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OS07.4 Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, as monotherapy in epidermal growth factor receptor (EGFR) amplified (EGFRamp), recurrent glioblastoma (rGBM)

ABSTRACT: Abstract Background: Patients (pts) with rGBM have a poor prognosis. EGFRamp is present in ~50% of GBMs. ABT-414 is an ADC that releases a potent toxin, monomethyl auristatin F (MMAF), inside cells with EGFRamp. Here we report the safety and efficacy of ABT-414 monotherapy at the recommended phase 2 dose (RPTD) in EGFRamp, rGBM. Methods: M12-356 (NCT01800695) is an open-label, Phase 1 study with three escalation cohorts. Study design and RPTD was reported previously (ASCO Meeting 2015, SNO Meeting 2015). Sixty pts, all with EGFRamp, rGBM, were enrolled as part of the escalation (12 pts) or expansion (48 pts) cohort treated with ABT-414 monotherapy at 1.25?mg/kg. Adults with measurable (RANO), bevacizumab-naïve, rGBMs with EGFRamp confirmed centrally were eligible. Results: As of March 1, 2016, 60 pts with EGFRamp, rGBM underwent treatment. Median age was 58 years (range, 35–80). Pts underwent 1, 2 (43% each) or 3 (13%) prior therapies. The most common treatment emergent adverse events (TEAEs) (?20% pts) included blurred vision (65%), headache, fatigue (30% each), eye pain and photophobia (28% each). Grade 3/4 TEAEs (>1 pt) were keratitis (13%), corneal epithelial microcysts (8%), blurred vision (5%), dry eye, ulcerative keratitis and reduced visual acuity (3% each). The best RANO responses of 56 pts with complete data were: 3 (5%) partial responses, 24 (43%) stable diseases and 29 (52%) progressive diseases. Median duration of overall response in 3 patients with partial responses was 4.4 months (range, 1.9–5.6). The 6-month progression-free survival (PFS6) estimate was 25.3% [95% CI=14.8, 37.2]. Conclusions: ABT-414 monotherapy displayed frequent but mostly grade 1/2 ocular toxicities. An encouraging PFS6 (25%) was observed in this rGBM population where 56% had ?2 prior therapies. A global randomized trial of ABT-414, alone or with TMZ, vs. TMZ or lomustine, is underway in EGFRamp, rGBM (NCT02343406).

SUBMITTER: van den Bent M

PROVIDER: S-EPMC5463590 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Project description:Abstract Background: Recurrent GBM (rGBM) has dismal prognosis. Almost 50% GBM tumors harbor amplified (amp) EGFR. ABT-414 is a tumor specific ADC combining an antibody targeting a unique conformation of EGFR (ABT-806) to a microtubule cytotoxin, monomethyl auristatin F (MMAF). Here we report the safety and efficacy of ABT-414 monotherapy at recommended phase 2 dose (RPTD) in EGFR amp, rGBM. Methods: M12-356 (NCT01800695) is an open-label, phase 1, 3-arm study: Arm A (ABT-414+radiation/temozolomide (TMZ) in newly diagnosed GBM (nGBM)), Arm B (ABT-414+TMZ in nGBM as adjuvant therapy, or in rGBM) and Arm C (ABT-414 monotherapy in rGBM). Each arm had an escalation cohort to determine the RPTD and an expansion cohort to establish the safety and preliminary efficacy at RPTD. Results of Arm C expansion cohort at 1.25?mg/kg RPTD (IV infusion) are shown here. Eligible patients (pts) were adults with KPS score ?70, EGFR amp (confirmed centrally), rGBM, normal end-organ function and no prior bevacizumab. Results: As of January 7, 2016, 48 EGFR amp, rGBM pts were treated in this cohort. The median age was 59 years (range, 35–80). Most pts had prior therapies: 40% had 1, 48% had 2, 10% had ?3 prior therapies. Most common treatment emergent adverse events (TEAEs) (?25% pts) were blurred vision (60%), headache, photophobia (29% each), dry eye, eye pain, fatigue (27% each). The most common serious AE (>1 pt) was seizure (8%). Grade 3/4 TEAEs (>1 pt) were keratitis (15%), corneal epithelial microcysts (8%), hemiparesis, hyperglycemia, muscular weakness, seizure (6% each), blurred vision, ulcerative keratitis (4% each). No dose-limiting toxicities were reported. Best RANO responses of 44 pts with complete data were: 2 partial responses, 18 stable disease, 24 progressive disease. The 6-month progression-free survival (PFS6) estimate was 30% [95% CI=17, 44]. Conclusions: ABT-414 monotherapy, at 1.25?mg/kg RPTD, displayed frequent yet reversible ocular toxicities. An encouraging tumor stability/response and PFS6 were observed in this highly refractory EGFR amp, rGBM. A global randomized trial of ABT-414, alone or with TMZ, vs. TMZ or lomustine, is underway in EGFR amp, rGBM (NCT02343406).

Project description:BACKGROUND:Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. METHODS:This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. RESULTS:Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional. CONCLUSIONS:Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174-83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Project description:Abstract BACKGROUND Depatuxizumab-mafodotin is an EGFR-directed monoclonal antibody that targets activated EGFR (wild type or EGFRvIII) conjugated to a microtubule inhibitor. EGFRamp correlated with recurrent GBM response in a phase I trial (M12-356, NCT01800695), thus becoming a centrally determined inclusion criterion in an ensuing phase II/III randomized study for newly diagnosed disease now accruing (RTOG 3508, M13-813, NCT02573324). Centrally detected EGFRvIII mutation and MGMT promoter methylation are also stratification factors in RTOG 3508 to balance randomization for biomarkers of potential predictive or prognostic significance. Allowing use of locally determined molecular profiling may reduce accrual barriers by avoiding added time of tissue shipping and repeat central testing. However, discordant results between local and central tests could confound interpretation of clinical trial results. Therefore, we compared local vs. central biomarker results among patients screened for M12-356 or RTOG 3508 at Columbia University Medical Center (CUMC). METHODS We retrospectively tabulated local and central EGFRamp, EGFRvIII, and MGMT results. EGFRamp was analyzed by FISH/CISH and EGFRvIII and MGMT by PCR, although the assays for each differed slightly between laboratories. RESULTS 109 GBMs were molecularly profiled from 73 patients who underwent 1–4 resection(s) and screened for M12-356 (n=44) or RTOG 3508 (n=29) at CUMC. EGFRamp, EGFRvIII, and MGMT promoter methylation each was observed in 54, 36, and 27% of tumors tested locally vs. 68, 33, and 43% centrally, respectively. Concordance between laboratories was observed 88%, 86%, and 61%. CONCLUSIONS EGFRamp and EGFRvIII results were mainly concordant (over 85%) between local and central laboratories. EGFRamp frequency was higher centrally, likely biased by investigators who preferentially sent cases known to harbor EGFRamp locally for central testing. Of concern, MGMT results were discordant in 39%. Allowing local MGMT testing for stratification could unacceptably imbalance randomization if confirmed in a larger dataset.

Project description:Abstract Introduction Liquid biopsy for the detection and monitoring of brain tumors is of significant clinical interest. The ability to non-invasively profile tumors can avoid a risky biopsy and opens avenues for testing novel therapies by accurately stratifying patients to receive the right therapy. Here, we provide evidence of EV RNA-based diagnosis, patient stratification, and assessment of response to therapy in the setting of a clinical trial evaluating the efficacy of dacomitinib, an EGFR tyrosine kinase inhibitor in patients with recurrent, EGFR amplified GBM(NCT01112527). Methods We performed RNASeq on long RNA extracted from the serum samples, pre-treatment and 1-month post-treatment. Results Firstly, longRNASeq allowed the detection of thousands of mRNA, lincRNAs and antisense RNAs enabling the study of a wider repertoire of potential RNA based biomarkers. Secondly, we observed a differential expression profile in serum EV RNA of GBM patients and healthy controls. Combining our findings with TCGA data and literature screening, we generated a 25 gene signature representative of critical pathways in several hallmarks of cancer. Thirdly, we observed a differential expression profile in serum EV RNA of responders to dacomitinib compared to non-responders in pre-treatment serum. Specifically, the EV mRNAs ZNF35 and LAMTOR2 distinguish responders from non-responders (p-adjusted = 2.6E-8 and 2.4E-6, respectively) allowing potential patient stratification. Finally, we observed a differential expression profile in serum EV RNA of responders to dacomitinib compared to non-responders in post-treatment serum. EV mRNA DNMT3A is significantly enriched (p-adjusted = 1.8E-4) in post-treatment serum of responders compared to non-responders to dacomitinib allowing potential monitoring of response to therapy. Conclusion This study represents the first longitudinal profiling of the EV transcriptome in a cohort of genomically selected GBM patients. These findings are a tantalizing step toward liquid biopsy-based biomarkers for the detection of GBM, as well as patient stratification and monitoring.

Dataset Information

OS07.4 Efficacy of a novel antibody-drug conjugate (ADC), ABT-414, as monotherapy in epidermal growth factor receptor (EGFR) amplified (EGFRamp), recurrent glioblastoma (rGBM)

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