ACTR-55. TUMOR VOLUME AS A PREDICTOR OF RESPONSE TO ANTI-EGFR ADC ABT-414 Free

Adverse biophysical factors (abnormal vessels and increased interstitial pressure) are increased in larger brain tumors, which negatively impacts penetration of antibody drug conjugates (ADC). The tumour-specific anti-EGFR ADC, depatuxizumab mafadotin (depatux-m), demonstrated encouraging activity in a Phase 1 glioblastoma study (M12-356 study, NCT01800695). The impact of tumour size on depatux-m efficacy was investigated. PRECLINICAL STUDY: Forty mice were engrafted with patient derived xenografts from an M12-356 patient. Eight mice were imaged in a zirconium-labelled depatux-m (3mg/kg) biodistribution study at small (70mm3,n=2) or large (350mm3,n=2) tumour volumes; another 4 mice were imaged with a control ADC. In the controls, non-specific uptake due to blood pool activity was 5% ID/g. In the 89Zr-depatux-m treated groups, mice with larger tumours had significantly less uptake compared smaller tumours (11 vs 21 %ID/gram, p<0.0001). Similarly, tumour inhibition due to depatux-m (3mg/kg every 3 days for 3 weeks, n=16 mice) was significantly less when treatment commenced at larger volumes (27% vs 93%, p<0.001). CLINICAL STUDY: To confirm our preclinical data, two reviewers (EL, AS) retrospectively undertook a blinded volumetric analysis of baseline tumor volumes in M12-356. Inter-rater agreement was excellent. Response was compared by chi-square analysis and OS by log-rank. 110 patients with EGFR-amplified, recurrent glioblastoma were treated with depatux-m, alone or in combination with temozolomide. Patients with larger tumours had significant worse response rates (0% in > 25cm3 vs 17% in < 25cm3, p=0.009) and worse overall survival (0.52 vs 0.81 years, p=0.001). The results were similar in patients treated with depatux-m monotherapy for response (n=60, 0% vs 10%, p=0.287) and survival (n=62, 0.50 vs 0.89 years, p=0.001)

Increased tumour volumes results in significant reduction in ADC penetration. The impact of this as a modifiable factor, within the broader prognostic impact of increased tumour volume, warrants further investigation with prospective and/or randomized data.