e21552 Background: IL-2R agonists that are well tolerated and can selectively enhance immune activation may improve outcomes of patients with cancer. ANV419 is a potent and highly selective IL-2Rβγ binding agonist, consisting of an antibody specific for the IL-2Rα-binding domain of IL-2, fused to native hIL-2. It is currently being investigated in a phase I/II dose finding study in patients with relapsed/refractory advanced solid tumors (ANV419-001). The primary objective of ANV419-001 is to describe the safety and tolerability of ANV419. Methods: ANV419 is administered intravenously over 15 minutes every 2 weeks, without premedication. Thirteen patients with melanoma (cutaneous (n = 3), uveal (n = 2), mucosal (n = 2), choroidal (n = 1)), renal cell carcinoma (n = 1), hepatocellular carcinoma (n = 1), colorectal cancer (n = 1), esophageal adenocarcinoma (n = 1) and adenoid cystic carcinoma (n = 1) have been dosed in six cohorts. Patients received 3mcg/kg (n = 1), 6mcg/kg (n = 1), 12mcg/kg (n = 1), 24mcg/kg (n = 4), 48mcg/kg (n = 3) 72mcg/kg (n = 3) and 108 mcg/kg (ongoing) of ANV419. Results: ANV419 is well tolerated, all related AEs are Grade 1 or Grade 2 and no DLTs have been observed. Most patients experienced chills (G1), with or without low-grade fever (G1), 2-4 hours after post- infusion, which resolved with antipyretic treatment. Two G2 AEs related to ANV419 have been reported in two patients. One patient was reported to have G2 Cytokine Release Syndrome (hypotension (G2), fever (G1), chills (G1)) and one patient experienced transient, self-limiting G2 elevation of liver function tests. Four Serious Adverse Events were reported in three patients (urinary tract infection, lethargy, thoracic pain and abdominal pain), none of which were considered related to ANV419. Pharmacodynamic evaluation on day 4 post-dosing, showed an effector cell selective, dose dependent increase of Ki-67 positive CD8 T cells (2%, 14%, 37%, 62%, 62%, vs. baseline mean (BLM) 2%) and NK cells (30%, 62%, 75%, 85%, 80%, vs BLM 6%) with a dose independent frequency of Ki67+ Tregs ranging from 4% to 25% (BLM 7%) at 3, 6, 12, 24 and 48 mcg/kg doses respectively. At 72mcg/kg mean CD8 T cell and NK proliferation was 70% and 51% respectively, while the mean Treg proliferation increased to 48%. Pharmacokinetic data (including patients treated with up to 24 mcg/kg ANV419) show a dose proportional increase of the ANV419 plasma concentration. The estimated half-life at the 24mcg/kg dose is 17.6 hrs. Four patients continue to receive ANV419. Of the 11 patients who received at least two cycles of ANV419, 4 were assessed to have stable disease. One patient progressed after 24 weeks of confirmed stable disease. Conclusions: Overall, ANV419 is well tolerated and selectively induces expansion and proliferation of CD8 T cells and NK cells, but not Tregs up to a dose of at least 48mcg/kg. Updated data will be shared during the meeting. Clinical trial information: NCT04855929.

9018 Background: VS-6766 is a small molecule RAF/MEK clamp that results in the reduction of p-MEK and p-ERK. Preclinical data show synergy of VS-6766 with the mTOR inhibitor everolimus across a panel of KRAS mutated (mt) NSCLC cell lines. This clinical trial evaluated the safety and efficacy of a novel intermittent regimen of VS-6766 and everolimus with an expansion in KRAS mt NSCLC (NCT02407509). Methods: The trial used a 3+3 dose escalation design with an intermittent once a week schedule A, and if tolerated, twice a week schedule B (Mon-Thu or Tue-Fri) for both drugs on a 3 weeks on/1 week off, 28 day cycle. Patients with RAS or RAF mt cancers were eligible for the dose escalation cohort, and 20 patients with KRAS mt NSCLC will be treated in the dose expansion cohort. Toxicity was evaluated by NCI CTC V4 and efficacy was evaluated using RECIST 1.1. Results: A total of 28 patients have been treated; median age 60 yrs (range 36-78), and median lines of previous treatment 3 (range 0-7). Sixteen patients have been treated in the dose escalation (3 in schedule A and 13 in the schedule B). The doses of 4 mg of VS-6766 and 5 mg everolimus (once weekly) were tolerated with no dose limiting toxicities (DLTs) and the dose intensity escalated to schedule B (twice weekly). At 4 mg VS-6766 twice weekly, DLTs were observed in two out of six patients and included grade 4 CPK elevation and grade 3 rash. Thus, the dose in schedule B (twice weekly) was de-escalated to 3.2 mg VS-6766 and the dose of everolimus was kept at 5 mg. No DLTs were reported in 6 patients and thus this was declared as the recommended phase 2 dose (RP2D). At the RP2D, the grade 3-4 drug related AE were rash (18%) and pruritus (7%). In the dose escalation cohorts, 3 partial responses (PRs) were reported (2 KRAS G12D low grade serous ovarian cancer and 1 NRAS Q61K mt thyroid cancer). In the KRAS mt NSCLC expansion cohort, 10 patients are evaluable for efficacy and 2 confirmed responses were reported ( KRAS mutations G12V and G13A) with an objective response rate (ORR) 20% to date. The disease control rate (PR + SD) at the first scheduled evaluation was 90%. The median progression free survival (PFS) in the KRAS mt NSCLC cohort is 6.35 months (95% CI 3.52 – not reached). Updated ORR and PFS data will be presented. Conclusions: A tolerable intermittent dosing schedule targeting both the MAPK and PI3K pathways has been established. The combination of VS-6766 with everolimus has shown activity in patients with a variety of KRAS mutation variants including responses in KRAS mt NSCLC.

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