IMC-C103C, a MAGE-A4×CD3 bispecific, shows clinical activity and tolerability in advanced solid tumors
Background
Patients with advanced solid tumors often face limited treatment options, especially after prior therapies. The cancer-testis antigen MAGE-A4, presented by HLA-A*02:01, represents a promising target due to its restricted expression in healthy tissues but high prevalence in various malignancies. Current standard-of-care approaches frequently lack the specificity to effectively target these tumor-associated antigens while sparing healthy cells. IMC-C103C, an ImmTAC bispecific T cell engager, aims to bridge this gap by specifically directing T cells to MAGE-A4-expressing tumor cells, offering a novel immunotherapeutic strategy.
Study Design
This phase 1/2 study (IMC-C103C-101; NCT03973333) enrolled 68 patients with HLA-A*02:01+ previously treated advanced solid tumors, with 64% having ovarian carcinoma (OC). Patients received IMC-C103C via weekly intravenous infusion, starting with step-up dosing. Dose escalation, from 0.5 to 240 µg, was guided by the mTPI-2 method. Key objectives were to evaluate safety and preliminary anti-tumor activity, with pharmacokinetics, pharmacodynamics, and biomarker assessments also performed. A lower-dose regimen of 15-45-140 µg was selected for expansion based on activity and tolerability.
Results
IMC-C103C was well tolerated, with no dose-limiting toxicities exceeding the maximum tolerated dose at the two highest levels (1/6 and 2/10 patients). No treatment-related discontinuations or deaths occurred. The most common treatment-related adverse events were cytokine-mediated, primarily grade 1/2 cytokine release syndrome and associated symptoms. MAGE-A4 expression was observed in 71% of patient tumors, though at a low median H-score of 16. Initial clinical and pharmacodynamic activity emerged at doses of 15 µg, becoming more consistent at doses ≥90 µg. At these higher doses, patients with MAGE-A4+ OC showed deeper reductions in tumor size and circulating tumor DNA. Importantly, these patients also trended towards longer overall survival compared to those with MAGE-A4- OC. This suggests a dose-dependent effect and potential efficacy in a specific patient subset.
At doses ≥90 µg, patients with MAGE-A4+ ovarian carcinoma demonstrated deeper tumor reductions and a trend towards longer overall survival.
Key Findings
- IMC-C103C was well tolerated up to 140 µg with no treatment-related discontinuations or deaths.
- No dose-limiting toxicities were observed at the two highest dose levels (1/6 and 2/10 patients).
- Clinical activity was observed at 15 µg and became consistent at doses ≥90 µg.
- MAGE-A4+ ovarian carcinoma patients receiving ≥90 µg showed deeper tumor reductions and a trend towards longer overall survival.
- The most common adverse events were grade 1/2 cytokine release syndrome.
Why It Matters
This first-in-human study provides crucial validation for IMC-C103C as a promising, targeted immunotherapy for MAGE-A4-expressing advanced solid tumors, particularly in ovarian carcinoma where new options are desperately needed. The observed clinical activity and favorable tolerability profile at doses up to 140 µg suggest a viable therapeutic window. While still in early phases, these findings pave the way for further clinical development, potentially leading to a new treatment paradigm for patients with specific HLA and MAGE-A4 profiles. Future protocols will likely focus on optimizing the 15-45-140 µg regimen and exploring combination strategies to enhance efficacy and broaden applicability.
imc-c103c
mage-a4
t-cell-engager
bispecific
solid-tumors
ovarian-carcinoma