AND METHODS The approval was based on monarchE, a phase III, open-label, 2-cohort, multicenter trial of patients with EBC randomly assigned to receive abemaciclib plus ET (n = 2,808) or ET alone (n = 2,829). Abemaciclib was given at 150 mg orally twice daily for 2 years. RESULTS Invasive disease-free survival (IDFS) in the intent-to-treat population was statistically significant at the second IDFS interim analysis (IA; March 2020; hazard ratio [HR; 95% CI], 0.747 [0.598 to 0.932]; P = .0096); however, only 12.5% of patients had completed adjuvant therapy, and the HR for overall survival (OS) was > 1. A prespecified, controlled analysis of IDFS in patients with Ki-67 ≥ 20% in cohort 1 was statistically significant at the final IDFS analysis (July 2020; HR [95% CI], 0.643 [0.475 to 0.872]; P = .0042). At the first OS IA (April 2021), the majority of patients had completed adjuvant therapy, IDFS remained consistent, and potential detriment in OS was not observed for this subgroup (HR [95% CI], 0.767 [0.511 to 1.152]). The HR for OS in the intent-to-treat population at OS IA remained > 1 (HR [95% CI], 1.091 [0.818 to 1.455]). More patients in the abemaciclib plus ET arm experienced treatment emergent adverse events (all grades 98.4% v 88.8%, grade 3 ≥ 49.7% v 16.3%). CONCLUSION The approval of abemaciclib in adjuvant EBC was limited to patients with high risk of recurrence and Ki-67 ≥ 20%, given their favorable benefit:risk with a statistically significant IDFS advantage and no observed detriment on survival.

On December 16, 2020, the FDA granted regular approval to margetuximab-cmkb (MARGENZA), in combination with chemotherapy, for the treatment of adult patients with HER2-positive (HER2+) metastatic breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. Approval was based on data from SOPHIA, a multicenter, randomized, open-label, active controlled study comparing margetuximab with trastuzumab, in combination with chemotherapy. The primary efficacy endpoint was progression-free survival (PFS) by blinded independent central review. SOPHIA demonstrated a 0.9-month difference in median PFS between the two treatment arms [5.8 vs. 4.9 months, respectively; stratified HR, 0.76 (95% confidence interval: 0.59-0.98; P = 0.0334)]. Overall survival (OS) was immature at the data cut-off date of September 10, 2019. Infusion-related reactions (IRR) are an important safety signal associated with margetuximab plus chemotherapy. In SOPHIA, 13% of patients treated with margetuximab plus chemotherapy reported IRRs, of which 1.5% were grade 3. The most commonly reported adverse drug reactions (>10%) with margetuximab in combination with chemotherapy were fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, IRR, palmar-plantar erythrodysesthesia, and extremity pain. Overall, the favorable risk-benefit profile for margetuximab when added to chemotherapy supported its approval for the intended indication.

Background: Aligning with 21st Century Cures legislation, FDA is exploring various methodologies to advance appropriate uses of Real-World Data (RWD) to generate Real-World Evidence (RWE). Inclusion of RWD to support regulatory decision making has increased in oncology, and this review specifically focused on characterizing RWD submissions for the treatment of breast cancer (BC). Methods: A systematic search was conducted using internal FDA databases to identify RWD submissions from 2010 to 2020. Search terms included real world evidence, real world data, cancer registry, administrative claims, external control arm, and other terms relevant to RWD/RWE. Relevant regulatory submissions were reviewed, pre-defined common data elements were extracted, and the subset applicable to breast cancer was evaluated. Results: Of 142 regulatory submissions that included RWD, 6 specifically evaluated BC indications and 3 were for solid tumor indications with potential applicability to BC, corresponding to 4 new molecular entities. Regulatory objectives included support for labeling changes including efficacy (expanded indications), safety , and dose or administration modifications. The most commonly used design was a retrospective observational study with structured electronic health records (EHRs) or medical claims data, supplemented by unstructured data from medical records or chart review for missing data elements. Four of the 6 BC submissions were significantly limited by a high degree of data missingness and confounding, with some studies including key covariates that were missing in >50% of the structured data. RWD was used to provide contextual evidence for label expansion for populations not included or adequately represented in the registration trial. Of note, for the application expanding the label to include treatment of male BC, the regulatory decision was primarily based on clinical trial data. The primary rwEndpoints submitted were overall survival (rwOS), progression free survival (rwPFS), response rate (rwORR) and time to next treatment (TTNT). Safety outcomes were investigated in all but 1 of the studies, most commonly as a secondary RWD endpoint. Conclusion: In our review of regulatory submissions relevant to breast cancer therapies, RWD has largely been used to contextualize and complement prospective clinical trial data. Evaluating that selected RWD is fit for purpose to address the regulatory objective(s) and all analytical plans are prespecified allows for robust data characterization, and appropriate evaluation. Data relevance (availability of key variables) along with reliability assessment which includes evaluating data for completeness, consistency, and trends over time are necessary for the rigorous evaluation of RWE in drug development. Data missingness is a key issue in RWD, especially when structured data are not available and specific variables are unlikely to be captured in a reliable way in the unstructured data or further validation is not feasible. To optimize RWD as evidence for specific patient populations, attention to the proportion of patients excluded is necessary to avoid concerns regarding the generalizability of the data. Careful selection of rwEndpoints must be aligned with the study design and objective, include data such as prior, concomitant and subsequent anti-cancer treatments, and the ability for outcome validation to be methodologically appropriate. When contemplating a regulatory submission using RWD, early consultation with the appropriate FDA review division can provide additional feedback on the appropriate use of RWD or pragmatic designs. Citation Format: Melanie E Royce, Jennifer J. Lee, Christy L. Osgood, Laleh Amiri-Kordestani, Julia A. Beaver, Paul G. Kluetz, Donna R. Rivera. Methodological approaches to the use of real-world data(RWD) for medical products to treat breast cancer: An FDA oncology center of excellence evaluation of RWD submissions [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-19-02.

Over the last decade, the treatment of patients with breast cancer has been greatly impacted by the approval of multiple drugs and indications. This summary describes 30 FDA approvals of treatments for breast cancer from 2010 to 2020. The trial design endpoints, results, and regulatory considerations are described for each approved indication. Of the 30 indications, 23 (76.6%) received regular and 7 (23.3%) received accelerated approval. Twenty-six approvals were granted in metastatic breast cancer (MBC) and four in early breast cancer. Approval decisions for the 26 MBC indications were initially supported by progression-free survival (PFS) in 21 (80.8%), overall survival (OS) or a combination of OS and PFS in two (7.7%), and objective response rate (ORR) in three (11.5%). The four approvals in early breast cancer utilized pathologic complete response (pCR) in one (25%) and invasive disease-free survival (iDFS) in three (75%) trials. Among the 30 indications, 22 received priority review, seven were granted Breakthrough Therapy Designation, and 10 applications participated in one or more pilot Oncology Center of Excellence regulatory review initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. FDA initiatives to advance breast cancer drug development are also described.

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.

Abstract Background: Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with use of histone deacetylase (HDAC) inhibitors such as entinostat. The ENCORE 301 randomized phase II study reported an improvement in progression-free (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer. Protein lysine acetylation in peripheral blood mononuclear cells (PBMCs) was associated with prolonged PFS in the entinostat arm. Methods: E2112 is a multicenter randomized double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease had progressed on a non-steroidal AI in the adjuvant or metastatic setting (NCT02115282). Study participants were also required to have an ECOG performance status 0-1 with measurable or non-measurable (limited to 20% of the study population) disease. One prior chemotherapy for metastatic disease and prior treatment with fulvestrant and a CDK4/6 inhibitor was permitted but not required. Participants received exemestane 25mg po daily and entinostat (EE)/placebo (EP) 5mg po every week. Primary endpoints were PFS (central review) and OS. One-sided type 1 error 0.025 was split between two hypothesis tests: 0.001 for PFS test and 0.024 for OS. PFS tested in the first 360 pts, 88.5% power to detect 42% reduction in the hazard of PFS failure (median PFS, 4.1 to 7.1 months); OS tested in all 600 pts, 80% power to detect 25% reduction in the hazard of death (median OS, 22 to 29.3 months). Secondary endpoints included safety, objective response rate (ORR), and changes in protein lysine acetylation status in PBMCs (CD3+ T cells, CD14+ monocytes, CD19+ B cells, pan-leukocyte marker CD45+ cells, CD56+ NK cells) between C1D1 and C1D15 (integrated biomarker). Results: A total of 608 participants were randomized between March 2014 and October 2018 (305 EE, 303 EP), 98% enrolled in USA. Characteristics were well balanced between the arms. Median age was 63 years (range, 29-91), 99% female, 95% postmenopausal, 80% white and 15% black. A majority (84%) had disease resistant to AI in the metastatic setting at study entry, 78% had measurable disease and 60% visceral disease. Prior treatments included chemotherapy (60%), fulvestrant (30%), CDK4/6 inhibitor (35%), everolimus (3%). Median prior lines of chemotherapy was 1 (range, 0-4) and endocrine therapy was 2 (range, 1-7); in adjuvant/metastatic setting. Grade 3/4 adverse events in EE arm included neutrophil count decreased (20%), hypophosphatemia (14%), anemia (8%), white blood cell decreased (6%), fatigue (4%), diarrhea (4%), and platelet count decreased (3%). At final analysis, median PFS was 3.3 months (EE) versus 3.1 months (EP) (HR=0.87, 95% CI: 0.67, 1.13, p=0.30). Median OS was 23.4 months (EE) versus 21.7 months (EP) (HR=0.99, 95% CI: 0.82, 1.21, p=0.94). ORR was 4.6% (EE) and 4.3% (EP). The median fold change in lysine acetylation in PBMCs was approximately 1.5 in EE arm, and 1 in EP arm. Participants on EE had significantly higher increase in lysine acetylation by C1D15 than patients on EP (397 paired samples available for analysis, p<0.001 for all). Additional biomarker analyses will be presented at time of meeting. Conclusion: The combination of exemestane and entinostat did not improve survival in AI resistant advanced HR-positive, HER2-negative breast cancer. Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. Citation Format: Roisin M Connolly, Fengmin Zhao, Kathy D Miller, Min-Jung Lee, Richard L Piekarz, Karen L Smith, Ursa Brown-Glaberman, Jennifer S Winn, Bryan A Faller, Adedayo A Onitilo, Mark E Burkard, George T Budd, Ellis G Levine, Melanie E Royce, Peter A Kaufman, Alexandra Thomas, Jane B Trepel, Antonio C Wolff, Joseph A Sparano. E2112: Randomized phase 3 trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. A trial of the ECOG-ACRIN cancer research group [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-02.

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 50middot9-not estimable) in the CDKI group and was 45middot7 months (95% CI 41middot7-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. Copyright Published by Elsevier Ltd.

Abstract Background Aligning with 21st Century Cures legislation, FDA is exploring methodologies to advance appropriate uses of Real World Data (RWD) to generate Real World Evidence (RWE). RWD to support regulatory decision making has markedly increased in oncology. This review specifically focused on the analysis of RWD containing submissions for medical products in development for the treatment of hematological malignancies and associated treatment related conditions (e.g., Cytokine Release Syndrome (CRS), Graft Versus Host Disease (GVHD). Methods A systematic search was conducted using internal FDA databases to identify RWD submissions from 2010 to 2020. Search terms included: real world evidence, real world data, electronic health record, cancer registry, administrative claims, external control arm, observational cohort, historical control arm, real world Overall Survival (rwOS) , real world Response Rate (rwRR), real world Overall Response Rate rwORR and real world Complete Response (rwCR). Regulatory submissions specific to malignant hematology and associated treatment related conditions were reviewed, and pre-defined common data elements were extracted and validated by independent dual review. Descriptive statistics were calculated. Results A total of 142 regulatory submissions included RWD from 2011-2020. A subset of 94 RWD submissions met the criteria for further evaluation, of which 20 (21%) submissions corresponding with 14 molecular entities were for hematologic malignancies or treatment related conditions (e.g., CRS, GVHD). RWD submissions increased substantially over time, with 14 (70%) of submissions received between 2019-2020. Specific evaluation for pediatric indications was referenced in 15% of submissions. The most commonly referenced RWD source was EHR data (55%), followed by use of multiple sources (20%), and registry data (15%). Approximately 90% of the submissions aimed to support treatment effectiveness. Primary RWD study objectives included supporting approval of a new molecular entity (NME) (40%), expanding an approved indication (25%), conversion from accelerated to regular approval (15%), and providing data to inform postmarketing safety evaluation (20%). Among RWD submissions, response endpoints (e.g., rwORR, rwCR, rwPR, Partial Response) and overall survival (e.g., rwOS) were most frequently selected as primary outcomes for 50% and 20% of proposals respectively; however, these outcomes were included as any endpoint in 65% and 75% of submissions. Conclusion This review demonstrates increasing use of various RWD sources to support evidence generation for drug development in hematologic malignancies and associated treatment related conditions with the primary objective of supporting demonstration of effectiveness using rwOS or real world response measures as primary endpoints. Given the increased inclusion of RWD in regulatory submissions, further methodological development is needed, including in the selection and validation of rwEndpoints. Appropriate study design must be aligned with a clear regulatory objective to ensure that RWD can be adequately evaluated. Additionally, the development of standardized metrics for data characterization and transparency in reporting of RWD are foundational steps to the evaluation of fit for purpose RWD to support regulatory decision making. Disclosures No relevant conflicts of interest to declare.

e18787 Background: Aligning with 21st Century Cures legislation, the FDA is exploring trial design modernization and methodology to advance appropriate uses of Real World Data (RWD) to generate Real World Evidence (RWE). The Oncology Center of Excellence RWE Program was established in 2020 to advance RWE efforts specific to oncology drug development. Inclusion of RWD to support regulatory decision making has increased in oncology, and a landscape analysis was conducted to characterize the RWD included in submissions. Methods: A systematic search was conducted using internal FDA databases to identify RWD submissions from 2010 to 2020. Search terms included: real world evidence, real world data, electronic health record, cancer registry, administrative claims, external control arm, observational cohort, historical control arm, rwOS, rwRR, rwCR, and rwORR. Relevant regulatory submissions were reviewed, and pre-defined common data elements were extracted. A team of FDA reviewers assessed agreement through subset validation (20%). Descriptive statistics were calculated. Results: A total of 142 regulatory submissions included RWD from 2011 to 2020. A subset of 94 submissions met the criteria for evaluation, consisting of 78 unique studies evaluating 56 molecular entities. RWD submissions increased substantially over time, with 28 submissions in 2020. Nearly half of the RWD submissions were for solid tumor indications (68%), with lung cancer being the most predominant site. More than one third of the RWD submissions (37%) were for rare indications. The most common primary RWD study objective was effectiveness (62%) and the most commonly referenced RWD source was EHR/clinical data (54%). The most frequently used primary RWD endpoints were survival (rwOS, 35%) and response (rwORR/PR/BTR, 31%) outcomes (Table). Conclusions: Our review demonstrates a dramatic increase in RWD submissions to support FDA oncology drug development programs. Submissions included a variety of study objectives, data sources, and endpoints. While this landscape analysis provides a picture of potential regulatory objectives, the adequacy of each proposal to support regulatory decision making was not evaluated. Establishing a set of clear regulatory objectives can help advance the development of metrics for robust data characterization and outcome validation to ensure that RWD can be appropriately evaluated and provide the rigor necessary to be considered adequate RWE.[Table: see text]

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]

PURPOSE Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. PATIENTS AND METHODS E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio = 0.87; 95% CI, 0.67 to 1.13; P = .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio = 0.99; 95% CI, 0.82 to 1.21; P = .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.

INTRODUCTION:Differences in breast cancer survival by race and ethnicity are often assumed to be a fairly recent phenomenon, and are hypothesized to have arisen due to gaps in receipt of screening or therapy. The emergence of these differences in calendar time have implications for identification of their origin. We sought to determine whether breast cancer survival differences by race or ethnicity arose in tandem with the advent of screening or therapeutic advances. MATERIALS AND METHODS:A cohort of women diagnosed with invasive breast cancer from 1975-2009 in 18 population-based registries were followed for five-year breast cancer cause-specific survival. Differences in survival according to race/ethnicity and estrogen receptor status were quantified in Cox proportional hazards models, with estimation of hazard ratios (HR), 95% confidence intervals (CI), and absolute risk differences. For 2010, we also assessed differences in survival by breast cancer subtypes defined by hormone receptor and Her2/neu status. RESULTS:Among over 930,000 women, initial differences in five-year breast cancer-specific survival by race became apparent among 1975-1979 diagnoses and continued to be evident, with stronger disparities apparent in those of Black vs. White Non-Hispanic (WNH) race and among estrogen-receptor positive vs. negative disease. Within breast cancer subtype, all included race/ethnic groups experienced disparate survival in comparison with WNH women for triple-negative disease. Black women had a consistent gap in absolute survival of .10-.12, compared with WNH women, from 1975-1979 through all included time periods, such that 5- year survival of Black women diagnosed in 2005-09 lagged more than 20 years behind that of WNH women. DISCUSSION:Survival differed by race for diagnoses that predate the introduction of mammographic screening and most therapeutic advances. Absolute differences in survival by race and ethnicity have remained almost constant over 40 years of observation, suggesting early origins for some contributors.