BACKGROUND:Eftilagimod alpha (efti) is a major histocompatibility complex class II agonist activating antigen-presenting cells which leads to greater systemic type 1 T helper response and more cytotoxic CD8+ T-cell activation. This phase I trial evaluated the administration of efti, a soluble lymphocyte activation gene-3 (LAG-3) protein, combined with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab in advanced solid tumors.PATIENTS AND METHODS:Patients with heavily pretreated metastatic solid tumors received intravenous avelumab (800 mg) combined with subcutaneously administered efti (6 or 30 mg) for up to 12 cycles, followed by avelumab monotherapy. The primary endpoint was the assessment of the recommended phase II dose (RP2D) of efti in combination with avelumab.RESULTS:Twelve patients with different tumor entities were enrolled (six patients in each cohort). During treatment, no dose-limiting toxicities occurred, and the severity of most adverse events was grade 1 or 2. In total, nine serious adverse events were documented, resulting in a fatal outcome in two cases, but none of them were assessed to be treatment related. Five patients (42%) achieved partial response. The median progression-free survival was 1.96 months and the median overall survival was not reached, with a 12-month survival rate of 75%.CONCLUSION:Subcutaneously administered efti plus avelumab was well tolerated, and efti of 30 mg was determined to be RP2D. The activity is promising and warrants further investigation in future phase II trials.

Strata (St) A / B of the INSIGHT study evaluate feasibility of intratumoral (i.t.) and intraperitoneal (i.p.) IMP321 monotherapy in advanced solid tumors. The MHC class II agonist activates antigen presenting cells followed by CD8 T cell activation. This is an investigator-initiated study with currently 4 St: i.t. (A) or i.p. IMP321 (B); s.c. IMP321 with SOC (C) or combined with avelumab (D). Here we focused on St A / B. In St A, patients (pts) received i.t. injections (inj) with IMP321 escalation 6-12-24-30mg in cohort (coh) 1 and the max. tolerated dose (MTD) in coh 2. In St B, pts with peritoneal carcinomatosis received i.p. IMP321 (dose escalation 1-3-6-12-30mg in coh 1 and MTD in coh 2). In both St pts with a benefit after the last inj. were offered s.c. IMP321 for up to 52 weeks. Main endpoint was safety. Recruitment has been completed with 8 pts treated in St A (coh 1: 3 pts. [2 gastric cancer, 1 peritoneal mesothelioma]; coh 2: 5 pts [cancer of head & neck, colon {2}, papilla, lung]) and 4 pts in St B coh 1 (2 gastric, 2 colon cancer). No dose limiting toxicities occurred. 14 serious adverse events (SAEs) have been reported: 8 in St A (2 in 1 pt of coh 1, 6 in 4 pts of coh 2) and 6 in 3 pts of St B coh 1. 1 SAE in coh 2 of St A was related to study procedure (sudden death NOS grade 5). 1 AESI (St A coh 1) probably related to IMP321 (chills grade 3). Of the heavily pretreated pts, 5 had stable disease (SD) (3 gastric, 2 colon cancer), 5 progressive disease (RECIST) and 2 clinical progression. 2 of the SD pts. had PFS of 3mo (1 gastric St A; 1 colon St B) and 2 SD pts. had PFS of 4mo (2 gastric St B). The SD gastric cancer pt of St A with PFS of 3 mo had an OS of 28 mo with increase of PD-L1 in the immune cells from 20% at baseline (BL) to 30% (D29 + D71). 3 SD pts with gastric cancer showed high CD45, CD163 expression at BL (tissue). Blood cytokine profile: 1 SD St B pt showed a significant increase in CXCL10, 4h - 24h after inj. measured on D1/D29, with similar peaks for IFN ɣ, combined with a moderate increase in CD4 and CD8 cells. Increase in IFN ɣ with additional Nk-cells was also seen in 1 SD St A pt. Intratumoral and intraperitoneal IMP321 can be safely administered up to 30 mg with signals of clinical and cytokine activity.

3099 Background: Stratum D of the INSIGHT study investigates the feasibility and safety of s.c. application of IMP321 (eftilagimod alpha) combined with the PD-L1 inhibitor avelumab in advanced stage solid tumors. The MHC class II agonist IMP321 activates antigen-presenting cells followed by CD8 T-cell activation. The addition of avelumab aims at enhancing activity by combining IMP321’s activating effects on immune cells with the release of immune inhibitory effects caused by interruption of the PD-1/PD-L1 axis. Methods: This investigator-initiated phase I trial consists of four strata: intratumoral (A) or intraperitoneal IMP321 (B); s.c. IMP321 with SOC (C) or with PD-L1 inhibition (D). This abstract focuses on Stratum D. Patients (pts) receive 800mg avelumab i.v. q2w along with s.c. IMP321 injections (6mg IMP321 in cohort 1 and 30mg IMP321 in cohort 2). 12 pts are planned in stratum D : 6 pts in cohort 1 and 6 pts in cohort 2. Primary endpoint is safety. Results: So far, 8 pts have been enrolled (6 in cohort 1 and 2 in cohort 2). In 6 pts (cohort 1) treated for different tumor indications (gastric, gallbladder, colon cancer, pleural mesothelioma), no dose limiting toxicities occurred. 3 serious adverse events (SAEs) (1 acute kidney injury grade 5 in 1 pt, 2 preileus grade 3 in 1 pt) were reported, none of them was related to any of the study drugs. In total, 34 adverse events (AEs; grade 1-2, 21; grade 3, 12; no grade 4; grade 5, 1) have been documented in 5 pts. Most common grade 1-2 AEs were pain, nausea, and injection site reaction in 50%, 33%, and 17% of the pts. Most common grade 3 AEs were nausea/vomiting, preileus/ileus, and ascites in 33%, 33%, and 17% of the pts. One AE grade 5 (acute kidney injury) was reported. 4 AEs grade 1-2 were possibly or definitely related to IMP321 (injection site reaction 2x; fever; lipohypertrophy), 6 AEs grade 1-2 were possibly or definitely related to avelumab (nausea 2x; chills; fever; dyspnea; lipohypertrophy). All AEs grade 3-5 were unrelated to any of the study drugs. Of the 8 pts enrolled so far, 4 had disease progression (acc. to RECIST 1.1), 1 partial response, 1 stable disease with some extent of tumor shrinkage, and 2 have not had tumor assessment yet. Conclusions: Combination treatment with avelumab 800mg and IMP321 6mg is safe and well tolerated. Cohort 2 will be presented at the meeting. Clinical trial information: NCT03252938 .