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2635 Background: Immune Checkpoint Inhibitors (ICIs) are associated with unique immune-related adverse events (irAEs). IrAEs can occur at any timepoint of ICI treatment. Late irAEs are not well reported in the literature. Herein, we attempt to characterize irAEs that occur 6-month, one year and two years after ICI treatment initiation. Methods: We identified patients treated with ICIs (anti-CTLA-4, anti-PD(L)-1 either alone or in combination or with chemotherapy) across Hackensack Meridian Health hospital and MedStar Georgetown University Health systems from 12011 to 4/2018. Patients' baseline demographics, treatment history, and irAEs were collected from EHR. CTCAE V4.03 was used to grade irAEs. Results: We identified 1332 patients treated with 1443 unique ICIs. The ICI therapies were nivolumab 38% (543), pembrolizumab 23% (332), ipilimumab plus nivolumab 12% (180), ipilimumab 11% (161), Atezolizumab 3% (47) and others 13% (180). Tumor types were lung cancer 34% (496), melanoma 27% (389), GI cancers 6% (92), kidney cancer 6% (87), and other cancers 26% (379). The median age was 66 (21-87), age >75 37% (541), Caucasian 67% (970). We identified a total of 911 any grade irAEs among 37% (552) therapies. Among, 911 irAEs, grade 1-2, grade ≥3 and unknown grade irAEs were 39% (572), 12% (182) and 11% (157), respectively. The most common any grade irAEs were skin rash 22% (202), colitis 13% (120), and hepatitis 12% (108). 84% of all irAEs and 85% of ≥ Grade 3 irAEs occurred within 6 months of treatment initiation. Of the 350, patients on active treatment at six months, 37 % (132) and 7% (26) developed any grade and grade ≥3 irAEs, respectively. irAEs that had > 10% of their occurrences after six months were skin rash and colitis 14% each. Other common irAEs were hypothyroidism, hepatitis, joint pain, pruritis and pneumonitis at 7% each. Among 170 patients on active treatment at one year, 37% (62) and 7% (12) developed any grade and grade ≥3 irAEs respectively. irAEs with >10% incidence after one year of treatment were rash 19% and hepatitis 13%. Conclusions: Our RWE findings suggest although 85% irAEs occurs within the first six months of treatment, late irAEs can occur with ICI treatment. The incidence and pattern of late irAEs appears similar to early irAEs, (e.g., skin rash, colitis, hypothyroidism and hepatitis) with pneumonitis being a notable exception. It is uncertain if these results will be influenced by changing patterns of ICI use (e.g. different diseases and/or regimens) over time.[Table: see text]

2641 Background: Immune Checkpoint Inhibitors (ICI) have revolutionized current cancer treatment. Nevertheless, outcomes data across various patient cohorts are lacking. To address this knowledge gap, we conducted a comprehensive analysis of real-world data (RWD) that included patient cohorts traditionally underrepresented in clinical trials. Methods: We identified patients (pts) treated with ICI (anti-CTLA-4, anti-PD(L)1 or their combination at 6 US academic and community hospitals from 1/2011 – 4/2018. Clinical data obtained from EHR and CTCAE V4.03 was used to define immune-related adverse events (irAEs). Results: A total of 1332 pts treated with 1443 unique ICI treatments were included in the cohort. The median age was 66 (21-87), Male 58% (827), Caucasian 70% (1004), African American (AA) 16% (232), other race 14% (207), ECOG PS 0,1 79% (1130), chronic viral infection 5% [hepatitis B (24), hepatitis C (32) and HIV (17)], with BMI > 30 22% (287) and autoimmune disease (AID) 15% (215). Lung cancer (NSCLC) 34% (423), and melanoma 27% (389) were top 2 tumor types and nivolumab 38% (544), pembrolizumab 23% (332), and ipilimumab plus nivolumab 12% (180) were the most common ICI treatments. Overall survival (OS) was worse for patients with ECOG ≥2 (0.34 - 0.63) vs. ECOG 0,1 (1.27 - 1.73, P 75 27% (120), AA 28% (124), Female 50% (224), ECOG PS ≥2 23% (104), BMI >30 15% (62), chronic viral infections 10% (44), and AID 14% (62). The ICI therapies were nivolumab 55% (245), pembrolizumab 23% (102), and atezolizumab 6% (27) and 16% (others). Data is contained in the table. Conclusions: Overall, in our RWD, OS appeared to be similar across above cohorts except poor OS for pts with ECOG ≥2. irAEs also appeared to be similar across cohorts except less with ECOG ≥2. In NSCLC cohort, we noted similar findings except less irAEs in Male cohort. Prospective studies are needed to confirm the above findings.[Table: see text]

TPS2640 Background: AKT is a frequently hyperactivated oncogenic kinase in human cancers (Degenhardt 2006). Inhibition of AKT activates autophagy, promoting tumor survival, and hence AKT inhibitors...

2553 Background: Angiogenesis inhibitors promote autophagy, a response to nutrient deprivation in which autophagosomes (AP) and lysosomes fuse to recycle intracellular constituents, leading to sustained tumor viability. We hypothesized that the VEGF-R2, c-kit, PDGFR inhibitor Su induces autophagy. The autophagy inhibitor HCQ may then interfere with autophagy dependent tumor survival, possibly improving patient (pt) outcomes. Methods: This trial determined the MTD of Su+HCQ in pts with advanced malignancies using a 3+3 design. Su 50 mg qd was given in 4 week on/2 week off cycles (C) with daily HCQ in escalating dose cohorts. A MTD expansion cohort of 12 pts was also enrolled. Modulation of autophagy was measured by changes in the AP marker light chain-3 (LC3)II/I ratio in paired PBMC samples from C1 and C2. Results: 21 pts, median age 59, PS 0 (7), 1 (13) or 2 (1) enrolled, including 5 colon, 2 renal and 5 sarcomatous tumors. 4 DLTs were observed: 3 DLTs (gr 3 confusion, gr 3 colon fistula, gr 3 thrombocytopenia) in DL2 (50 mg Su, 200 mg bid HCQ), and 1 DLT (gr 3 dehydration) in DL1 (50 mg Su, 200 mg HCQ). DL1 was thus declared the MTD. Gr 3/ 4 toxicities included: related to Su, thrombocytopenia (14%), fatigue (19%), neutropenia (14%), hypertension (14%), intestinal perforation (10%); related to HCQ, fatigue (14%). PK data of Su alone, its active metabolite SU012662 and the total were evaluated using noncompartmental analysis. Cmax and AUCs of the active metabolite SU012662 significantly increased (p 3 cycles (median 73 days). Inconsistent autophagy modulation was seen in PBMCs. LC3 immunohistochemistry on baseline tumor blocks to assess individual tumor autophagy levels is in progress. Conclusions: pK interaction between Su and HCQ resulting in accumulation of Su metabolites may be responsible for the predominantly Su-associated toxicities observed which prohibited further HCQ dose escalation. Lack of evidence for autophagy modulation is likely due to the inability to escalate HCQ to doses necessary to induce autophagy inhibition. Further study of this combination seems unwarranted. Clinical trial information: NCT00813423.

TPS3112 Background: Metabotropic glutamate receptor 1 (GRM1) has been identified as a potential therapeutic target in melanoma. Over 60% of human melanomas express this cell surface glutamate receptor and excitation of GRM1 results in the activation of MAPK and PI3K/AKT pathways. Riluzole, an oral GRM1 blocking agent, results in growth arrest of melanoma cells in vitro and in vivo. We previously reported that administration of riluzole to melanoma patients suppressed activity of the PI3K/AKT and MAPK pathways in paired tumor samples (Yip Clin Cancer Res 2009). In preclinical studies, the efficacy of riluzole was attenuated in melanoma cells harboring BRAFV600E mutations, but sorafenib, a RAF kinase inhibitor, enhanced the effect of riluzole on these cells. The combination of riluzole and sorafenib was additive or synergistic in both BRAF mutant and BRAF wildtype melanoma cells in vitro and in BRAF wildtype cells in a xenograft model (Lee HJ Clin Cancer Res 2011). We thus designed a phase I trial to test the combination of riluzole with sorafenib in patients with solid tumors and advanced melanoma. Methods: The primary objective of this trial is identification of the maximum tolerated dose (MTD). An expansion cohort at the MTD is planned for patients with advanced melanoma to examine the correlation of clinical or radiographic response with signaling through the MAPK and PI3K/AKT pathways and with GRM1 receptor status of individual tumors. Eligible patients must have advanced solid tumors (phase I) or stage III unresectable/stage IV melanoma with biopsiable tumor (expansion cohort) and ECOG PS ≤ 2. Riluzole will be administered at 100 mg twice daily combined with sorafenib beginning at 200 mg daily and escalating in subsequent cohorts at 200 mg increments. Correlative studies: Tumors will be assessed for BRAF and NRAS mutational status. Pretreatment tumor blocks will be examined for GRM1 receptor status by immunohistochemistry. Pre and post treatment levels of pERK and pAKT will be measured in paired tumor samples to assess effects of treatment on MAPK and PI3K signaling. Limited sampling pharmacokinetic studies will be performed. Progress: Accrual to three cohorts is complete without DLT. Accrual to the final planned cohort is in progress.