External control arms in oncology: current use and future directions.

Although randomized control trials allow for a comparison of treatment arms with minimal concern for confounding by known and unknown factors, a randomized study is not feasible in certain disease settings. When a randomized design is not possible, incorporating external control data into the study design can be an effective way to expand the interpretability of the results of an experimental arm by introducing the ability to carry out a formal or an informal comparative analysis. This paper provides an introduction to the concepts of external controls in oncology trials, followed by a review of relevant and current research on this topic. The paper also focuses on general considerations for designing a trial that may incorporate external control data, followed by case studies of the marketing applications submitted to the Food and Drug Administration that included external control data.

Analysis of time-to-treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small-cell lung cancer.

BACKGROUND: Pragmatic end points, such as time-to-treatment discontinuation (TTD), defined as the date of starting a medication to the date of treatment discontinuation or death has been proposed as a potential efficacy end point for real-world evidence (RWE) trials, where imaging evaluation is less structured and standardized. PATIENTS AND METHODS: We studied 18 randomized clinical trials of patients with metastatic non-small-cell lung cancer (mNSCLC), initiated after 2007 and submitted to U.S. Food and Drug Administration. TTD was calculated as date of randomization to date of discontinuation or death and compared to progression-free survival (PFS) and overall survival (OS) across all patients, as well as in treatment-defined subgroups [EGFR mutation-positive treated with tyrosine kinase inhibitor (TKI), EGFR wild-type treated with TKI, ALK-positive treated with TKI, immune checkpoint inhibitor (ICI), chemotherapy doublet with maintenance, chemotherapy monotherapy]. RESULTS: Overall across 8947 patients, TTD was more closely associated with PFS (r = 0.87, 95% CI 0.86-0.87) than with OS (0.68, 95% CI 0.67-0.69). Early TTD (PFS-TTD ≥ 3 months) occurred in 7.7% of patients overall, and was more common with chemo monotherapy (15.0%) while late TTD (TTD-PFS ≥ 3 months) occurred in 6.0% of patients overall, and was more common in EGFR-positive and ALK-positive patients (12.4% and 22.9%). In oncogene-targeted subgroups (EGFR positive and ALK positive), median TTDs (13.4 and 14.1 months) exceeded median PFS (11.4 and 11.3 months). CONCLUSIONS: At the patient level, TTD is associated with PFS across therapeutic classes. Median TTD exceeds median PFS for biomarker-selected patients receiving oncogene-targeted therapies. TTD should be prospectively studied further as an end point for pragmatic randomized RWE trials only for continuously administered therapies.

Concomitant botanical medicine use among patients participating in commercial prostate cancer trials.

OBJECTIVES: Patients with cancer frequently use botanical medications. The concomitant use of such medications by patients on commercial trials has not been well-described, despite the importance of these trials for evaluating the safety and efficacy of new agents. We sought to describe the use of botanical medications taken by patients with prostate cancer enrolled on global commercial trials. DESIGN: Retrospective study. SETTING: Regulatory repository of commercial clinical trial data. INTERVENTIONS: Anti-cancer therapy. MAIN OUTCOME MEASURES: Botanical and medication use data were pooled across six international commercial randomized trials for metastatic prostate cancer with detailed information on medication and indications. Botanical products were considered to have potential for drug interaction if they led to a change in drug exposure in human trials. Potential for interaction was ascertained by PubMed review. Descriptive statistics were used for analysis. RESULTS: Of 7318 enrolled patients, 700 (10 %) reported botanical use at any time and 653 (9%) reported use of botanical products while on trial. Nearly half of botanical product types were not classified by plant (43 %). The highest proportion of botanical use was among patients in Asian countries (32 %), followed by patients in North America (13 %). Eighty-six different types of botanical products were used; of these, nineteen had a patient-reported anti-cancer indication. CONCLUSIONS: Botanical medicine use among patients with prostate cancer in commercial trials is moderate, although it varies by region. Practitioners should be aware of the use of botanical interventions in a clinical trial context.

Age-related differences in patient-reported outcomes in patients with advanced lung cancer receiving anti-PD-1/PD-L1 therapy.

BACKGROUND: Older adults with lung cancer often have comorbidities that may increase risk of symptomatic adverse events (AEs) and physical function decline. The objective of this study was to examine age-related differences in patient-reported symptoms and functional domains in patients with advanced lung cancer receiving immunotherapy drugs. METHODS: Three randomized controlled trials of anti-programmed death receptor-1/programmed death-ligand 1 therapy in patients with advanced non-small cell lung cancer that included patient-reported outcomes (PROs) were identified. Baseline PRO data were pooled for treatment arms from 2 trials that included the same PRO tools. Age-related differences in baseline mean scores for each of the health-related quality of life functional and symptom scales were assessed for patients ≥70 years and <70 years. Mean change from Baseline at 3 months was also calculated and plotted for each age group. The adequacy of PRO assessments was assessed by comparing clinician-reported AE data in the 3 trials to the item content of the PRO tools included. RESULTS: Across the 3 trials, 75 of patients were under 70 and 26% patients were 70 and older. Comparing baseline scores in the 2 trials with the same PRO tool, older adults reported small differences including lower physical functioning, less pain, insomnia and financial difficulties, and higher social functioning than younger patients at baseline. No large differences in the distributions of mean change from baseline in function or symptom were identified. Several common clinician-reported symptomatic AEs were not assessed by the PRO strategy employed in the 3 trials. Three clinician-reported symptomatic AEs (rash, fever, and pruritus) that were commonly reported in the safety data (9%-19%) were not assessed using the PRO tools employed. CONCLUSION: While several small differences were seen, there did not appear to be large differences at baseline or in the distributions of change from baseline in PRO functional domains between younger and older patients with lung cancer undergoing anti-programmed death receptor -1/programmed death-ligand 1 therapy. Relevant symptomatic side effects were not assessed by PRO measures in these trials, and this is a limitation of current PRO assessment strategies.

Combined PET/CT Imaging in Oncology. Impact on Patient Management.

Purpose: In this work, we describe five oncology patients whose clinical management were uniquely benefited by a novel scanner that acquires positron emission tomography (PET) and x-ray computed tomography (CT) in the same imaging session.Procedures: Co-registered 2-[F(18)]-fluoro-2-deoxy-D-glucose (FDG)-PET and CT images were acquired using a combined PET/CT scanner. Pathology and clinical follow-up data were used to confirm PET/CT scan results.Results: The combined PET/CT scanner demonstrated the ability to distinguish malignant lesions from normal physiologic FDG uptake in the striated muscles of the head and neck as well as excretory and bowel activity in the abdomen and pelvis. Additionally, the technology positively affected patient management through localization for surgical and radiation therapy planning as well as assessment of tumor response.Conclusion: Our experience indicates that simultaneous acquisition of co-registered PET and CT images enabled physicians to more precisely discriminate between physiologic and malignant FDG uptake and more accurately localize lesions, improving the value of diagnostic PET in oncologic applications.