A multicenter, phase II trial of GC1118, a novel anti‐EGFR antibody, for recurrent glioblastoma patients with EGFR amplification

Abstract

BackgroundWe evaluated the therapeutic efficacy of GC1118, a novel anti‐epidermal growth factor receptor (EGFR) monoclonal antibody, in recurrent glioblastoma (GBM) patients with EGFR amplification.MethodsThis study was a multicenter, open‐label, single‐arm phase II trial. Recurrent GBM patients with EGFR amplification were eligible: EGFR amplification was determined using fluorescence in situ hybridization analysis when a sample had both the EGFR/CEP7 ratio of ≥2 and a tight cluster EGFR signal in ≥10% of recorded cells. GC1118 was administered intravenously at a dose of 4 mg/kg once weekly. The primary endpoint was the 6‐month progression‐free survival rate (PFS6). Next‐generation sequencing was performed to investigate the molecular biomarkers related to the response to GC1118.ResultsBetween April 2018 and December 2020, 21 patients were enrolled in the study and received GC1118 treatment. Eighteen patients were eligible for efficacy analysis. The PFS6 was 5.6% (95% confidence interval, 0.3%–25.8%, Wilson method). The median progression‐free survival was 1.7 months (range: 28 days–7.2 months) and median overall survival was 5.7 months (range: 2–22.0 months). GC1118 was well tolerated except skin toxicities. Skin rash was the most frequent adverse event and four patients experienced Grade 3 skin‐related toxicity. Genomic analysis revealed that the immune‐related signatures were upregulated in patients with tumor regression.ConclusionThis study did not meet the primary endpoint (PFS6); however, we found that immune signatures were significantly upregulated in the tumors with regression upon GC1118 therapy, which signifies the potential of immune‐mediated antitumor efficacy of GC1118.

Epidermal Growth Factor Receptor Inhibitors in Glioblastoma: Current Status and Future Possibilities

“…Similar to gefitinib, it was found that GC1118 effectively targeted tumor tissue and upregulated immune signatures. However, alone it was not enough to improve progression-free survival (PFS) because of tumor evolution affecting drug efficacy and an insufficient suppression of growth pathways (Table 1) [62]. These findings further suggest the need for a strong, synergistic inhibition of downstream EGFR growth pathways and the need for new TKIs that specifically target ECD variants in glioblastoma.…”

Glioblastoma Therapy: Past, Present and Future

“…ZD9291/BEV combination was marginally effective in most rGB patients with simultaneous EGFR amplification and EGFRvIII mutation, but it is interesting to mention that OS was superior to regorafenib (7.4 months) and a subgroup experienced a long-lasting meaningful benefit [ 533 ]. Several anti-EGFR monoclonal antibodies, such as cetuximab, GC1118, ABT-806, ABT-414 and nimotuzumab ( Table 3 and Figure 3 ) failed in clinical trials to increase OS in GB patients [ 423 , 424 , 429 , 430 , 451 , 534 , 535 ]. Depatuxizumab mafodotin (depatux-M, ABT-414) is a tumor-specific antibody–drug conjugate comprising ABT-806 and the toxin monomethyl auristatin-F.…”

Revolutionizing Brain Tumor Care: Emerging Technologies and Strategies

“…The new selective and highly potent small-molecule EGFR inhibitor with improved CNS penetration, ERAS-801, has received FDA clearance in 2021. ERAS-801 is currently being evaluated in patients with recurrent GBM (NCT05222802) [ 125 ]. In patient-derived GBM models, ERAS-801 showed a survival benefit of 93% in EGFR mutant and/or amplified models, significant brain penetrance, and prolonged survival compared to previously approved EGFR-tyrosine kinase inhibitors like erlotinib ( Figure 1 ).…”