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3552 Background: Delta-like 3 (DLL3) is highly and specifically expressed in solid tumors, such as neuroendocrine carcinomas (NECs), malignant melanoma (MM), and medullary thyroid carcinoma (MTC). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Methods: This Phase 1/2 study (NCT02709889) enrolled patients with relapsed/refractory DLL3+ (>1% by IHC) advanced solid tumors and ECOG performance status of 0-1. Rova-T was given IV at 0.2, 0.3, or 0.4 mg/kg on d 1 of each 6-wk cycle (q6wk) for dose escalation (3+3 design) in disease-specific cohorts in Phase I. The recommended Phase 2 dose (RP2D) was tested in Phase II. Safety and dose-limiting toxicities (DLTs) were primary endpoints; efficacy outcomes were secondary endpoints. Results: The study enrolled 200 patients; 101 had NECs (large cell NEC [n=13], neuroendocrine prostate cancer [n=21], high-grade gastroenteropancreatic NEC [n=36], other [n=31]) and 99 had other solid tumors (MM [n=20], MTC [n=13], glioblastoma [GBM; n=23], other [n=43]). The median age was 61 y (range, 28-84); 63% were male. The RP2D was 0.3 mg/kg q6wk for 2 cycles in all cohorts. There were 7 DLTs in 5 patients: 2 with 0.2 mg/kg (Grade [Gr] 3 photosensitivity reaction, Gr 3 dyspnea), 2 with 0.3 mg/kg (1 with Gr 2 effusion, Gr 3 tumor lysis syndrome, and Gr 3 rhabdomyolysis; 1 with Gr 4 kidney injury), and 1 with 0.4 mg/kg (Gr 4 thrombocytopenia). Despite only 1 DLT identified with 0.4 mg/kg, the totality of the safety data suggested that this dose is not well tolerated. Common adverse events (AEs) in patients given 0.3 mg/kg (n=145) are shown (Table). Serious AEs occurred in 77/145 patients (53%), most commonly (≥3%) malignant neoplasm progression (n=18; 12%), pleural effusion (n=7; 5%), pericardial effusion (n=6; 4%), and dyspnea (n=5; 3%). The objective response rate (ORR) was 11% (21/200): 14 had NEC, 2 had MM, 2 had MTC, 2 had small cell carcinoma (SCC) not of lung origin (all partial responses), and 1 had GBM (complete response). In patients with NECs given 0.3 mg/kg, ORR, clinical benefit rate, and progression-free survival trended in favor of those with high DLL3-expressing tumors (≥50% by IHC) which represented 51% of NECs. Conclusions: Rova-T was tolerable in patients with advanced solid tumors at 0.3 mg/kg q6wk for 2 cycles. Antitumor activity was observed in patients with NEC, MM, MTC, SCC, and GBM. Clinical trial information: NCT02709889 . [Table: see text]

Abstract Purpose Delta-like protein 3 (DLL3) is being developed as a predictive biomarker for DLL3-targeting antibody-drug conjugate and other therapies. Given the neuroendocrine features of Merkel cell carcinoma (MCC), we sought to evaluate DLL3 expression and its role in MCC. Experimental Design Formalin-fixed and paraffin-embedded MCC cases were consecutively selected. Immunohistochemistry was performed for DLL3 (SC16.65 antibody) and polyomavirus large T-antigen (sc-136172 antibody). Slides were read out for percentage of positive tumor cells. Cox proportional hazards model was applied to assess the association between DLL3 expression and overall survival (OS). A patient with a DLL3-expressing MCC was treated with rovalpituzumab tesirine (Rova-T) in the “other tumor” cohort of NCT02709889 and assessed for response. Results The median H-score of DLL3 expression of 65 patients included was 60 (interquartile range, 30–100). Fifty-eight cases (89%) had ≥1% tumor cells positive for DLL3 expression with any intensity, of which the median DLL3 expression was 50% (interquartile range, 25%–70%). Thirty-four cases (52%) had ≥50% tumor cells positive for DLL3 expression with any intensity. Higher H-score of DLL3 expression was associated with higher polyomavirus nuclear expression (p = .003) when it was dichotomized to negative versus positive. H-score of DLL3 expression did not predict OS of patients with MCC (p = .4) after being adjusted for common clinicopathological factors. A patient treated with Rova-T for refractory metastatic MCC achieved partial response. Conclusions DLL3 overexpression is very common in MCC by immunohistochemistry. The response to treatment suggests that DLL3 expression may have predictive relevance for DLL3-targeting therapies in MCC. Implications for Practice Delta-like protein 3 (DLL3) is being developed as a predictive biomarker to identify patients for treatment with DLL3-targeting agents. Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. It was found that DLL3 overexpression is very common in MCC by immunohistochemistry and significantly associated with Merkel cell polyomavirus expression. Despite the lack of prognostic significance in this cohort, DLL3 expression may have predictive relevance for DLL3-targeting therapies in MCC. The high levels of DLL3 expression in a subset of MCC may potentially be used to select patients to receive DLL3-targeting therapies.

Abstract Dendritic cells (DCs) are the most potent antigen-presenting cells which bridges innate and adaptive immunity, but how DC-derived signals regulate and induce T cell lineage choices remains unclear. The p38 MAPK pathway plays an essential role in regulating cellular processes such as cell differentiation, growth, and death. In this study, SB203580 was employed to selectively inhibit p38 pathway in bone marrow derived DCs (BMDCs) to investigate the effects of this pathway on the characteristic phenotype and function of DCs, especially the induction on T helper cell differentiation. We found that inhibition of p38 increased the proliferation of BMDCs, but did not alter their phagocytic ability. Also, inhibition of p38 enhanced the activation of BMDCs, as evidenced by the up-regulated expression of DCs-related surface markers including CD80, CD86 and MHCII. However, the secretion levels of IL-12 and IL-10 in BMDCs were reduced significantly, whereas the level of IL-6 was not influenced by the p38 inhibitor. In addition, we immunized the mice with BMDCs vaccines and studied the production of antigen-specific Th17 T cell in spleen. Our data demonstrated that p38-inhibited DCs vaccine could induce more antigen-specific Th17 T cells than regular DCs vaccine in vivo. Collectively, these results support the hypothesis that the p38 pathway plays a critical role in the immunologic activation of DCs. Our findings suggest that inhibition p38 pathway in DCs may be a new strategy for generating potent DC vaccines for cancer immunotherapy. Citation Format: Yan Luo, Shreeder Barath, Deborah A. Bahr, Navnita Dutta, Geraldine Raja, Martin J. Cannon, Keith L. Knutson. Inhibition of p38 MAPK in dendritic cells enhances their antigen presentation and induces Th17 T cell differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1464.

Abstract Rationale: Epstein–Barr virus (EBV)-related lymphoepithelioma-like cholangiocarcinoma (LELCC) is an extremely rare primary liver tumor with nonspecific clinical manifestations. The clinicopathological features of EBV-associated LELCC have been reported in a few cases. But reports of the tumor's imaging characteristics, particularly ultrasonographic findings, are very rare. Patient concerns: The first patient was a 64-year-old man with left upper quadrant pain and no nausea and dizziness for about 3 months. The second patient was a 40-year-old man, had an incidental finding of a hepatic tumor in a routine health checkup at a local hospital. Diagnoses: In the first patient, the abdominal ultrasound demonstrated a slightly heterogeneous hypoechoic nodule in segment 3 of the liver. The nodule was about 2.0 cm × 1.7 cm in size, with a clear margin and regular shape. Color Doppler flow imaging (CDFI) revealed no blood flow signals in this nodule. According to the clinical information and imaging features, it was difficult to determine the diagnosis of the nodule. In the second patient, gray-scale ultrasound revealed a slightly heterogeneous hypoechoic mass measuring 3.5 cm × 2.5 cm with well-defined margin and regular shape at the superior segment of the left hepatic lateral lobe. There was a blurrily hypoechoic halo around the mass. In contrast-enhanced ultrasound (CEUS), the mass was homogeneous hyperenhancement in the arterial phase. In the portal phase and late phase, the center enhancement of the mass washed out gradually, presenting hypoenhancement, Therefore, the tumor was diagnosed as malignancy. Intervention: Finally, a laparoscopic left hepatic lateral lobectomy was performed in the first patient. The second patient underwent a left hepatectomy with cholecystectomy. Outcomes: The first patient has been alive without recurrence or distant metastases for 11 months since the surgery. The second patient received routine follow-up after surgery. Until now, he has been tumor-free for 32 months. Lessons: We mainly focus on the ultrasound characteristics of EBV-associated LELCC, especially its enhancement patterns on CEUS, which may provide valuable information for diagnosis of the LELCC. When a liver tumor with typical CEUS patterns of malignancy is found in middle-aged adults with EBV positive, the possibility of EBV-related LELCC should be considered.

Introduction Cumulative network meta-analysis (NMA) is a method to provide a global comparison of multiple treatments with real-time update to evidence users. Several studies investigated the ranking of cumulative NMA and the recommendations of practice guidelines. However, to the best of our knowledge, no study has evaluated the cumulative NMA ranking and prescription patterns. Here, we present a protocol for a meta-epidemiological investigation to compare the results of cumulative NMA with the recommendations in postmenopausal osteoporosis practice guidelines and with the actual prescriptions. Method and analysis We will use the data of primary trials from the upcoming postmenopausal osteoporosis clinical practice guideline of the Endocrine Society. We will conduct cumulative NMA using all eligible trials and generate hierarchy of treatment rankings by using the surface under the cumulative ranking curve. We will search practice guidelines in relevant society websites. Two review authors will extract the practice recommendations. We will use data from the Medical Expenditures Panel Survey, a US representative sample of the non-institutionalised population, to determine the prescription patterns. Ethics and dissemination Because all data will be retrieved from public databases, institutional review board approval is not required. We will publish our findings in a peer-reviewed journal and present key findings at conferences. Trial registration number UMIN000031894: Pre-results.