Quality of life with cemiplimab plus chemotherapy for first-line treatment of advanced non-small cell lung cancer: Patient-reported outcomes from phase 3 EMPOWER-Lung 3.

BACKGROUND: EMPOWER-Lung 3, a randomized 2:1 phase 3 trial, showed clinically meaningful and statistically significant overall survival improvement with cemiplimab plus platinum-doublet chemotherapy versus placebo plus chemotherapy for first-line treatment of advanced non-small cell lung cancer. This study evaluated patient-reported outcomes (PROs). METHODS: PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks) for the first six doses, and then at start of every three cycles, using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) and Quality of Life-Lung Cancer Module (QLQ-LC13) questionnaires. Prespecified analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis performed for global health status/quality of life (GHS/QoL) and all scales from the questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and proportional hazards model. RESULTS: A total of 312 patients were assigned to receive cemiplimab plus platinum-doublet chemotherapy and 154 to receive placebo plus chemotherapy; 391 (83.9%) were male and the median age was 63.0 years (range, 25-84). For pain symptoms (EORTC QLQ-C30), a statistically significant overall improvement from baseline (-4.98, 95% confidence interval [CI] -8.36 to -1.60, p = .004) and a statistically significant delay in TTD (hazard ratio, 0.39; 95% CI, 0.26-0.60, p < .0001) favoring cemiplimab plus chemotherapy were observed. Statistically significant delays in TTD, all favoring cemiplimab plus chemotherapy, were also observed in functioning and symptom scales. A significant overall improvement from baseline in GHS/QoL was seen for cemiplimab plus chemotherapy compared with nonsignificant overall change from baseline for placebo plus chemotherapy (1.69, 95% CI, 0.20-3.19 vs. 1.08, 95% CI, -1.34 to 3.51; between arms, p = .673). No analyses yielded statistically significant PRO results favoring placebo plus chemotherapy for any QLQ-C30 or QLQ-LC13 scale. CONCLUSION: Cemiplimab plus chemotherapy resulted in significant overall improvement in pain symptoms and delayed TTD in cancer-related and lung cancer-specific symptoms and functions.

The value of new drugs for advanced prostate cancer.

BACKGROUND: The US Food and Drug Administration has recently approved a number of new cancer drugs. The clinical trials that serve as the basis for new cancer drug approvals may not reflect how the drugs will perform in routine practice and do not measure the impact of the drugs on spending. The authors sought to evaluate the real-world effectiveness and value of drugs recently approved for advanced prostate cancer. METHODS: Using Surveillance, Epidemiology, and End Results-Medicare data, the authors identified fee-for-service Medicare beneficiaries aged 65 years or older who began treatment with a drug approved for metastatic castration-resistant prostate cancer in 2007-2009, when only 1 drug was approved for metastatic castration-resistant prostate cancer, and in 2014-2016, when 5 additional drugs were approved. They calculated life expectancy and lifetime medical costs (ie, Medicare reimbursements) for each group. RESULTS: Between 2007-2009 and 2014-2016, life expectancy increased by 12.6 months. Lifetime medical costs increased by $87,000. The incremental cost per life-year gained was $83,000. CONCLUSION: The release of 5 new drugs coincided with increases in survival rates and spending. This study's estimates indicate that the new drugs collectively were cost-effective.

Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.

BACKGROUND: The poly(adenosine diphosphate-ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 ( BRCA1/2). METHODS: We conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician's choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P=0.11 [57% of projected events]). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P<0.001). Hematologic grade 3-4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively. Patient-reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status-quality-of-life and breast symptoms scales were observed. CONCLUSIONS: Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib. (Funded by Medivation [Pfizer]; EMBRACA ClinicalTrials.gov number, NCT01945775 .).

Talazoparib in Patients with a Germline BRCA-Mutated Advanced Breast Cancer: Detailed Safety Analyses from the Phase III EMBRACA Trial.

BACKGROUND: In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression-free survival (PFS) compared with physician's choice of chemotherapy (PCT) in germline BRCA1/2-mutated HER2-negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail. MATERIALS AND METHODS: Overall, 412 patients received ≥1 dose of talazoparib (n = 286) or PCT (n = 126). Adverse events (AEs) were evaluated, including timing, duration, and potential overlap of selected AEs. The relationship between talazoparib plasma exposure and grade ≥3 anemia was analyzed. Time-varying Cox proportional hazard models assessed the impact of dose reductions on PFS. Patient-reported outcomes (PROs) in patients with common AEs and health resource utilization (HRU) were assessed in both treatment arms. RESULTS: The most common AEs with talazoparib were hematologic (195 [68.2%] patients) and typically occurred within the first 3-4 months of receiving talazoparib. Grade 3-4 anemia lasted approximately 7 days for both arms. Overlapping grade 3-4 hematologic AEs were infrequent with talazoparib. Higher talazoparib exposure was associated with grade ≥3 anemia. Permanent discontinuation of talazoparib due to hematologic AEs was low (<2%). A total of 150 (52.4%) patients receiving talazoparib had AEs associated with dose reduction. Hematologic toxicities were managed by supportive care medication (including transfusion) and dose modifications. Among patients with anemia or nausea and/or vomiting AEs, PROs favored talazoparib. After accounting for the treatment-emergent period, talazoparib was generally associated with a lower rate of hospitalization and supportive care medication use compared with chemotherapy. CONCLUSION: Talazoparib was associated with superior efficacy, favorable PROs, and lower HRU rate versus chemotherapy in gBRCA-mutated ABC. Toxicities were manageable with talazoparib dose modification and supportive care. IMPLICATIONS FOR PRACTICE: Talazoparib was generally well tolerated in patients with germline BRCA-mutated HER2-negative advanced breast cancer in the EMBRACA trial. Common toxicities with talazoparib were primarily hematologic and infrequently resulted in permanent drug discontinuation (<2% of patients discontinued talazoparib due to hematologic toxicity). Hematologic toxicities typically occurred during the first 3-4 months of treatment and were managed by dose modifications and supportive care measures. A significant efficacy benefit, improved patient-reported outcomes, lower rate of health resource utilization and a tolerable safety profile support incorporating talazoparib into routine management of germline BRCA-mutated locally advanced/metastatic breast cancer.

Clinical and economic burden associated with stage III to IV triple-negative breast cancer: A SEER-Medicare historical cohort study in elderly women in the United States.

BACKGROUND: The current study was performed to describe patient characteristics, treatment patterns, survival, health care resource use (HRU), and costs among older women in the United States with advanced (American Joint Committee on Cancer stage III/IV) triple-negative breast cancer (TNBC) in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. METHODS: Women who were aged ≥66 years at the time of diagnosis and diagnosed with advanced TNBC between January 1, 2007, and January 1, 2011, in the SEER-Medicare database and who were followed for survival through December 31, 2013, were eligible. Patient demographic and clinical characteristics at the time of diagnosis, subsequent treatment patterns, and survival outcomes were analyzed. HRU and costs for the first 3 months after diagnosis, the last 3 months of life, and the time in between are summarized. All analyses were stratified by American Joint Committee on Cancer stage of disease. RESULTS: There were 1244 patients newly diagnosed with advanced TNBC; the majority were aged ≥75 years (61% with stage III disease and 57.4% with stage IV disease) and white (>70% of patients in both disease stage groups). The most common treatment approaches were surgery combined with chemotherapy for patients for stage III disease (50.6%) and chemotherapy alone or with radiotherapy for patients with stage IV disease (31.3%). Diverse chemotherapy regimens were administered for each line of therapy; nevertheless, the medications used were consistent with national guidelines. Patients with stage III and stage IV disease were found to have a similar mean number of hospitalizations and outpatient visits, but mean monthly costs were greater for patients with stage IV disease at all 3 time points. The mean cost per patient-month (in 2013 US dollars) was $4810 for patients with stage III disease and $9159 for patients with stage IV disease. CONCLUSIONS: Among older women with advanced TNBC, significant treatment variations and considerable HRU and costs exist. Further research is needed to find effective treatments with which to reduce the clinical and economic burden of this disease. Cancer 2018;124:2104-14. © 2018 American Cancer Society.

Clinical and economic burden associated with cardiovascular events among patients with hyperlipidemia: a retrospective cohort study.

BACKGROUND: Annual direct costs for cardiovascular (CV) diseases in the United States are approximately $195.6 billion, with many high-risk patients remaining at risk for major cardiovascular events (CVE). This study evaluated the direct clinical and economic burden associated with new CVE up to 3 years post-event among patients with hyperlipidemia. METHODS: Hyperlipidemic patients with a primary inpatient claim for new CVE (myocardial infarction, unstable angina, ischemic stroke, transient ischemic attack, coronary artery bypass graft, percutaneous coronary intervention and heart failure) were identified using IMS LifeLink PharMetrics Plus data from January 1, 2006 through June 30, 2012. Patients were stratified by CV risk into history of CVE, modified coronary heart disease risk equivalent, moderate- and low-risk cohorts. Of the eligible patients, propensity score matched 243,640 patients with or without new CVE were included to compare healthcare resource utilization and direct costs ranging from the acute (1-month) phase through 3 years post-CVE date (follow-up period). RESULTS: Myocardial infarction was the most common CVE in all the risk cohorts. During the acute phase, among patients with new CVE, the average incremental inpatient length of stay and incremental costs ranged from 4.4-6.2 days and $25,666-$30,321, respectively. Acute-phase incremental costs accounted for 61-75% of first-year costs, but incremental costs also remained high during years 2 and 3 post-CVE. CONCLUSIONS: Among hyperlipidemic patients with new CVE, healthcare utilization and costs incurred were significantly higher than for those without CVE during the acute phase, and remained higher up to 3 years post-event, across all risk cohorts.

The relationship between Lp(a) and CVD outcomes: a systematic review.

Robust associations between lipoprotein(a) [Lp(a)] and CVD outcomes among general populations have been published in previous studies. However, associations in high risk primary prevention and secondary prevention populations are less well defined. In order to investigate this further, a systematic review was performed including prospective studies, which assessed the relationship between Lp(a) and CVD outcomes using multivariable analyses. Additional information was gathered on Lp(a) assays, multivariable modelling and population characteristics. Literature searches from inception up to December 2015 retrieved 2850 records. From these 60 studies were included. Across 39 primary prevention studies in the general population (hazard ratios ranged from 1.16 to 2.97) and seven high risk primary prevention studies (hazard ratios ranged from 1.01 to 3.7), there was evidence of a statistically significant relationship between increased Lp(a) and an increased risk of future CVD. Results in 14 studies of secondary prevention populations were also suggestive of a modest statistically significant relationship (hazard ratios ranged from 0.75 to 3.7).Therefore current evidence would suggest that increased Lp(a) levels are associated with modest increases in the risk of future CVD events in both general and higher risk populations. However, further studies are required to confirm these findings.

Association between urologist characteristics and radiation oncologist consultation for patients with locoregional prostate cancer.

BACKGROUND: Physicians managing patients with prostate cancer play a critical role in subsequent specialist consultations and initial treatment choice, especially in cases for which no consensus exists regarding optimal treatment strategy. The NCCN Guidelines for Prostate Cancer recommend radiation as a therapy option for patients with locoregional prostate cancer. PURPOSE: The authors examined the association of urologist characteristics with the likelihood that patients would consult radiation oncologists. METHODS: A retrospective cohort of 39,934 patients aged 66 years or older who were diagnosed with locoregional prostate cancer between 2004 and 2007, and the 2405 urologists who performed the patient diagnostic biopsies were constructed using the SEER-Medicare linked database and the American Medical Association Physician Masterfile. Logistic multilevel regression analysis was used to evaluate the influence of urologists' characteristics on radiation oncologist consultation within 9 months of locoregional prostate cancer diagnosis. RESULTS: Overall, 24,549 (61.5%) patients consulted a radiation oncologist. After adjusting for patient and urologist characteristics, patients diagnosed by urologists in noninstitutional settings (eg, physician office) were significantly more likely to consult a radiation oncologist (odds ratio [OR], 1.40; 95% CI, 1.17-1.67; P=.0002) compared with those diagnosed by urologists in institutional settings with a major medical school affiliation. In addition, patients diagnosed by urologists older than 57 years were significantly more likely to consult a radiation oncologist (OR, 1.21; 95% CI, 1.07-1.38, P=.003).

Productivity loss and indirect costs associated with cardiovascular events and related clinical procedures.

BACKGROUND: The high acute costs of cardiovascular disease and acute cardiovascular events are well established, particularly in terms of direct medical costs. The costs associated with lost work productivity have been described in a broad sense, but little is known about workplace absenteeism or short term disability costs among high cardiovascular risk patients. The objective of this study was to quantify workplace absenteeism (WA) and short-term disability (STD) hours and costs associated with cardiovascular events and related clinical procedures (CVERP) in United States employees with high cardiovascular risk. METHODS: Medical, WA and/or STD data from the Truven Health MarketScan® Research Databases were used to select full-time employees aged 18-64 with hyperlipidemia during 2002-2011. Two cohorts (with and without CVERP) were created and screened for medical, drug, WA, and STD eligibility. The CVERP cohort was matched with a non-CVERP cohort using propensity score matching. Work loss hours and indirect costs were calculated for patients with and without CVERP and by CVERP type. Wages were based on the 2013 age-, gender-, and geographic region-adjusted wage rate from the United States Bureau of Labor Statistics. RESULTS: A total of 5,808 WA-eligible, 21,006 STD-eligible, and 3,362 combined WA and STD eligible patients with CVERP were well matched to patients without CVERP, creating three cohorts of patients with CVERP and three cohorts of patients without CVERP. Demographics were similar across cohorts (mean age 52.2-53.1 years, male 81.3-86.8%). During the first month of follow-up, patients with CVERP had more WA/STD-related hours lost compared with patients without CVERP (WA-eligible: 23.4 more hours, STD-eligible: 51.7 more hours, WA and STD-eligible: 56.3 more hours) (p < 0.001). Corresponding costs were $683, $895, and $1,119 higher, respectively (p < 0.001). Differences narrowed with longer follow-up. In the first month and year of follow-up, patients with coronary artery bypass graft experienced the highest WA/STD-related hours lost and costs compared with patients with other CVERP. CONCLUSIONS: CVERP were associated with substantial work loss and indirect costs. Prevention or reduction of CVERP could result in WA and STD-related cost savings for employers.

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer with PD-L1 ≥ 1 %: A subgroup analysis from the EMPOWER-Lung 3 part 2 trial.

OBJECTIVES: EMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, assessed cemiplimab (anti-programmed cell death protein 1) plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer (NSCLC) without EGFR, ALK, or ROS1 aberrations, regardless of histology or PD-L1 expression levels. We report results from subgroup analysis of patients with PD-L1 expression ≥ 1 %. MATERIALS AND METHODS: Patients were randomized to receive cemiplimab 350 mg or placebo with chemotherapy every 3 weeks for up to 108 weeks. Overall survival (OS), progression-free survival (PFS), overall response rates (ORRs), patient-reported outcomes (PROs), and safety were assessed. RESULTS: Of the 327 patients with PD-L1 ≥ 1 % (466 in the overall study), 217 received cemiplimab plus chemotherapy and 110 received chemotherapy alone. After median follow-up of 28.0 months, median OS for cemiplimab plus chemotherapy was 23.5 months (95 % confidence interval [CI]: 20.9-27.2) vs. 12.1 months (95 % CI: 10.1-15.7) for chemotherapy alone (hazard ratio [HR] = 0.51, 95 % CI: 0.38-0.69, P < 0.0001); median PFS was 8.3 months (95 % CI: 6.7-10.8) versus 5.5 months (95 % CI: 4.3-6.2; HR = 0.48; 95 % CI: 0.37-0.62, P < 0.0001), and ORR was 47.9 % versus 22.7 %, respectively. PRO results favored cemiplimab plus chemotherapy over chemotherapy alone. Improved efficacy over chemotherapy alone was observed in both squamous and non-squamous histology. Safety was consistent with previous reports. CONCLUSION: In this subgroup analysis from EMPOWER-Lung 3 part 2, cemiplimab plus chemotherapy demonstrated clinical benefit over chemotherapy alone in patients with advanced squamous or non-squamous NSCLC with PD-L1 ≥ 1 %.

Determinants of the combined use of external beam radiotherapy and brachytherapy for low-risk, clinically localized prostate cancer.

BACKGROUND: Prostate cancer treatment choices have been shown to vary by physician and patient characteristics. For patients with low-risk, clinically localized prostate cancer, the authors examined the impact of their clinical, sociodemographic, and radiation oncologists' (RO) characteristics on the likelihood that the patients would receive combined external beam radiotherapy and brachytherapy, a treatment regimen that is at variance with clinical guidelines. METHODS: The Surveillance, Epidemiology and End Results (SEER)-Medicare linked database and the American Medical Association Physician Masterfile were used in a retrospective analysis of 5531 patients with low-risk, clinically localized prostate cancer who were diagnosed between 2004 and 2007, and the 708 ROs who treated them. Hierarchical logistic regression analyses were used to evaluate the relationship between patient and RO characteristics and the use of combined therapy within 6 months of diagnosis. RESULTS: Overall, 356 patients (6.4%) received combined therapy. Nonclinical factors were found to be associated with combined therapy. After adjusting for patient and RO characteristics, the odds of receiving combined therapy for patients residing in Georgia were found to be significantly greater than for all other SEER regions. Black patients were significantly less likely to receive combined therapy (odds ratio, 0.62; 95% confidence interval, 0.40-0.96 [P= .03]) compared with white patients. In addition, ROs accounted for 36.6% of the variation in patients receiving combined therapy. CONCLUSIONS: Geographic and sociodemographic factors were found to be significantly associated with guideline-discordant combined therapy for patients diagnosed with low-risk, clinically localized prostate cancer. Which RO a patient consults is important in determining whether they receive combined therapy.

Aiding the Adoption of Master Protocols by Optimizing Patient Engagement.

Master protocols (MPs) are an important addition to the clinical trial repertoire. As defined by the U.S. Food and Drug Administration (FDA), this term means "a protocol designed with multiple sub-studies, which may have different objectives (goals) and involve coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure." This means we now have a unique, scientifically based MP that describes how a clinical trial will be conducted using one or more potential candidate therapies to treat patients in one or more diseases. Patient engagement (PE) is also a critical factor that has been recognized by FDA through its Patient-Focused Drug Development (PFDD) initiative, and by the European Medicines Agency (EMA), which states on its website that it has been actively interacting with patients since the creation of the Agency in 1995. We propose that utilizing these PE principles in MPs can make them more successful for sponsors, providers, and patients. Potential benefits of MPs for patients awaiting treatment can include treatments that better fit a patient's needs; availability of more treatments; and faster access to treatments. These make it possible to develop innovative therapies (especially for rare diseases and/or unique subpopulations, e.g., pediatrics), to minimize untoward side effects through careful dose escalation practices and, by sharing a control arm, to lower the probability of being assigned to a placebo arm for clinical trial participants. This paper is authored by select members of the American Statistical Association (ASA)/DahShu Master Protocol Working Group (MPWG) People and Patient Engagement (PE) Subteam. DahShu is a 501(c)(3) non-profit organization, founded to promote research and education in data science. This manuscript does not include direct feedback from US or non-US regulators, though multiple regulatory-related references are cited to confirm our observation that improving patient engagement is supported by regulators. This manuscript represents the authors' independent perspective on the Master Protocol; it does not represent the official policy or viewpoint of FDA or any other regulatory organization or the views of the authors' employers. The objective of this manuscript is to provide drug developers, contract research organizations (CROs), third party capital investors, patient advocacy groups (PAGs), and biopharmaceutical executives with a better understanding of how including the patient voice throughout MP development and conduct creates more efficient clinical trials. The PE Subteam also plans to publish a Plain Language Summary (PLS) of this publication for clinical trial participants, patients, caregivers, and the public as they seek to understand the risks and benefits of MP clinical trial participation.

Regulatory and HTA Considerations for Development of Real-World Data Derived External Controls.

Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real-world data (RWD) to generate real-world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD-derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit-for-purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD-derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias.

Effectively Leveraging RWD for External Controls: A Systematic Literature Review of Regulatory and HTA Decisions.

Real-world data (RWD)-derived external controls can be used to contextualize efficacy findings for investigational therapies evaluated in uncontrolled trials. As the number of submissions to regulatory and health technology assessment (HTA) bodies using external controls rises, and in light of recent regulatory and HTA guidance on the appropriate use of RWD, there is a need to address the operational and methodological challenges impeding the quality of real-world evidence (RWE) generation and the consistency in evaluation of RWE across agencies. This systematic review summarizes publicly available information on the use of external controls to contextualize outcomes from uncontrolled trials for all indications from January 1, 2015, through August 20, 2021, that were submitted to the European Medicines Agency, the US Food and Drug Administration, and/or select major HTA bodies (National Institute for Health and Care Excellence (NICE), Haute Autorité de Santé (HAS), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), and Gemeinsamer Bundesausschuss (G-BA)). By systematically reviewing submissions to regulatory and HTA bodies in the context of recent guidance, this study provides quantitative and qualitative insights into how external control design and analytic choices may be viewed by different agencies in practice. The primary operational and methodological aspects identified for discussion include, but are not limited to, engagement of regulators and HTA bodies, approaches to handling missing data (a component of data quality), and selection of real-world endpoints. Continued collaboration and guidance to address these and other aspects will inform and assist stakeholders attempting to generate evidence using external controls.

Cemiplimab Plus Chemotherapy Versus Chemotherapy Alone in Advanced NSCLC: 2-Year Follow-Up From the Phase 3 EMPOWER-Lung 3 Part 2 Trial.

INTRODUCTION: EMPOWER-Lung 3 part 2 (NCT03409614), a double-blind, placebo-controlled phase 3 study, investigated cemiplimab (antiprogrammed cell death protein 1) plus chemotherapy versus placebo plus chemotherapy in patients with advanced NSCLC without EGFR, ALK, or ROS1 aberrations, with either squamous or nonsquamous histology, irrespective of programmed death-ligand 1 levels. At primary analysis, after 16.4 months of follow-up, cemiplimab plus chemotherapy improved median overall survival (OS) versus chemotherapy alone (21.9 versus 13.0 mo, hazard ratio [HR] = 0.71, 95% confidence interval [CI]: 0.53-0.93, p = 0.014). Here, we report protocol-specified final OS and 2-year follow-up results. METHODS: Patients (N = 466) were randomized 2:1 to receive histology-specific platinum-doublet chemotherapy, with 350 mg cemiplimab (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks. Primary end point was OS; secondary end points included progression-free survival and objective response rates. RESULTS: After 28.4 months of median follow-up, median OS was 21.1 months (95% CI: 15.9-23.5) for cemiplimab plus chemotherapy versus 12.9 months (95% CI: 10.6-15.7) for chemotherapy alone (HR = 0.65, 95% CI: 0.51-0.82, p = 0.0003); median progression-free survival was 8.2 months (95% CI: 6.4-9.0) versus 5.5 months (95% CI: 4.3-6.2) (HR = 0.55, 95% CI: 0.44-0.68, p < 0.0001), and objective response rates were 43.6% versus 22.1%, respectively. Safety was generally consistent with previously reported data. Incidence of treatment-emergent adverse events of grade 3 or higher was 48.7% with cemiplimab plus chemotherapy and 32.7% with chemotherapy alone. CONCLUSIONS: At protocol-specified final OS analysis with 28.4 months of follow-up, the EMPOWER-Lung 3 study continued to reveal benefit of cemiplimab plus chemotherapy versus chemotherapy alone in patients with advanced squamous or nonsquamous NSCLC, across programmed death-ligand 1 levels.

Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: population-level projections for 2020-2025.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) treatments have been rapidly evolving for patients treated in later lines of therapy (LoT). Country-specific cancer registry data for the US and Western Europe (WE) were combined with physician survey results to project the incidence, prevalence, and number of DLBCL and FL patients eligible for and treated by LoT between 2020 and 2025. The total number of incidents and prevalent cases of DLBCL and FL is expected to increase between 2020 and 2025 in the US and WE. 56% and 53% of the third line plus (3L+) eligible DLBCL patients and 60% and 55% of eligible FL patients initiated treatment in the US and WE, respectively. Further research is warranted to understand the reasons behind the high proportion of treatment eligible patients who do not initiate treatment, and potential differences between countries, especially in the 3L + settings.

Awareness and Availability of Routine Germline BRCA1/2 Mutation Testing in Patients with Advanced Breast Cancer in Germany.

Introduction: Diagnostic testing of germline mutations in breast cancer susceptibility genes 1 or 2 (gBRCA1/2) in patients with human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC; locally advanced or metastatic breast cancer) is necessary to assess eligibility for poly(ADP-ribose) polymerase inhibitors (PARPi). We investigated awareness, clinical practice, and the availability of gBRCA1/2 mutation testing in the German outpatient oncology setting. Methods: Office-based oncologists completed a 23-item online survey. Responses were evaluated collectively and by center type. Results: Of 50 oncologists, 33 and 17 were medical and gynecological oncologists, respectively. Oncologists treated a median of 65 (range 14-350) patients with ABC per year. The strongest decision factors to initiate gBRCA1/2 mutation testing were: patient's known family history of gBRCA1/2 mutation-related cancer(s), guideline recommendations, and triple-negative breast cancer (TNBC). In routine practice, 86% of oncologists tested for gBRCA1/2 mutations. Most oncologists (76-98%) reported testing patients with a known family history of gBRCA1/2 mutation-related cancer(s) irrespective of receptor status. For unknown family history, 92% of oncologists reported testing patients with advanced TNBC versus 30% for HR+/HER2- ABC. Oncologists (66%) rated the awareness of therapeutic relevance of gBRCA1/2 mutation testing for targeted treatment selection as good to satisfactory; 22% rated awareness as poor to in-sufficient. Conclusion: Diagnostic gBRCA1/2 mutation testing in patients with HER2- ABC is available and routinely performed in Germany's outpatient oncology setting. However, specific patient subgroups were not routinely tested despite therapeutic indications. Given PARPi availability, opportunities exist to improve testing rates especially for patients with HR+/HER2- ABC without a known family history of gBRCA1/2 mutation-related cancer(s).

Machine learning models for identifying predictors of clinical outcomes with first-line immune checkpoint inhibitor therapy in advanced non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) are standard-of-care as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC) without actionable oncogenic driver mutations. While clinical trials demonstrated benefits of ICIs over chemotherapy, variation in outcomes across patients has been observed and trial populations may not be representative of clinical practice. Predictive models can help understand heterogeneity of treatment effects, identify predictors of meaningful clinical outcomes, and may inform treatment decisions. We applied machine learning (ML)-based survival models to a real-world cohort of patients with aNSCLC who received 1L ICI therapy extracted from a US-based electronic health record database. Model performance was evaluated using metrics including concordance index (c-index), and we used explainability techniques to identify significant predictors of overall survival (OS) and progression-free survival (PFS). The ML model achieved c-indices of 0.672 and 0.612 for OS and PFS, respectively, and Kaplan-Meier survival curves showed significant differences between low- and high-risk groups for OS and PFS (both log-rank test p < 0.0001). Identified predictors were mostly consistent with the published literature and/or clinical expectations and largely overlapped for OS and PFS; Eastern Cooperative Oncology Group performance status, programmed cell death-ligand 1 expression levels, and serum albumin were among the top 5 predictors for both outcomes. Prospective and independent data set evaluation is required to confirm these results.

Characterizing the Shifting Real-World Treatment Landscape by PD-L1 Testing Status and Expression Level in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Contemporary real-world data on advanced non-small cell lung cancer (aNSCLC) treatment patterns across programmed cell death-ligand 1 (PD-L1) expression levels and testing status are limited. METHODS: A retrospective cohort was selected of adults newly diagnosed with aNSCLC between January 1, 2018, and July 31, 2021, who initiated first-line treatments, which were described by PD-L1 status and expression levels (≥ 50%, 1-49%, < 1%). Treatment received before and after PD-L1 test results were described for patients initiating first-line treatment before PD-L1 results. For patients who initiated chemotherapy alone before PD-L1 results, the probability of receiving immune checkpoint inhibitors (ICIs) after PD-L1 results was estimated by PD-L1 level and associated factors were explored. RESULTS: Among 12,202 patients with aNSCLC initiating first-line treatment [54.7% male, mean (standard deviation) age 69.2 (9.4) years], the most common therapies were ICI-based regimens across PD-L1 levels, and chemotherapy alone among PD-L1-untested patients. Use of chemotherapy alone decreased between 2018 and 2019 and stabilized thereafter, accounting for 21-29% of first-line treatments across PD-L1 levels and 48% of untested patients in 2021. Of 1468 patients initiating first-line treatment before PD-L1 results, treatments remained unchanged in most patients after PD-L1 results. Among patients initiating chemotherapy alone before PD-L1 results, the probability of receiving ICIs within 45 days after test results was 40.5% [95% confidence interval (CI) 31.6-48.3%], 28.6% (95% CI 20.3-36.0%), and 22.9% (95% CI 16.9-28.4%) at PD-L1 ≥ 50%, 1-49%, and < 1%, respectively. CONCLUSION: While ICI-based regimens accounted for most first-line treatments across PD-L1 levels, chemotherapy alone was initiated in > 20% of patients tested for PD-L1 and 48% of untested patients in 2021. Patients who initiated chemotherapy alone had a low probability of receiving ICIs after PD-L1 test results. These results highlight the need for understanding the role and timing of PD-L1 test results for informing treatment decisions for patients with aNSCLC.

Patient-reported outcomes labeling for oncology drugs: Multidisciplinary perspectives on current status and future directions.

Introduction: Regulatory agencies encourage the incorporation of the patient voices throughout clinical drug development. Patient-Reported Outcomes (PROs) offer one way of doing this and their use has markedly increased in many therapeutic areas, particularly oncology, in recent years. However, few oncology drug labels include PRO data and those which do, offer little consistency. Objective: To provide multidisciplinary perspectives (patient, pharmaceutical industry, PRO researcher, regulatory expert) on PRO data in oncology drug labels. Methods: PRO data in the labels of drugs approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for oncology indications between 2010 and 2020 were critically reviewed by authors who provided their insights on the advantages and disadvantages/gaps. Results: Forty-six oncology drugs included PRO data in their labels. Differences were observed between FDA and EMA PRO labeling (e.g., PRO concept, use of tables and graphs to display PROs or reference to clinical meaningfulness). In providing their perspectives on the number and nature of PROs in labels, authors noted limitations including: the low proportion of oncology drugs with PRO labeling, limited PRO information in labels, lack of patient-friendly language, and potential bias towards positive outcomes. Lack of consistency within- and between-agencies was noted. Conclusion: Despite regulatory agencies' commitment to incorporate patient voices in regulatory decisions, availability of PRO information is limited in oncology drug labels. While several PRO guidance documents are available from regulatory and Health Technology Assessment agencies, harmonization of PRO guidance for labeling inclusion around the world is needed to better inform prescribers and consequently their patients in the process of shared medical decisions.