First-in-human phase Ib trial of M9241 (NHS-IL12) plus avelumab in patients with advanced solid tumors, including dose expansion in patients with advanced urothelial carcinoma

Abstract

BackgroundIn preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab.MethodsIn the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1–4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated.ResultsAt data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug–drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges.ConclusionsM9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.

Preclinical and clinical studies of a tumor targeting IL-12 immunocytokine

“…In a phase 1b study (NCT02994953), patients with locally advanced or metastatic solid tumors treated with NHS-IL12 and avelumab experienced clinical responses, with some patients achieving prolonged clinical benefit; notably two patients with advanced bladder cancer experienced prolonged complete responses. The safety profile was similar to that observed with individual agents (58).…”

“…Multiple preclinical and clinical studies have demonstrated the tumor suppressive ability of NHS-IL12 as a single agent ( 22 , 35 – 37 , 56 ). Mounting preclinical and clinical evidence supports the use of NHS-IL12 as an integral component of combination therapies for the treatment of solid cancers, including in combination with immune checkpoint blockade and other treatment modalities ( 35 , 40 , 43 , 45 , 46 , 52 , 53 , 58 , 60 , 61 ). A unique aspect of NHS-IL12 versus rIL-12 is its ability to localize to the tumor, thereby eliciting local IFNγ production via activation, maturation, and expansion of NK and CD8 + TILs.…”

“…These findings underscore the importance of targeting different components of the TME for an effective cancer therapy involving NHS-IL12. In one example, in a phase 1b study (NCT02994953), patients with metastatic solid tumors treated with NHS-IL12 and avelumab experienced clinical responses, with some patients achieving prolonged partial and complete responses ( 58 ).…”

Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory

“…This was not the case for VLV-IL-17ECD and VLV-shRNA PDL-1 (data not shown). Although treatment with IL-12 alone represents an ideal approach for tumor immunotherapy due to its ability to activate cytotoxic T lymphocytes (39-45), it had modest effects in clinical trials (46,47). Indeed, when we compared the immunological changes induced by CARG-2020 and VLV-IL12, we observed major differences in the regulation of M1/M2 macrophages and MDSCs.…”

A phase I trial of SON-1010, a tumor-targeted, interleukin-12-linked, albumin-binding cytokine, shows favorable pharmacokinetics, pharmacodynamics, and safety in healthy volunteers

“…The MTD of NHS-IL12 was determined to be 16.8 μg/kg, which is much higher than the MTD for rIL-12 of 0.5 to 1 μg/kg, suggesting the possibility of steric hindrance of the cytokine portion of NHS-IL12. Note that NHS-IL12 was originally administered every 4 weeks as monotherapy and is currently being developed in combination with a checkpoint inhibitor given every 2 weeks ( 40 ).…”