Nathan C. Nussbaum

Patient experience in the treatment of metastatic castration-resistant prostate cancer: state of the science

Background:Contemporary therapies for metastatic castration-resistant prostate cancer (mCRPC) have shown survival improvements, which do not account for patient experience and health-related quality of life (HRQoL).Methods:This literature review included a search of MEDLINE for randomized clinical trials enrolling ⩾50 patients with mCRPC and reporting on patient-reported outcomes (PROs) since 2010.Results:Nineteen of 25 publications describing seven treatment regimens (10 clinical trials and nine associated secondary analyses) met the inclusion criteria and were critically appraised. The most commonly used measures were the Functional Assessment of Cancer Therapy-Prostate (n=5 trials) and Brief Pain Inventory Short Form (n=4 trials) questionnaires. The published data indicated that HRQoL and pain status augmented the clinical efficacy data by providing a better understanding of treatment impact in mCRPC. Abiraterone acetate and prednisone, enzalutamide, radium-223 dichloride and sipuleucel-T offered varying levels of HRQoL benefit and/or pain mitigation versus their respective comparators, whereas three treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no meaningful impact on HRQoL or pain. The main limitation of the data were that the PROs utilized were not developed for use in mCRPC patients and hence may not have comprehensively captured symptoms important to this population.Conclusions:Recently published randomized clinical trials of new agents for mCRPC have captured elements of the patient experience while on treatment. Further research is required to standardize methods for measuring, quantifying and reporting on HRQoL and pain in patients with mCRPC in the clinical practice setting.

The Neoadjuvant Treatment of Rectal Cancer: A Review

Rectal adenocarcinoma is an important cause of cancer-related deaths worldwide, and key anatomic differences between the rectum and the colon have significant implications for management of rectal cancer, especially in the curative setting. For stage II and III rectal cancers, combined chemoradiotherapy offers the lowest rates of local and distant relapse, and is delivered neoadjuvantly to improve tolerability and optimize surgical outcomes, particularly when sphincter-sparing surgery is an endpoint. We review both pivotal trial data that has shaped the current standard of care, fluoropyrimidine-based chemoradiotherapy, while also presenting results from more recent studies, which aim to outperform this standard. Strategies combining 5FU radiotherapy with oxaliplatin, VEGF inhibition, EGFR inhibition, other targeted agents, and/or use of induction chemotherapy hold promise but thus far have failed to improve outcomes in randomized trials. Results of studies such as the ongoing PROSPECT trial may help further define our current therapeutic algorithm for stage II and III rectal cancer.

Characteristics of Real‐World Metastatic Non‐Small Cell Lung Cancer Patients Treated with Nivolumab and Pembrolizumab During the Year Following Approval

BACKGROUND Evidence from cancer clinical trials can be difficult to generalize to real-world patient populations, but can be complemented by real-world evidence to optimize personalization of care. Further, real-world usage patterns of programmed cell death protein 1 (PD-1) inhibitors following approval can inform future studies of subpopulations underrepresented in clinical trials. MATERIALS AND METHODS We performed a multicenter analysis using electronic health record data collected during routine care of patients treated in community cancer care clinics in the Flatiron Health network. Real-world metastatic non-small cell lung cancer (NSCLC) patients who received nivolumab or pembrolizumab in the metastatic setting (n = 1,344) were selected from a starting random sample of 55,969 NSCLC patients with two or more documented visits from January 1, 2011, through March 31, 2016. The primary study outcome measurement was demographic and treatment characteristics of the cohort. RESULTS Median age at PD-1 inhibitor initiation was 69 years (interquartile range 61-75). Patients were 56% male, 88% smokers, 65% nonsquamous histology, and 64% diagnosed at stage IV. Of 1,344 patients, 112 (8%) were tested for programmed death-ligand 1 expression. Overall, 50% received nivolumab or pembrolizumab in the second line, with a substantial proportion of third and later line use that began to decline in Q4 2015. CONCLUSION During the year following U.S. regulatory approval of PD-1 inhibitors for treatment of NSCLC, real-world patients receiving nivolumab or pembrolizumab were older at treatment initiation and more had smoking history relative to clinical trial cohorts. Studies of outcomes in underrepresented subgroups are needed to inform real-world treatment decisions. IMPLICATIONS FOR PRACTICE 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.

Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non–Small Cell Lung Cancer in the Community Oncology Setting

Importance Broad-based genomic sequencing is being used more frequently for patients with advanced non–small cell lung cancer (NSCLC). However, little is known about the association between broad-based genomic sequencing and treatment selection or survival among patients with advanced NSCLC in a community oncology setting. Objective To compare clinical outcomes between patients with advanced NSCLC who received broad-based genomic sequencing vs a control group of patients who received routine testing for EGFR mutations and/or ALK rearrangements alone. Design, Setting, and Participants Retrospective cohort study of patients with chart-confirmed advanced NSCLC between January 1, 2011, and July 31, 2016, and who received care at 1 of 191 oncology practices across the United States using the Flatiron Health Database. Patients were diagnosed with stage IIIB/IV or unresectable nonsquamous NSCLC who received at least 1 line of antineoplastic treatment. Exposures Receipt of either broad-based genomic sequencing or routine testing (EGFR and/or ALK only). Broad-based genomic sequencing included any multigene panel sequencing assay examining more than 30 genes prior to third-line treatment. Main Outcomes and Measures Primary outcomes were 12-month mortality and overall survival from the start of first-line treatment. Secondary outcomes included frequency of genetic alterations and treatments received. Results Among 5688 individuals with advanced NSCLC (median age, 67 years [interquartile range, 41-85], 63.6% white, 80% with a history of smoking); 875 (15.4%) received broad-based genomic sequencing and 4813 (84.6%) received routine testing. Among patients who received broad-based genomic sequencing, 4.5% received targeted treatment based on testing results, 9.8% received routine EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. Unadjusted mortality rates at 12 months were 49.2% for patients undergoing broad-based genomic sequencing and 35.9% for patients undergoing routine testing. Using an instrumental variable analysis, there was no significant association between broad-based genomic sequencing and 12-month mortality (predicted probability of death at 12 months, 41.1% for broad-based genomic sequencing vs 44.4% for routine testing; difference −3.6% [95% CI, −18.4% to 11.1%]; P = .63). The results were consistent in the propensity score–matched survival analysis (42.0% vs 45.1%; hazard ratio, 0.92 [95% CI, 0.73 to 1.11]; P = .40) vs unmatched cohort (hazard ratio, 0.69 [95% CI, 0.62 to 0.77]; log-rank P < .001). Conclusions and Relevance Among patients with advanced non–small cell lung cancer receiving care in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.

Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials

Importance The US Food and Drug Administration (FDA) is increasing its pace of approvals for novel cancer therapeutics, including for immune checkpoint inhibitors of programmed cell death 1 protein (anti–PD-1 agents). However, little is known about how quickly anti–PD-1 agents agents reach eligible patients in practice or whether such patients differ from those studied in clinical trials that lead to FDA approval (pivotal clinical trials). Objectives To assess the speed with which anti–PD-1 agents agents reached eligible patients in practice and to compare the ages of patients treated in clinical practice with the ages of those treated in pivotal clinical trials. Design, Setting, and Participants This retrospective cohort study, performed from January 1, 2011, through August 31, 2016, included patients from the Flatiron Health Network who were eligible for anti–PD-1 agents treatment of selected cancer types, which included melanoma, non–small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Main Outcomes and Measures Cumulative proportions of eligible patients receiving anti–PD-1 agents treatment and their age distributions. Results The study identified 3089 patients who were eligible for anti–PD-1 agents treatment (median age, 66 [interquartile range, 56-75] years for patients with melanoma, 66 [interquartile range, 58-72] years for patients with RCC, and 67 [interquartile range, 59-74] years for patients with NSCLC; 1742 male [56.4%] and 1347 [43.6%] female; 2066 [66.9%] white). Of these patients, 2123 (68.7%) received anti–PD-1 agents treatment, including 439 eligible patients with melanoma (79.1%), 1417 eligible patients with NSCLC (65.6%), and 267 eligible patients with RCC (71.2%). Within 4 months after FDA approval, greater than 60% of eligible patients in each cohort had received anti–PD-1 agents treatment. Overall, similar proportions of older and younger patients received anti–PD-1 agents treatment during the first 9 months after FDA approval. However, there were significant differences in age between clinical trial participants and patients receiving anti–PD-1 agents treatment in clinical practice, with more patients being older than 65 years in clinical practice (range, 327 of 1365 [60.6%] to 46 of 72 [63.9%]) than in pivotal clinical trials (range, 38 of 120 [31.7%] to 223 of 544 [41.0%]; all P < .001). Conclusions and Relevance Anti-PD-1 agents rapidly reached patients in clinical practice, and patients treated in clinical practice differed significantly from patients treated in pivotal clinical trials. Future actions are needed to ensure that rapid adoption occurs on the basis of representative trial evidence.

Age-related real-world outcomes for patients (pts) with metastatic colorectal cancer (mCRC).

3613Background: There are scant data regarding the diagnosis, treatment, and outcomes for mCRC pts diagnosed at a very young age ( < 30 yrs). We therefore explored age-related pt and tumor characte...