The Development of the Oncology Center of Excellence Patient-Friendly Language Glossary of Oncology Clinical Trial Terms.

Oncology clinical trials terms and definitions have become increasingly complex, which has led to shortcomings among research staff and healthcare providers in informing clinical trial participants with the study results and consenting procedures in simple language. Understanding oncology clinical trial terms is of critical importance to assist patients and caregivers in making cancer treatment decisions, including enrollment into clinical trials. The U.S. Food and Drug Administration's (FDA) Oncology Center of Excellence (OCE) organized a physician and patient advocate-led focus group, with the primary goal of publishing a patient-centric public glossary of select cancer clinical trial terms for healthcare providers, patients, and caregivers. This commentary reports the results of the focus group sessions that gave FDA OCE valuable insights into how patients perceive clinical trial terms and how oncology clinical trial definitions can be improved to effectively communicate information to the patients to make better informed decisions about their treatment options.

US Food and Drug Administration Analysis of Patient-Reported Diarrhea and Its Impact on Function and Quality of Life in Patients Receiving Treatment for Breast Cancer.

OBJECTIVES: Many trials conclude "no clinically meaningful detriment" to health-related quality of life (HRQL) or function between arms, even when notable differential toxicity is observed. Mean change from baseline analyses of function or HRQL can possibly obscure important change in subgroups experiencing symptomatic toxicity. We evaluate the impact of diarrhea, a key treatment arm toxicity, on patient-reported HRQL and functioning in clinical trials submitted to US Food and Drug Administration. METHODS: This study used 4 randomized, breast cancer trials (adjuvant to late-line metastatic) as case examples. Diarrhea, physical functioning (PF), and global health status and quality of life (GHS/QoL) from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were analyzed at baseline and approximately 3 and 6 months. RESULTS: Generally, patients reporting very much diarrhea at months 3 and 6 had worse PF (9-19 points lower) and GHS/QoL (16-19 points lower) than patients reporting no diarrhea regardless of treatment arm. In the change from baseline analysis, patients reporting very much diarrhea also experienced a greater decrease in PF (6-13 points) and GHS/QoL (6-16 points) versus patients reporting no diarrhea in both arms. CONCLUSIONS: In trials with moderate to large differences in symptomatic toxicity by arm, reporting "no meaningful difference in functioning and HRQL between arms" based on mean change from baseline analysis is insufficient and may obscure important impacts on subgroups experiencing symptomatic adverse events. Additional exploratory analyses with simple data visualizations evaluating functioning or HRQL in patient subgroups experiencing expected symptomatic toxicities can further inform the safety and tolerability of an investigational agent.

Overall survival in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer treated with a cyclin-dependent kinase 4/6 inhibitor plus fulvestrant: a US Food and Drug Administration pooled analysis.

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.

FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer.

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)-positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. IMPLICATIONS FOR PRACTICE: These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient-positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.

CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis.

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.

Patient-Friendly Language to Facilitate Treatment Choice for Patients with Cancer.

Resources are needed to assist patients in understanding their diagnoses and considering treatment options. This commentary focuses on improving the language used to communicate disease and treatment information so that patients can make informed decisions.

Luminal A Breast Cancer and Molecular Assays: A Review.

PURPOSE: Chemotherapy has been the historical mainstay of treatment for patients with breast cancer, with immunohistochemical markers and tumor characteristics driving treatment decisions. The discovery of different intrinsic subtypes of breast cancer has advanced the understanding of breast cancer, with gene-based assays shedding further light on tumor behavior and response to treatment. DESIGN: This review focuses on the landscape of the luminal A subtype, its definition based on immunohistochemistry (IHC) and gene assays, the prognostic and predictive value of these assays, guideline recommendations, and treatment implications. RESULTS: Clinical studies of the prognostic value of gene-based and IHC-based assays in patients with luminal A-subtype breast cancers suggest a better prognosis for these patients compared with those with breast cancers of other subtypes. CONCLUSION: In today's era of precision medicine, the best treatment regimen for patients with luminal A-subtype tumors is still undetermined, but available data raise the question whether chemotherapy can be omitted and endocrine therapy alone is sufficient for this patient population. IMPLICATIONS FOR PRACTICE: Immunohistochemical markers have traditionally guided treatment decisions in breast cancer. However, advances in gene-expression profiling and availability of gene-based assays have launched these newer tests into everyday clinical practice. Luminal A-subtype tumors are a unique subset that may have favorable tumor biology. Properly defining this tumor subtype is important and may identify a subset of patients for whom endocrine therapy alone is sufficient.

Imaging anatomy and pathology of extraocular muscles in adults.

The extraocular muscles (EOM) are involved in a variety of disease processes with characteristic findings on imaging. EOM anatomy is described, followed by a review of adult EOM pathology. The imaging characteristics are explained with examples. The pattern of EOM disease on imaging, in corroboration with clinical findings, can often lead the radiologist towards a specific diagnosis.

Reflections and Roadmaps: Career Development beyond the FDA-AACR Oncology Educational Fellowship.

In 2020, the FDA's Oncology Center of Excellence, in collaboration with the American Association for Cancer Research, launched a novel educational partnership known as the FDA-AACR Oncology Educational Fellowship. This year-long program is aimed for hematology/oncology fellows, scientists, and early-career investigators, offering an in-depth exploration of the regulatory review process by blending didactic learning with practical cases discussing oncology drug approvals. The fellowship has been met with enthusiastic feedback, with participants lauding its role in demystifying the regulatory landscape and enhancing their professional careers. This article reflects on the experiences of four alumni, showcasing the program's transformative impact across diverse oncology career paths in government, academia, and industry.

Preparing for survivorship: quality of life in breast cancer survivors.

INTRODUCTION: Breast cancer affects over 200,000 women each year; however, with earlier diagnosis and more effective treatment, patients are living longer, even in the presence of metastatic disease. Current estimates place patients with breast cancer as the largest population of cancer survivors in the United States. Given the successes in treatment, quality of life (QOL) of breast cancer survivors has become a more important consideration. AIM: The aim of this study is to examine QOL throughout the cancer journey. METHODS: The cancer journey will be conceptualized across disease states. MAIN OUTCOME MEASURES: Understanding of the longitudinal journey associated with dynamic changes in physical, mental, and psychosocial spheres that occur with cancer, cancer treatment, and the sequelae of both. Conceptualization of changes is shown through the QOL as the survivor moves through the phases of cancer. RESULTS: QOL is not a static concept, and breast cancer survivors undergo dynamic changes in QOL starting at diagnosis, as they progress through treatment and enter posttreatment. Some domains that make up QOL (i.e., sexual functioning and role functioning) can show persistent detriments related to cancer and its treatment. CONCLUSIONS: In this article, we will provide a snapshot of some research performed to better understand the QOL of breast cancer survivors using a disease states model of breast cancer.

Maslow and the motivation hierarchy: measuring satisfaction of the needs.

For each of the 5 needs in Maslow's motivational hierarchy (physiological, safety-security, belongingness, esteem, and self-actualization), operational definitions were developed from Maslow's theory of motivation. New measures were created based on the operational definitions (1) to assess the satisfaction of each need, (2) to assess their expected correlations (a) with each of the other needs and (b) with four social and personality measures (i.e., family support, traditional values, anxiety/worry, and life satisfaction), and (3) to test the ability of the satisfaction level of each need to statistically predict the satisfaction level of the next higher-level need. Psychometric tests of the scales conducted on questionnaire results from 386 adult respondents from the general population lent strong support for the validity and reliability of all 5 needs measures. Significant positive correlations among the scales were also found; that is, the more each lower-level need was satisfied, the more the next higher-level need was satisfied. Additionally, as predicted, family support, traditional values, and life satisfaction had significant positive correlations with the satisfaction of all 5 needs, and the anxiety/worry facet of neuroticism had significant negative correlations with the satisfaction of all the needs. Multiple regression analyses revealed that the satisfaction of each higher-level need was statistically predicted by the satisfaction of the need immediately below it in the hierarchy, as expected from Maslow's theory.

Deoxycholic Acid for Dercum Disease: Repurposing a Cosmetic Agent to Treat a Rare Disease.

Dercum disease is a rare condition characterized by multiple painful fatty tumors distributed throughout the body. There currently are no US Food and Drug Administration-approved treatments for Dercum disease, and the treatments tried have shown little to no efficacy, leaving many patients with a profoundly negative impact on quality of life. We present a case series of 3 patients who were diagnosed with Dercum disease and were treated with deoxycholic acid (DCA), a therapy approved for adipolysis of submental fat. The patients experienced a reduction in tumor size with radiographic evidence as well as a notable reduction in symptoms.

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer.

On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.

Dopamine agonists and risk: impulse control disorders in Parkinson's disease.

Impulse control disorders are common in Parkinson's disease, occurring in 13.6% of patients. Using a pharmacological manipulation and a novel risk taking task while performing functional magnetic resonance imaging, we investigated the relationship between dopamine agonists and risk taking in patients with Parkinson's disease with and without impulse control disorders. During functional magnetic resonance imaging, subjects chose between two choices of equal expected value: a 'Sure' choice and a 'Gamble' choice of moderate risk. To commence each trial, in the 'Gain' condition, individuals started at $0 and in the 'Loss' condition individuals started at -$50 below the 'Sure' amount. The difference between the maximum and minimum outcomes from each gamble (i.e. range) was used as an index of risk ('Gamble Risk'). Sixteen healthy volunteers were behaviourally tested. Fourteen impulse control disorder (problem gambling or compulsive shopping) and 14 matched Parkinson's disease controls were tested ON and OFF dopamine agonists. Patients with impulse control disorder made more risky choices in the 'Gain' relative to the 'Loss' condition along with decreased orbitofrontal cortex and anterior cingulate activity, with the opposite observed in Parkinson's disease controls. In patients with impulse control disorder, dopamine agonists were associated with enhanced sensitivity to risk along with decreased ventral striatal activity again with the opposite in Parkinson's disease controls. Patients with impulse control disorder appear to have a bias towards risky choices independent of the effect of loss aversion. Dopamine agonists enhance sensitivity to risk in patients with impulse control disorder possibly by impairing risk evaluation in the striatum. Our results provide a potential explanation of why dopamine agonists may lead to an unconscious bias towards risk in susceptible individuals.

Using Technology to Enhance Cancer Clinical Trial Participation.

The COVID-19 pandemic presented many challenges to health care systems, including oncology clinical research programs. There were substantial negative effects on oncology clinical trial screening, enrollment, and study activities that forced institutions and regulatory bodies to develop innovative solutions to maintain robust and equitable participation in these trials. Digital pathology innovations at Memorial Sloan Kettering Cancer Center have streamlined the diagnostic life cycle for patients with cancer, and the seamless integration of digital pathology services with next-generation sequencing and other molecular pathology services have accelerated the time to diagnosis and receipt of molecular results. Timely access to these results, coupled with Memorial Sloan Kettering Cancer Center's knowledge engine OncoKB, enhances patient clinical trial coordination precisely and efficiently. At the Sarah Cannon Research Institute, centralized remote clinical trial matching and screening, virtual molecular tumor boards, and centralized molecular interpretation support services have empowered clinic staff to identify more efficiently potential participants in clinical research, despite the COVID-19 pandemic. In addition, the U.S. Food and Drug Administration Oncology Center of Excellence has been involved in several efforts to address challenges for patients with cancer during the COVID-19 pandemic, including writing guidance documents and participating in efforts to modernize clinical trials. The enclosed personal experience of a patient with cancer currently participating in an oncology clinical trial emphasizes the need for continued decreasing of barriers to study participation. Clinical trial advances that were accelerated by the pandemic will ultimately help patients with cancer and the greater oncology health care community.

Comparing Five Criteria for Evaluating Glaucomatous Visual Fields.

PURPOSE: No consensus exists on the relative superiority among criteria for evaluating glaucomatous visual field (VF) damage. We compared the sensitivities and specificities of 5 criteria-Glaucoma Hemifield Test (GHT), Hoddap-Anderson-Parrish 2 (HAP2), Foster, United Kingdom Glaucoma Treatment Study (UKGTS), and Low-pressure Glaucoma Treatment Study (LoGTS)-across various levels of functional and structural glaucomatous damage. DESIGN: Retrospective cross-sectional study. METHODS: This single-center study included patients with suspect or known glaucoma with reliable VF (Humphrey 24-2 Swedish Interactive Thresholding Algorithm) and optical coherence tomography (OCT; Spectralis, Heidelberg Engineering) examinations within a 4-month period. One eye per patient was included. The level of functional and structural damage was defined by mean deviation (MD) and by an OCT score, respectively. We created the OCT score by counting the number of abnormal (MD percentile [P] <1%) global and sectoral averages of optic nerve head MRW, circumpapillary RNFL thickness, and macular GCL thickness. We inferred specificities and sensitivities from positive rates of the criteria in patients with low glaucomatous damage (MD at P ≥ 10% or OCT score = 0) and with higher damage (MD at P < 10% or OCT score > 0), respectively. RESULTS: We included 1230 patients. In patients with low glaucomatous damage, HAP2 and UKGTS had higher positive rates, suggesting lower specificities, whereas GHT, Foster, and LoGTS had lower positive rates, suggesting higher specificities. In patients with higher glaucomatous damage, HAP2 and UKGTS had higher positive rates, indicating higher sensitivities, whereas GHT, Foster, and LoGTS had lower positive rates, indicating lower sensitivities. CONCLUSIONS: No criteria had uniformly superior performance. Selection of criteria should consider the degree of damage anticipated and the desire for either higher sensitivity or specificity.

U.S. FDA Drug Approvals for Gynecological Malignancies: A Decade in Review.

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.

U.S. FDA Drug Approvals for Breast Cancer: A Decade in Review.

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.

U.S. Food and Drug Administration: Initial Experience with the Real-Time Oncology Review Program.

The FDA Oncology Center of Excellence commenced the Real-Time Oncology Review (RTOR) pilot project in February 2018 to facilitate earlier submission of topline results and datasets to support an earlier start to the FDA application review. RTOR was initially begun to support supplemental drug applications to add new indications, dosing regimens, or other clinical information to the prescribing information, but was later expanded to include original new drug applications and biological license applications for new molecular entities (NME). From February 2018 to April 2020, RTOR was used to support the submission and review of drug approvals for 20 oncology applications (11 for solid tumor and nine for hematologic malignancy indications). Two were NME drug approvals and 18 were supplemental approvals. All of the applications received priority review and nine (45%) applications had received breakthrough therapy designation status. FDA received the RTOR submissions a median of 5.7 weeks (range 1.7-16.2 weeks) prior to the full application submission. The median time from application submission to FDA approval was 3.3 months (range 0.4-5.9 months). RTOR was also integrated with other review programs including the Assessment Aid and Project Orbis programs. Innovative regulatory processes are critical to expedite the rigorous review of impactful products across the FDA.