IMPORTANCENeuroendocrine neoplasms (NENs) have historically been grouped homogenously in clinical trials, despite their heterogeneity. Given the adoption of a more advanced pathologic classification system and drug licensure of several targeted therapies over the last decade, information is needed on whether study characteristics of NEN studies have evolved. OBJECTIVE To assess changes in study design, eligibility, accrual, sponsorship, and outcomes between phase II or III NEN clinical trials that began enrollment from 2000 to 2009 vs 2010 to 2020. DESIGN, SETTING, AND PARTICIPANTS This quality improvement study used a systematic survey of completed studies published between January 1, 2000, and December 31, 2020. Therapeutic phase II and III NEN studies were identified through a database search of Medline (via PubMed), EMBASE (OvidSP), Cumulative Index of Nursing and Allied Health Literature (EBSCOhost), Web of Science (Clarivate), Cochrane Database of Systematic Reviews (Wiley), ClinicalTrials.gov (National Institutes of Health), EU Clinical Trials Register, and National Cancer Institute Clinical Trials. Data were analyzed between March and June 2021. MAIN OUTCOMES AND MEASURES Study characteristic proportions between the 2 enrollment periods. RESULTS Of 3243 identified studies, 119 studies met criteria for inclusion, of which 117 studies (54 studies that began enrollment between 2000-2009 and 63 studies that began enrollment between 2010-2020) included exact dates of enrollment and were compared. Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were less likely to include all NENs (13 studies [21%] vs 34 studies [63%]; P < .001) and more likely to include select NENs (eg, gastrointestinal neuroendocrine tumors, 25 studies [40%] vs 11 studies [20%]; P = .02; pancreatic neuroendocrine tumors, 32 studies [51%] vs 16 studies [30%]; P = .02). Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were more likely to specify tumor differentiation (59 studies [98%] vs 34 studies [63%]; P < .001) or Ki-67 index (23 studies [38%] vs 5 studies [9%]; P < .001) in inclusion criteria. Studies that began enrollment after 2010, compared with studies that began enrollment from 2000 to 2009, were more likely to use progression-free survival (22 studies [35%] vs 9 studies [18%]; P = .04) rather than objective response rate (19 studies [30%] vs 27 studies [53%]; P = .01) as a primary or coprimary end point. CONCLUSIONS AND RELEVANCE These findings suggest that NEN trials enrolling over the last decade were more focused on select tumor populations, compared with studies that began (continued) Key Points Question Have study characteristics of studies in patients with neuroendocrine neoplasms (NENs) changed over the last 2 decades (2000-2009 vs 2010-2020)? Findings In this quality improvement study, 119 therapeutic phase II and III studies were identified after conducting a systematic survey of NEN studies completed between Jan...

e16216 Background: Vascular endothelial growth factor mediated signaling is central to NETs. As such, multiple avRTKIs have been tested in NETs over the last 2 decades, mostly in small phase II studies. In fact, there have been no randomized phase III trials conducted in United States apart from the one leading to approval of sunitinib in pancreatic (p) NETs. Several other avRTKIs have demonstrated clinical promise including surufatinib in phase III trials conducted in China; this drug is currently under FDA review for potential approval. In the current SRMA, we aim to address this deficiency by benchmarking efficacy and safety profiles of avRTKIs. Methods: A literature search was done to identify all phase II and phase III studies of avRTKIs in pts with NETs published between 1/1/2000–7/31/2021. Data abstraction was performed by one author and validated by another. Efficacy was assessed by aggregating progression-free survival (PFS) and overall response rate (ORR) data. PFS and ORR were assessed using a random effects model separately for pts with pNETs and extra-pancreatic (ep) NETs. Toxicity was assessed by calculating the relative risk (RR) compared to control arm and incidence of adverse events (AEs) of interest. Results: Of 92 identified studies, 17 (with 8 individual avRTKIs) were included in the meta-analysis after excluding redundant studies; baseline study characteristics are listed in the Table.A total of 1611 pts (853 men, 758 women) were available for the analysis; 1194 received avRTKIs. The ORR in pNETs was 18% (95% confidence interval (CI) 13-25%) while the ORR in pts with epNETs was 8% (95% CI 5-12%); test for differences between pNETs and epNETs (x12 = 8.47, p < .01). The median PFS in pNETs was 13.9 months (95% CI 11.43-16.38 months) while median PFS in epNETs was 12.71 months (95% CI 9.37-16.05 months); test for differences between pNETs and epNETs (x12 = .32, p = .57). The incidence (and RR compared to control) of most common ≥ grade 3/4 AEs were hypertension 22.4% (4.48, p < .001), diarrhea 6.4% (RR 3.03, p = .005), neutropenia 5.2% (20.4, p = .036) and proteinuria 4.6% (27.25, p = .001). Incidence (and RR compared to control) of rare but serious complications included non-central nervous system bleeding 8.7% (2.17, p < .001) and cardiac dysfunction 6.4% (2.52, p = .01). Conclusions: Among pts tx with avRTKIs, pts with pNETs demonstrated improved ORR but not PFS compared to these outcomes in pts with epNETs. In addition, this study also benchmarks the incidence and RR of AEs in pts with NETs treated with avRTKIs who are often on therapy longer than other pts.[Table: see text]

e13603 Background: In the era of PO, systemic therapies for patients (pts) with solid tumors have fundamentally changed from chemotherapy (CT) to targeted therapy (TT) and immunotherapy (IO). No study to the best of our knowledge has described PHIstt in this era. In this systematic survey, we describe the evolving features of PHIstt which began enrollment between 2010-2020, focusing on type of dose escalation scheme (DES) utilized, use of expansion cohorts (ECs) and nature of adverse events (AEs). Methods: The primary aim was to estimate the proportion of PHIstt which used rule-based DES. A literature search was performed by a biomedical librarian to identify PHIstt in adult patients published between January 1, 2000 – December 31, 2020 from a selection of 12 journals that publish PHIstt. However, we included studies enrolling between 2010-2020 to better capture agents in the PO era. We included trials with both single and multiple agents, and single and multiple modalities if the systemic therapy tested was being escalated. We excluded studies which only included intra-tumoral therapy, radiation therapy, or supportive care. Two reviewers assessed studies for inclusion and performed data abstraction; a 3rd reviewer established concordance. Results: Of 10,744 studies retrieved, 10,195 were non-topical or began enrollment prior to 2010; 437 studies in pts aged ≥ 18 years with advanced solid tumors were included. A median of 31 pts were enrolled per study (IQR 19-50), with median age 60 years in escalation cohorts. In studies reporting pt sex, 45.7% were female, and 53.9% were male. The most common classes of therapeutics were TT (47.6%), IO (22%), and CT (6.9%). Only 40.1% of studies reported ECs in the primary paper, and 46.6% of ECs used genomic selection. Rule-based designs (which assign patients to dose levels based upon prespecified rules of actual AE observations) were used in 89% of PHIstt; a 3+3 DES was used in 80.5% of these studies. With regards to grade 3/4 AE reporting, 56.6% of studies reported treatment-related AEs, 21.3% reported treatment-emergent AEs and 10.7% did not specify how they were reported. The most common class of grade 3/4 AEs was hematologic (37.1%). The most common dose-limiting toxicity classes were other (64.6%) and gastrointestinal (16.9%). Of all the drugs tested in PHIstt, 37.5% were tested subsequently in phase II while 10.3% garnered licensure. Conclusions: There is room for improvement in the trial design of PHIstt which may lead to more regulatory success. Some areas we identified include the more regular adoption of genomically selected ECs, more consistent reporting of AEs and diversification beyond rule-based designs to better assess safety/efficacy profiles of non-CT agents. Dose-Escalation Designs. [Table: see text]