Citations

8001 Background: The ALCHEMIST clinical trial platform, launched by the National Clinical Trials Network (NCTN) in 2014, screened patients with resected non-small cell lung cancer (NSCLC) for molecular markers and tailored post-operative adjuvant therapy trials. A081105 evaluated whether adjuvant erlotinib improved overall survival (OS) following complete resection in patients with early stage EGFR mutated lung adenocarcinoma. Methods: A081105 was a randomized phase III trial enrolling patients with completely resected stage IB (≥4 cm), II, or IIIA non-squamous NSCLC (per the 7 th TNM staging classification) harboring EGFR exon 19 deletion or L858R mutations. Patients were randomized 1:1 to erlotinib 150 mg daily for up to 2 years or placebo/observation, stratified by stage, prior chemotherapy, EGFR mutation subtype, and ECOG performance status. The primary endpoint was OS in the per-protocol (PP) population with centrally confirmed EGFR mutations, designed to detect a hazard ratio (HR) of 0.67 in favor of erlotinib with a power of 86% and one sided type I error rate of 5%. Secondary endpoints included OS and disease free survival (DFS) in a modified intent-to-treat (mITT) population with local or centrally confirmed EGFR mutations, and safety. A prespecified backstop analysis was conducted after a minimum of 5 years of follow-up on all patients. Results: Trial enrollment was discontinued when 390 of the intended 450 patients had been enrolled due to the proven benefit of adjuvant osimertinib. Among 390 enrolled patients, the arms were balanced for age (median: 67.0 years), sex (70% female), race (70% white), stage (II: 51%, IIIA: 37%), prior chemotherapy (82%), ECOG PS 0 (60%), and exon 19 deletion (57%). Adjuvant erlotinib did not significantly improve OS compared with placebo/observation in the overall PP population (364 patients, 108 events, HR 0.89; 95% CI, 0.59–1.34; 1-sided P = 0.29) or within exon 19 deletion (HR: 0.94) or L858R mutation (HR: 0.82) subgroups. Five-year OS rates were 78.6% versus 77.9%, respectively. Results were consistent in the mITT analysis (379 patients, 113 events, HR 0.86; 95% CI, 0.58–1.28). Erlotinib improved DFS (mITT: 181 events, median: 68 vs 50 months, HR 0.74; 95% CI, 0.55–1.01). Across both arms, 11% of patients started non-protocol treatment (Osimertinib: 9%) prior to disease progression, and 9% withdrew consent for all follow-up prior to recurrence. In the erlotinib arm, 3 deaths on study were reported; grade 3 or higher adverse events were reported on 39% of patients. Median duration of treatment on Erlotinib arm was 16 months; only 37% of patients completed the planned treatment. Conclusions: In resected EGFR -mutant NSCLC, adjuvant erlotinib did not improve overall survival but improved DFS. Additional studies are exploring efficacy in selected subsets of patients using genomics and proteomic analyses. Clinical trial information: NCT02193282 .

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The “Summary of the Guidelines Updates” section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

Context.— Autism spectrum disorder is a neurodevelopmental condition that affects over 1% of the population worldwide. Developing effective preventions and treatments for autism will depend on understanding the neuropathology of the disorder. While evidence from magnetic resonance imaging indicates altered development of the autistic brain, it lacks the resolution needed to identify the cellular and molecular underpinnings of the disorder. Postmortem studies of human brain tissue currently represent the only viable option to pursuing these critical studies. Historically, the availability of autism brain tissue has been extremely limited. Objective.— To overcome this limitation, Autism BrainNet, funded by the Simons Foundation, was formed as a network of brain collection sites that work in a coordinated fashion to develop a library of human postmortem brain tissues for distribution to researchers worldwide. Autism BrainNet has collection sites (or Nodes) in California, Texas, and Massachusetts; affiliated, international Nodes are located in Oxford, England and Montreal, Quebec, Canada. Data Sources.— Pubmed, Autism BrainNet. Conclusions.— Because the death of autistic individuals is often because of an accident, drowning, suicide, or sudden unexpected death in epilepsy, they often are seen in a medical examiner's or coroner's office. Yet, autism is rarely considered when evaluating the cause of death. Advances in our understanding of chronic traumatic encephalopathy have occurred because medical examiners and neuropathologists questioned whether a pathologic change might exist in individuals who played contact sports and later developed severe behavioral problems. This article highlights the potential for equally significant breakthroughs in autism arising from the proactive efforts of medical examiners, pathologists, and coroners in partnership with Autism BrainNet.

Abstract Purpose: Romidepsin dosing recommendations for patients with malignancy and varying degrees of hepatic dysfunction was lacking at the time of regulatory approval for T-cell lymphoma. We conducted a multicenter phase I clinical trial (ETCTN-9008) via the NCI Organ Dysfunction Working Group to investigate safety, first cycle MTD, and pharmacokinetic profile of romidepsin in this setting. Patients and Methods: Patients with select advanced solid tumors or hematologic malignancies were stratified according to hepatic function. Romidepsin was administered intravenously on days 1, 8, and 15 of a 28-day cycle and escalation followed a 3 + 3 design in moderate and severe impairment cohorts. Blood samples for detailed pharmacokinetic analyses were collected after the first dose. Results: Thirty-one patients received one dose of romidepsin and were evaluable for pharmacokinetic analyses in normal (n = 12), mild (n = 8), moderate (n = 5), and severe (n = 6) cohorts. Adverse events across cohorts were similar, and dose-limiting toxicity occurred in two patients (mild and severe impairment cohorts). The MTD was not determined because the geometric mean AUC values of romidepsin in moderate (7 mg/m2) and severe (5 mg/m2) impairment cohort were 114% and 116% of the normal cohort (14 mg/m2). Conclusions: Data from the ETCTN-9008 trial led to changes in the romidepsin labeling to reflect starting dose adjustment for patients with cancer and moderate and severe hepatic impairment, with no adjustment for mild hepatic impairment.

TPS9077 Background: ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) is a clinical trial platform of the National Cancer Institute that offers biomarker analysis for high-risk resected non-small cell lung cancer (NSCLC) to support randomized trials of novel adjuvant therapies within the National Clinical Trials Network (NCTN). EA5142, a trial of adjuvant nivolumab for patients (pts) without EGFR / ALK alterations, has completed enrollment. Given the survival benefit seen with 1st-line chemo-immunotherapy (chemo-IO) for advanced NSCLC without EGFR / ALK alterations, there was compelling rationale for the launch of a trial offering concurrent immunotherapy with adjuvant chemo. Here we report updated enrollment to ALCHEMIST as of Jan 14, 2020. Methods: ALCHEMIST includes a screening trial (A151216, 5362 registered) that enrolls pts with completely resected clinical stage IB (≥4 cm)–IIIA (per AJCC 7) NSCLC. Tissue and blood are collected, biomarker testing includes EGFR sequencing, ALK FISH and PD-L1 IHC. 733 active sites are enrolling across the NCTN. Pts with EGFR mutations may enroll to adjuvant erlotinib vs observation (A081105, 352 randomized); those with ALK fusions may enroll to adjuvant crizotinib vs observation (E4512, 99 randomized). A trial offering adjuvant nivolumab vs observation regardless of PD-L1 status (EA5142, 935 randomized) recently completed enrollment. To support ongoing investigation of adjuvant immunotherapy, ALCHEMIST is adding A081801 (opens spring 2020). Pts will be randomized to one of 3 arms: chemo-IO with pembrolizumab during and after chemo vs sequential chemo followed by pembrolizumab vs chemo alone. Pts with pathological N2 nodes are eligible and can undergo postoperative radiotherapy after completing chemo. Pts are eligible if enrolled to A151216, negative for EGFR and ALK alterations, and with PD-L1 testing completed (required for stratification). Local testing for EGFR, ALK and PD-L1 will be accepted for enrollment; central testing will not delay randomization. Pts may not have received any therapy except surgery for the lung cancer and must be age >18, Eastern Cooperative Oncology Group performance status 0-1, have no active autoimmune disease requiring systemic treatment within 2 years, must not be pregnant or nursing, have no active second malignancy within 3 years and meet standard organ function values. By building off the ongoing ALCHEMIST platform, we hope to facilitate rapid enrollment to A081801 across participating NCTN sites. Clinical trial information: NCT02194738.

7513 Background: Early clinical studies with gefitinib (G) showed promising efficacy and mild toxicity in patients (pts) with advanced NSCLC. Thus, G was an ideal agent to evaluate in a maintenance setting in stage III disease following definitive treatment. Methods: Untreated pts with stage III NSCLC, a PS of 0–1 and adequate organ function were eligible. Patients received the SWOG 9504 core regimen (cisplatin 50 mg/m2, d1 & 8 plus etoposide 50 mg/m2 day 1–5, every 28 days for 2 cycles with concurrent thoracic radiation, 1.8–2 Gy fractions/day, total dose 61 Gy, followed by 3 cycles of docetaxel 75 mg/m2). Non- progressing pts were randomized to G 250 mg per day or placebo (P) until disease progression, intolerable toxicity or 5 years. The planned sample size was 672, to confer power of 0.89 to detect a 33% increase over the expected median survival of 21 months (one-sided 0.025 level logrank test). Randomization was stratified by stage and histology. Results: Enrollment began in July 2001. An unplanned interim analysis prompted by outside data was conducted in April 2005 and the alternative hypothesis of improved survival was rejected at the 0.0015 level for 243 randomized patients. The study closed and preliminary results were reported (ASCO 2005). Now with a median follow up of 27 months, median survival for the G arm (n=118) was 23 months and was 35 months for the P arm (n=125) (two sided p=0.013). Overall survival for the 571eligible patients was 19 months. ≥ Grade 3 toxicities in the G arm were rash (7%), diarrhea (7%) and pneumonitis (3%). Conclusion: In this unselected population G did not improve survival. Decreased survival was due to cancer not G toxicity. Three year survival estimates will be presented. Molecular studies of the EGFR pathway are underway and will be correlated with outcomes. No significant financial relationships to disclose.

Abstract Small pulmonary nodules are most often managed by surveillance imaging with computed tomography (CT) of the chest, but the optimal frequency and duration of surveillance are unknown. The Watch the Spot Trial is a multicenter, pragmatic, comparative-effectiveness trial with cluster randomization by hospital or health system that compares more- versus less-intensive strategies for active surveillance of small pulmonary nodules. The study plans to enroll approximately 35,200 patients with a small pulmonary nodule that is newly detected on chest CT imaging, either incidentally or by screening. Study protocols for more- and less-intensive surveillance were adapted from published guidelines. The primary outcome is the percentage of cancerous nodules that progress beyond American Joint Committee on Cancer seventh edition stage T1a. Secondary outcomes include patient-reported anxiety and emotional distress, nodule-related health care use, radiation exposure, and adherence with the assigned surveillance protocol. Distinctive aspects of the trial include: 1) the pragmatic integration of study procedures into existing clinical workflow; 2) the use of cluster randomization by hospital or health system; 3) the implementation and evaluation of a system-level intervention for protocol-based care; 4) the use of highly efficient, technology-enabled methods to identify and (passively) enroll participants; 5) reliance on data collected as part of routine clinical care, including data from electronic health records and state cancer registries; 6) linkage with state cancer registries for complete ascertainment of the primary study outcome; and 7) intensive engagement with a diverse group of patient and nonpatient stakeholders in the design and execution of the study.