Conventional cancer clinical trials can be slow and costly, often produce results with limited external validity, and are difficult for patients to participate in. Recent technological advances and a dynamic policy landscape in the United States have created a fertile ground for the use of real-world data (RWD) to improve current methods of clinical evidence generation. Sources of RWD include electronic health records, insurance claims, patient registries, and digital health solutions outside of conventional clinical trials. A definition focused on the original intent of data collected at the point of care can distinguish RWD from conventional clinical trial data. When the intent of data collection at the point of care is research, RWD can be generated using experimental designs similar to those employed in conventional clinical trials, but with several advantages that include gains in efficient execution of studies with an appropriate balance between internal and external validity. RWD can support active pharmacovigilance, insights into the natural history of disease, and the development of external control arms. Prospective collection of RWD can enable evidence generation based on pragmatic clinical trials (PCTs) that support randomized study designs and expand clinical research to the point of care. PCTs may help address the growing demands for access to experimental therapies while increasing patient participation in cancer clinical trials. Conducting valid real-world studies requires data quality assurance through auditable data abstraction methods and new incentives to drive electronic capture of clinically relevant data at the point of care.

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On a trial level, there is a strong association between ORR and PFS. An association between ORR and OS and between PFS and OS was not established, possibly because of cross-over and longer survival after progression in the targeted therapy and first-line trials. The patient-level analysis showed that responders have a better PFS and OS compared with nonresponders. A therapy in advanced NSCLC with a large magnitude of effect on ORR may have a large PFS effect.

On April 29, 2014, the FDA granted accelerated approval to ceritinib (ZYKADIA; Novartis Pharmaceuticals Corporation), a breakthrough therapy-designated drug, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval was based on a single-arm multicenter trial enrolling 163 patients with metastatic ALK-positive NSCLC who had disease progression on (91%) or intolerance to crizotinib. Patients received ceritinib at a starting dose of 750 mg orally once daily. The objective response rate (ORR) by a blinded independent review committee was 44% (95% CI, 36-52), and the median duration of response (DOR) was 7.1 months. The ORR by investigator assessment was similar. Safety was evaluated in 255 patients. The most common adverse reactions and laboratory abnormalities included diarrhea (86%), nausea (80%), increased alanine transaminase (80%), increased aspartate transaminase (75%), vomiting (60%), increased glucose (49%), and increased lipase (28%). Although 74% of patients required at least one dose reduction or interruption due to adverse reactions, the discontinuation rate due to adverse reactions was low (10%). With this safety profile, the benefit-risk analysis was considered favorable because of the clinically meaningful ORR and DOR.

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NCT01100931.

Evidence gathered in conventional clinical trials used to assess safety and efficacy of new therapies is not necessarily generalizable to real-world patients receiving these drugs following regulatory approval. Real-world evidence derived from electronic health record data can yield complementary evidence to enable optimal clinical decisions. Examined here is a cohort of programmed cell death protein 1 inhibitor-treated metastatic non-small cell lung cancer patients in the first year following regulatory approval of these therapies in this indication. The analysis revealed how the real-world cohort differed from the clinical trial cohorts, which will inform which patients are underrepresented and warrant additional studies.

Summary Background No standard therapy exists for refractory or relapsed, advanced thymic epithelial tumors (TETs). We investigated the efficacy of cixutumumab, a fully human, IgG1 monoclonal antibody targeting the insulin-like growth factor-1 receptor, in TETs after failure of prior chemotherapy. Methods In this multicentre, open-label, phase 2 trial we enrolled patients aged 18 years or older with histologically confirmed recurrent or refractory TETs, who had progressed after at least one prior platinum-containing chemotherapy regimen, had Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease and adequate organ function. Eligible patients received cixutumumab (20 mg/kg, intravenous) every three weeks until disease progression or development of intolerable toxicity. The primary endpoint was response rate, analyzed on an intention-to-treat basis. Multiple pharmacodynamic studies were performed. This trial has completed enrollment and is registered with ClinicalTrials.gov, number NCT00965250. Findings Between August 25, 2009, and March 27, 2012, 49 patients were enrolled (37 thymomas; 12 thymic carcinomas) and received a median of six cycles of cixutumumab (range 1–46). At final analysis median potential follow-up was 24 months (IQR 17·3–36·9). In the thymoma cohort five (14%) of 37 patients (95% CI 5–29%) achieved a partial response, 28 had stable disease and four had progressive disease. Corresponding numbers for the thymic carcinoma cohort were zero of 12 patients (95% CI 0–26%), five and seven. The most common grade 3–4 adverse events in both cohorts combined were hyperglycemia (5 [10%] of 49 patients), lipase elevation (3 [6%]), weight loss, tumor pain, and hyperuricemia (2 each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions (five new-onset) during treatment, the most common of which was pure red cell aplasia. Two (4%) of 49 treated patients died while on study. One case was attributed to disease progression and the other to disease–related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Interpretation Cixutumumab monotherapy is well tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Funding Division of Cancer Treatment and Diagnosis, National Cancer Institute/National Institutes of Health and ImClone Systems.