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On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2 -mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2 -mutated NSCLC. [ABSTRACT FROM AUTHOR]

In 2020, Novartis Pharmaceuticals Corporation and the U.S. Food and Drug Administration (FDA) started a 4‐year scientific collaboration to approach complex new data modalities and advanced analytics. The scientific question was to find novel radio‐genomics‐based prognostic and predictive factors for HR+/HER− metastatic breast cancer under a Research Collaboration Agreement. This collaboration has been providing valuable insights to help successfully implement future scientific projects, particularly using artificial intelligence and machine learning. This tutorial aims to provide tangible guidelines for a multi‐omics project that includes multidisciplinary expert teams, spanning across different institutions. We cover key ideas, such as "maintaining effective communication" and "following good data science practices," followed by the four steps of exploratory projects, namely (1) plan, (2) design, (3) develop, and (4) disseminate. We break each step into smaller concepts with strategies for implementation and provide illustrations from our collaboration to further give the readers actionable guidance. [ABSTRACT FROM AUTHOR]

Background: End-of-life (EOL) care for Latinos with chronic illness is a critically important problem. Latinos with chronic illness suffer worse health outcomes and poorer quality of care due to various issues occurring in care delivery systems. Latinos are less likely than non-Hispanic whites to prepare an advance directive (AD) for health-care decision-making that impacts treatment decisions for when EOL is near. Advance care planning (ACP) interventions tailored specifically for Latinos have rarely been implemented. Objective: The primary aim examines whether a motivational interviewing (MI) intervention increased rates of AD documentation among older Latinos. The secondary aim was to examine whether MI improved communication with providers and family members. Methods: We pilot tested a randomized controlled trial with older Latinos >50 years with one or more chronic illnesses, including cancer. Participants were randomly assigned to usual care (UC) receiving ACP education alone versus treatment (TX), which received ACP education, plus MI counseling including interactive decisional support, emotional support, and barrier navigation. Results: Results of logistic regression indicate TX group participants were significantly more likely to document an AD than UC, however were less ready to talk with health-care providers or family members. Those reporting navigational barriers for talking about dying is difficult showed a significant negative relationship for AD completion even with significant intervention effects. Conclusion: When using MI to motivate individuals toward ACP EOL conversations other factors are important to consider. Further research is needed, especially among Latinos to understand best practices for ACP education and counseling for EOL care. [ABSTRACT FROM AUTHOR]

Background: Advance care planning for end-of-life care emerged in the mid-1970's to address the need for tools, such as the advance directive (AD) legal document, to guide medical decision-making among seriously ill patients, their families, and healthcare providers. Objective: Study aims examine providers' perspectives on AD education that involve examining (1) a range of attitudes about educating patients, (2) whether prior knowledge was associated with practice behaviors in educating patients, and (3) specific factors among healthcare providers such as characteristics of work setting, knowledge, attitudes, and behaviors that may influence AD education and documentation. Design: To examine providers' views, we conducted a cross-sectional, online survey questionnaire of healthcare providers using social media outreach methods for recruitment. Methods: This study used a cross-sectional survey design to examine the proposed aims. Healthcare providers, recruited through a broad approach using snowball methods, were invited to participate in an online survey. Logistic regression analyses were used to examine providers' views toward AD education. Results: Of 520 participants, findings indicate that most healthcare providers said that they were knowledgeable about AD education. They also viewed providing education as beneficial to their practice. These findings suggest that having a positive attitude toward AD education and experiencing less organizational barriers indicate a higher likelihood that providers will educate patients regarding ADs. Conclusion: Various disciplines are represented in this study, which indicates that attitudes and knowledge influence AD discussions. The importance of AD discussions initiated by healthcare providers is critical to providing optimal patient-centered care. [ABSTRACT FROM AUTHOR]

Hispanic women living on the US-Mexico border have had higher cesarean delivery rates than other Hispanic women in the US. Using birth certificate and other data, we compared cesarean rates among Hispanic women living in US border counties with rates among other Hispanic women in border states during 2015. Using linear regression, we also determined which medical, hospital, and sociodemographic characteristics accounted for intercounty variations in rates. In border counties the rates were 38.3 percent for all births, 31.3 percent for low-risk nulliparous mothers, 21.0 percent for primary cesareans, and 94.7 percent for repeat cesareans. In nonborder counties the rates were 30.9 percent, 24.4 percent, 15.1 percent, and 90.5 percent, respectively. Maternal medical characteristics explained over 50 percent of the variation for all cesarean outcomes. Other characteristics that were major contributors to higher cesarean rates included for-profit hospital status, delivery by a physician as opposed to a midwife, and residence in a county with a larger Hispanic fraction of the population. Addressing potentially unnecessary cesareans among Hispanic women on the border will likely require a multicomponent strategy. [ABSTRACT FROM AUTHOR]

Background: Cesarean delivery occurs in one in three US births and poses risks for mothers and infants. Hispanic cesarean rates were higher than non-Hispanic white rates in the US in 2016. In 2009, cesarean rates among Hispanics on the US-Mexico border exceeded rates among US Hispanics. Since 2009, rates have declined nationwide, but border Hispanic rates have not been studied. Objective: To compare cesarean delivery rates and trends in Hispanics and non-Hispanic whites in border and nonborder counties of the four US border states before and after 2009. Study Design: We used data from birth certificates to calculate percentages of cesarean deliveries among all births and births to low-risk nulliparous women during 2000–2015, and among births to low-risk women with and without a previous cesarean during 2009–2015. We calculated 95% confidence intervals around rates and used regular and piecewise linear regression to estimate trends for four ethnic-geographic subpopulations defined by combinations of Hispanic ethnicity and border-nonborder status. Results: Of the four subpopulations, border Hispanic rates were highest every year for all cesarean outcomes. In 2015 they were 38.3% overall, 31.4% among low-risk nulliparous women, and 21.1% and 94.6% among low-risk women without and with a previous cesarean, respectively. Nonborder Hispanic rates in 2015 were lowest for all outcomes but repeat cesarean. Rates for all four subpopulations rose steadily during 2000–2009. Unlike rates for non-Hispanic whites, border and nonborder Hispanic rates did not decline post-2009. Most of the border Hispanic excess can be attributed to higher cesarean rates in Texas. Discussion: Border Hispanic cesarean rates remain higher than those among other Hispanics and non-Hispanic whites in border states and show no signs of declining. This continuing disparity warrants further analysis using individual as well as hospital, environmental and other contextual factors to help target prevention measures. [ABSTRACT FROM AUTHOR]

The medial olivocochlear efferent fibers control outer hair cell responses and inhibit the cochlear-amplifier gain. Measuring efferent function is both theoretically and clinically relevant. In humans, medial efferent inhibition can be assayed via otoacoustic emissions (OAEs). OAEs arise by two fundamentally different mechanisms—nonlinear distortion and coherent reflection. Distortion and reflection emissions are typically applied in isolation for studying the efferent inhibition. Such an approach inadvertently assumes that efferent-induced shifts in distortion and reflection emissions provide redundant information. In this study, efferent-induced shifts in distortion and reflection emissions (click-evoked and stimulus frequency OAEs) were measured in the same subjects—5- to 10-yr-old children. Consistent with the OAE generation theory, efferent-induced shifts in distortion and reflection emissions did not correlate, whereas the two reflection emission shifts correlated. This suggests that using either OAE types provides fragmented information on efferent inhibition and highlights the need to use both distortion and reflection emissions for describing efferent effects. [ABSTRACT FROM AUTHOR]

The Turkestan cockroach, Blatta lateralis (Walker), has become the most important peridomestic species in urban areas of the Southwestern United States. The aim of this study was to evaluate the use of botanical compounds to control this urban pest. We tested the acute toxicity and repellency of six botanical constituents and three essential oils on Turkestan cockroach nymphs. Chemical composition of the essential oils was also determined. Topical and fumigant assays with nymphs showed that thymol was the most toxic essential oil constituent, with a LD50 of 0.34 mg/nymph and a LC50 of 27.6 mg/liter air, respectively. Contact toxicity was also observed in assays with trans-Cinnamaldehyde, eugenol, geraniol, methyl eugenol, and p-Cymene. Methyl eugenol and geraniol had limited fumigant toxicity. The essential oils from red thyme, clove bud, and Java citronella exhibited toxicity against nymphs. Cockroaches avoided fresh dry residues of thymol and essential oils. Chemical analysis of the essential oils confirmed high contents of effective essential oil constituents. Our results demonstrated that essential oils and some of their constituents have potential as eco-friendly insecticides for the management of Turkestan cockroaches. [ABSTRACT FROM AUTHOR]

In this article, the operational details of the R packagePoisNorthat is designed for simulating multivariate data with count and continuous variables with a prespecified correlation matrix are described, and examples of some important functions are given. The data-generation mechanism is a combination of the “NORmal To Anything” principle and a recently established connection between Poisson and normal correlations. The package provides a unique and useful tool that has been lacking for generating multivariate mixed data with Poisson and normal components. [ABSTRACT FROM PUBLISHER]

This paper investigates estimating and testing treatment effects in randomized control trials where imperfect diagnostic device is used to assign subjects to treatment and control group(s). The paper focuses on pre-post design and proposes two new methods for estimating and testing treatment effects. Furthermore, methods for computing sample sizes for such design accounting for misclassification of the subjects are devised. The methods are compared with each other and with a traditional method that ignores the imperfection of the diagnostic device. In particular, the likelihood-based approach shows a significant advantage in terms of power, coverage probability and, consequently, in reduction of the required sample size. The application of the results are illustrated with data from an aging trial for dementia and data from electroencephalogram (EEG) recordings of alcoholic and non-alcoholic subjects. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Data sets originating from wide range of research studies are composed of multiple variables that are correlated and of dissimilar types, primarily of count, binary/ordinal and continuous attributes. The present paper builds on the previous works on multivariate data generation and develops a framework for generating multivariate mixed data with a pre-specified correlation matrix. The generated data consist of components that are marginally count, binary, ordinal and continuous, where the count and continuous variables follow the generalized Poisson and normal distributions, respectively. The use of the generalized Poisson distribution provides a flexible mechanism which allows under- and over-dispersed count variables generally encountered in practice. A step-by-step algorithm is provided and its performance is evaluated using simulated and real-data scenarios. [ABSTRACT FROM AUTHOR]

The present paper develops a procedure for simulating multivariate data with count and continuous variables with a pre-specified correlation matrix. The count and continuous variables are assumed to have Poisson and normal marginals, respectively. The data generation mechanism is a combination of the normal to anything principle and a newly established connection between Poisson and normal correlations in the mixture. A step-by-step algorithm is provided and its performance is evaluated using two simulated and one real-data scenarios. [ABSTRACT FROM PUBLISHER]

Meta-analysis has been used extensively for evaluation of efficacy and safety of medical interventions. Its advantages and utilities are well known. However, recent studies have raised questions about the accuracy of the commonly used moment-based meta-analytic methods in general and for rare binary outcomes in particular. The issue is further complicated for studies with heterogeneous effect sizes. Likelihood-based mixed-effects modeling provides an alternative to moment-based methods such as inverse-variance weighted fixed- and random-effects estimators. In this article, we compare and contrast different mixed-effect modeling strategies in the context of meta-analysis. Their performance in estimation and testing of overall effect and heterogeneity are evaluated when combining results from studies with a binary outcome. Models that allow heterogeneity in both baseline rate and treatment effect across studies have low type I and type II error rates, and their estimates are the least biased among the models considered. [ABSTRACT FROM PUBLISHER]

In this article, operational details of an R packageMultiOrdthat is designed for the generation of correlated ordinal data are described, and examples of some important functions are given. The package provides a valuable and needed tool that has been lacking for generating multivariate ordinal data. [ABSTRACT FROM PUBLISHER]

This article describes thepackageBinNor, which is designed for generating multiple binary and normal variables simultaneously given marginal characteristics and association structure via combining well-established results from the random number generation literature, based on the methodology proposed by Demirtas and Doganay. [ABSTRACT FROM AUTHOR]

We consider the problem of sample size determination for count data. Such data arise naturally in the context of multicenter (or cluster) randomized clinical trials, where patients are nested within research centers. We consider cluster-specific and population-averaged estimators (maximum likelihood based on generalized mixed-effect regression and generalized estimating equations, respectively) for subject-level and cluster-level randomized designs, respectively. We provide simple expressions for calculating the number of clusters when comparing event rates of two groups in cross-sectional studies. The expressions we derive have closed-form solutions and are based on either between-cluster variation or intercluster correlation for cross-sectional studies. We provide both theoretical and numerical comparisons of our methods with other existing methods. We specifically show that the performance of the proposed method is better for subject-level randomized designs, whereas the comparative performance depends on the rate ratio for the cluster-level randomized designs. We also provide a versatile method for longitudinal studies. Three real data examples illustrate the results. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: Our objective was to develop and validate a multi-feature nuclear score based on image analysis of direct DNA staining, and to test its association with field effects and subsequent detection of prostate cancer (PCa) in benign biopsies. Methods: Tissue sections from 39 prostatectomies were Feulgen-stained and digitally scanned (400×), providing maps of DNA content per pixel. PCa and benign epithelial nuclei were randomly selected for measurement of 52 basic morphometric features. Logistic regression models discriminating benign from PCa nuclei, and benign from malignant nuclear populations, were built and cross-validated by AUC analysis. Nuclear populations were randomly collected <1 mm or >5 mm from cancer foci, and from cancer-free prostates, HGPIN, and PCa Gleason grade 3–5. Nuclei also were collected from negative biopsy subjects who had a subsequent diagnosis of PCa and age-matched cancer-free controls (20 pairs). Results: A multi-feature nuclear score discriminated cancer from benign cell populations with AUCs of 0.91 and 0.79, respectively, in training and validation sets of patients. In prostatectomy samples, both nuclear- and population-level models revealed cancer-like features in benign nuclei adjacent to PCa, compared to nuclei that were more distant or from PCa-free glands. In negative biopsies, a validated model with 5 variance features yielded significantly higher scores in cases than controls (P = 0.026). Conclusions: A multifeature nuclear morphometric score, obtained by automated digital analysis, was validated for discrimination of benign from cancer nuclei. This score demonstrated field effects in benign epithelial nuclei at varying distance from PCa lesions, and was associated with subsequent PCa detection in negative biopsies. Impact: This nuclear score shows promise as a risk predictor among men with negative biopsies and as an intermediate biomarker in Phase II chemoprevention trials. The results also suggest that subvisual disturbances in nuclear structure precede the development of pre-neoplastic lesions. [ABSTRACT FROM AUTHOR]

Following the drug-approval process, concerns remain regarding the safety of new drugs that are introduced into the marketplace. In the case of rare adverse events, the number of subjects that are treated in randomized controlled trials is invariably inadequate to determine the safety of the new pharmaceutical. Identifying safety signals for new and/or existing drugs is a major priority in the protection of public health. Unfortunately, design, analysis, and available data are often quite limited for detecting in a timely fashion any potentially harmful effects of drugs. In this review, we examine a variety of approaches for determining the possibility of adverse drug reactions. Our review includes spontaneous reports, meta-analysis of randomized controlled clinical trials, ecological studies, and analysis of medical claims data. We consider both experimental design and analytic problems as well as potential solutions. Many of these methodologies are then illustrated through application to data on the possible relationship between taking antidepressants and increased risk of suicidality. [ABSTRACT FROM AUTHOR]

A new statistical methodology is developed for the analysis of spontaneous adverse event (AE) reports from post-marketing drug surveillance data. The method involves both empirical Bayes (EB) and fully Bayes estimation of rate multipliers for each drug within a class of drugs, for a particular AE, based on a mixed-effects Poisson regression model. Both parametric and semiparametric models for the random-effect distribution are examined. The method is applied to data from Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) on the relationship between antidepressants and suicide. We obtain point estimates and 95 per cent confidence (posterior) intervals for the rate multiplier for each drug (e.g. antidepressants), which can be used to determine whether a particular drug has an increased risk of association with a particular AE (e.g. suicide). Confidence (posterior) intervals that do not include 1.0 provide evidence for either significant protective or harmful associations of the drug and the adverse effect. We also examine EB, parametric Bayes, and semiparametric Bayes estimators of the rate multipliers and associated confidence (posterior) intervals. Results of our analysis of the FDA AERS data revealed that newer antidepressants are associated with lower rates of suicide adverse event reports compared with older antidepressants. We recommend improvements to the existing AERS system, which are likely to improve its public health value as an early warning system. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

FDA Oncology Center's @Falleh&#95;Fallah and colleagues discuss loss of equipoise and other trial conduct challenges in an era of breakthrough therapies - via @JCO&#95;ASCO.

Advances in anticancer therapies have provided crucial benefits for millions of patients who are living long and fulfilling lives. Although these successes should be celebrated, there is certainly room to continue improving cancer care. Increased long-term survival presents additional challenges for determining whether new therapies further extend patients' lives through clinical trials, commonly known as the gold standard endpoint of overall survival (OS). As a result, an increasing reliance is observed on earlier efficacy endpoints, which may or may not correlate with OS, to continue the timely pace of translating innovation into novel therapies available for patients. Even when not powered as an efficacy endpoint, OS remains a critical indication of safety for regulatory decisions and is a key aspect of the FDA's Project Endpoint. Unfortunately, in the pursuit of earlier endpoints, many registrational clinical trials lack adequate planning, collection, and analysis of OS data, which complicates interpretation of a net clinical benefit or harm. This article shares best practices, proposes novel statistical methodologies, and provides detailed recommendations to improve the rigor of using OS data to inform benefit-risk assessments, including incorporating the following in clinical trials intending to demonstrate the safety and effectiveness of cancer therapy: prospective collection of OS data, establishment of fit-for-purpose definitions of OS detriment, and prespecification of analysis plans for using OS data to evaluate for potential harm. These improvements hold promise to help regulators, patients, and providers better understand the benefits and risks of novel therapies., (©2024 American Association for Cancer Research.)

On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials that randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial, the median OS of patients receiving durvalumab was 12.8 months [95% confidence interval (CI), 11.1-14.0] and 11.5 months (95% CI, 10.1-12.5) in patients receiving placebo [hazard ratio (HR), 0.80 (95% CI, 0.66-0.97)]. In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI, 11.5-13.6) and 10.9 months (95% CI, 9.9-11.6) in patients receiving placebo [HR, 0.83 (95% CI, 0.72-0.95)]. The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals, and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic options for these patients., (©2024 American Association for Cancer Research.)

On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro, Bristol Myers Squibb Corporation) for the treatment of adult patients with locally advanced or metastatic receptor tyrosine kinase encoded by the ROS1 gene (ROS1)-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single-arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter "ROS1-positive") NSCLC (NCT03093116), who were either treatment naïve or had received prior ROS1 tyrosine kinase inhibitor (TKI) and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among the 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI, 68-88), median duration of response was 34.1 months (95% CI, 26-NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI, 25-52). The median duration of response was 14.8 months (95% CI, 7.6-NE); BICR-assessed responses were observed in CNS metastases in patients in both cohorts and in patients who developed resistance mutations following prior TKI therapy. The most common (>20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs., (©2024 American Association for Cancer Research.)

On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35-59] in the D+T arm and 11% (95% CI, 3.0-25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5-NE) in the D+T arm and not estimable (95% CI, 6.6- NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6- 11.8) [HR, 0.31 (95% CI, 0.17-0.55); P < 0.001] in the D+T and C+V arms, respectively. The most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation., (©2023 American Association for Cancer Research.)

On September 21, 2022, the FDA granted accelerated approval to selpercatinib (Retevmo, Eli Lilly and Company) for the treatment of adult patients with locally advanced or metastatic solid tumors with a rearranged during transfection (RET) gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. The approval was based on data from Study LOXO-RET-17001 (LIBRETTO-001; NCT03157128), an international, non-randomized, multi-cohort clinical trial that included patients with advanced solid tumors harboring RET alterations. The overall response rate in 41 patients with locally advanced or metastatic RET fusion-positive solid tumors other than non-small cell lung cancer (NSCLC) or thyroid cancer was 44% [95% confidence interval (CI), 28%-60%], with median duration of response 24.5 months (95% CI, 9.2-not evaluable). Patients with 10 of 14 tumor types with a variety of fusion partners had objective responses, including patients with the following tumors: pancreatic adenocarcinoma, colorectal, salivary, unknown primary, breast, soft-tissue sarcoma, bronchial carcinoid, ovarian, small intestine, and cholangiocarcinoma. The recommendation for approval was supported by results from LIBRETTO-001 in patients with RET fusion-positive NSCLC and thyroid cancer, which formed the basis of prior approvals in these tumor types. The most common adverse reactions (>25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. This is the first tissue-agnostic approval of a RET-directed targeted therapy., (©2023 American Association for Cancer Research.)

On September 15, 2021, the FDA granted accelerated approval to mobocertinib (Exkivity, Takeda Pharmaceuticals USA, Inc.) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The approval was based on data from Study AP32788-15-101 (NCT02716116), an international, non-randomized, multi-cohort clinical trial that included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. The overall response rate in 114 patients whose disease had progressed on or after platinum-based chemotherapy was 28% [95% confidence interval (CI), 20%-37%] with a median duration of response of 17.5 months (95% CI, 7.4-20.3). The most common adverse reactions (>20%) were diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Product labeling includes a Boxed Warning for QTc prolongation and torsades de pointes. This is the first approval of an oral targeted therapy for patients with advanced EGFR exon 20 insertion mutation-positive NSCLC., (©2022 American Association for Cancer Research.)

On July 26, 2021, the FDA granted approval to pembrolizumab in combination with chemotherapy for neoadjuvant treatment and then continued as a single agent for adjuvant treatment following surgery for patients with high-risk, early-stage triple-negative breast cancer. Approval was based on results from KEYNOTE-522, an ongoing randomized (2:1) trial evaluating pembrolizumab or placebo in combination with chemotherapy for neoadjuvant treatment and then as a single agent for adjuvant treatment. The co-primary endpoints were pathological complete response (pCR) rate and event-free survival (EFS). The trial demonstrated an improvement in pCR and EFS in the pembrolizumab arm compared with the control arm. The number of patients who experienced an EFS event was 123 (16%) and 93 (24%), respectively [HR: 0.63, 95% confidence interval (CI), 0.48-0.82, P = 0.00031]. Patients on the pembrolizumab arm experienced EFS benefit regardless of tumor PD-L1 status. The absolute pCR rate improvement with the addition of pembrolizumab was 7.5% (95% CI, 1.6-13.4). Among patients receiving pembrolizumab, 44% experienced an immune-related adverse reaction. This article summarizes FDA's review of pembrolizumab and the data supporting the favorable benefit-risk assessment., (©2022 American Association for Cancer Research.)

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., (©2021 American Association for Cancer Research.)

The FDA approved capmatinib and tepotinib on May 6, 2020, and February 3, 2021, respectively. Capmatinib is indicated for patients with metastatic non-small cell lung cancer (mNSCLC) whose tumors have a mutation leading to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. Tepotinib is indicated for mNSCLC harboring MET exon 14 skipping alterations. The approvals were based on trials GEOMETRY mono-1 (capmatinib) and VISION (tepotinib). In GEOMETRY mono-1, overall response rate (ORR) per Blinded Independent Review Committee (BIRC) was 68% [95% confidence interval (CI), 48-84] with median duration of response (DoR) 12.6 months (95% CI, 5.5-25.3) in 28 treatment-naïve patients and 41% (95% CI: 29, 53) with median DoR 9.7 months (95% CI, 5.5-13) in 69 previously treated patients with NSCLC with mutations leading to MET exon 14 skipping. In VISION, ORR per BIRC was 43% (95% CI: 32, 56) with median DoR 10.8 months (95% CI, 6.9-not estimable) in 69 treatment-naïve patients and 43% (95% CI, 33-55) with median DoR 11.1 months (95% CI, 9.5-18.5) in 83 previously-treated patients with NSCLC harboring MET exon 14 alterations. These are the first two therapies to be FDA approved specifically for patients with metastatic NSCLC with MET exon 14 skipping., (©2021 American Association for Cancer Research.)

Subgroup analyses are assessments of treatment effects based on certain patient characteristics out of the total study population and are important for interpretation of pivotal oncology trials. However, appropriate use of subgroup analyses results for regulatory decision-making and product labeling is challenging. Typically, drugs approved by the FDA are indicated for use in the total patient population studied; however, there are examples of restriction to a subgroup of patients despite positive study results in the entire study population and also extension of an indication to the entire study population despite positive results appearing primarily in one or more subgroups. In this article, we summarize key issues related to subgroup analyses in the benefit-risk assessment of cancer drugs and provide case examples to illustrate approaches that the FDA Oncology Center of Excellence has taken when considering the appropriate patient population for cancer drug approval. In general, if a subgroup is of interest, the subgroup analysis should be hypothesis-driven and have adequate sample size to demonstrate evidence of a treatment effect. In addition to statistical efficacy considerations, the decision on what subgroups to include in labeling relies on the pathophysiology of the disease, mechanistic justification, safety data, and external information available. The oncology drug review takes the totality of the data into consideration during the decision-making process to ensure the indication granted and product labeling appropriately reflect the scientific evidence to support patient population for whom the drug is safe and effective., (©2021 American Association for Cancer Research.)