Depatuxizumab mafodotin improves PFS, but not OS in EGFR-amplified glioblastoma

Interim analysis of a phase III randomized clinical trial shows that the addition of depatuxizumab mafodotin (depatux-m) to standard chemotherapy improves progression-free but not overall survival (OS) in patients with newly diagnosed glioblastoma (GBM) habrouring EGFR gene amplification (EGFR-amp).

Approximately 50 percent of newly diagnosed GBMs harbour EGFR-amp. [Clin Cancer Res 2019;25:3259-3265] Among these cases, half of the tumours have EGFR variant 3 (EGFRvIII) mutation, which produces a constitutively active form of the EGFR receptor. [FEBS J 2013;280:5350-5370] Depatux-m is an antibody-drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule cytotoxic payload, monomethyl auristatin F (mafodotin). [Cancer Res 2012;72:2924-2930; Mol Cancer Ther 2016;15:661-669] After binding to activated EGFR, the antibody and linked payload are endocytosed and degraded, releasing the toxin, which causes cell death. [Neoplasia 2007;9:1099-1110]

Present phase III trial, INTELLANCE-1, was conducted on the basis of encouraging preclinical and early-phase clinical data as well as the trend towards longer OS with depatux-m observed in the concurrent phase II INTELLANCE-2 trial of depatux-m in recurrent GBM with EGFR-amp. [Mol Cancer Ther 2016;15:661-669; Neuro-Oncology 2020;22:684-693]

In INTELLANCE-1, patients with EGFR-amp newly diagnosed GBM (n=639; median age, 60 years; range, 22–84 years; male, 62 percent) were randomized 1:1 to radiotherapy (RT), temozolomide (TMZ) and depatux-m or RT, TMZ and placebo. [Neuro Oncol 2023;25:339-350]

After median follow-up of 18.1 months among 293 surviving patients, there was no OS improvement with depatux-m vs placebo (median, 18.9 months vs 18.7 months). As the primary analysis for OS failed to demonstrate a significant difference between arms, subsequent endpoint analyses were exploratory. Progression-free survival (PFS) was longer with depatux-m vs placebo (median, 8.0 months vs 6.3 months; hazard ratio [HR], 0.84; 95 percent confidence interval [CI], 0.70–1.01; one-sided p=0.029), which was driven at least in part by the EGFRvIII-mutant subgroup (median, 8.3 months vs 5.9 months; HR, 0.72; 95 percent CI, 0.56–0.93; one-sided p=0.002). By contrast, there was no difference in PFS between depatux-m and placebo in patients without EGFRvIII mutation (median, 6.9 months vs 7.9 months; HR, 1.01, 95 percent CI, 0.76–1.33; 1-sided p=0.61).

“Despite encouraging preclinical and early-phase clinical data, it is possible that depatux-m is simply ineffective for treating GBM. Other potential biologic explanation is the possibility that depatux-m effectively killed off EGFR-amp [and particularly, EGFRvIII-mutant] tumour cells, lengthening PFS, but resistant clones emerged and voided any OS benefit,” commented the researchers.

Consistent with prior reports, the most common adverse events observed in depatux-m group were ocular. For example, corneal epitheliopathy (CE) of any grade and grade 3–4 occurred in 94 percent and 61 percent of patients on depatux-m, causing 12 percent of patients to discontinue treatment. Surprisingly, CE was also reported in 36 percent of patients in the placebo arm. CE of all grades was managed by a combination of both prophylactic and supportive measures and by dose interruptions or delays (44 percent). Thrombocytopenia was also more commonly observed among patients randomized to depatux-m than placebo (any-grade, 61 percent vs 36 percent; grade 3–4, 28 percent vs 12 percent).