Immune checkpoint inhibiting antibodies have antitumor activity across several tumor types, but can also elicit immune-mediated adverse events (imAEs). CX-072 is an investigational antibody prodrug (Probody™ therapeutic), reactive to the murine and human programmed death-ligand 1 (PD-L1) immune checkpoint. CX-072 can be activated to a fully avid antibody by tumor-associated proteases that remove the masking peptides blocking the antigen-binding domain, which may limit peripheral PD-L1 binding and therefore imAEs. CX-072 was radiolabeled with zirconium-89 (89Zr) to study its biodistribution and tumor- versus lymphoid tissue-targeting properties using positron emission tomography (PET).
CX-072, non-specific Probody™ therapeutic control (PbCtrl) and CX-072 parental antibody (CX-075) were radiolabeled with 89Zr. Human PD-L1-expressing MDA-MB-231 tumor-bearing BALB/c nude mice received 10 μg 89Zr-CX-072, 89Zr-PbCtrl or 89Zr-CX-075 (∼5 MBq) supplemented with 0, 40 or 240 µg of respective unlabeled antibody. Biodistribution was also evaluated in C57BL6/J mice bearing PD-L1-expressing MC38 syngeneic colon adenoma tumors. Mice underwent PET scans 1, 3 and 6 days post intravenous injection (pi), followed by ex vivo analysis.
In MDA-MB-231 tumors, 89Zr-CX-072 and 89Zr-CX-075 showed comparable uptake of 8.7 ± 1.0%ID/g and 8.8 ± 2.9%ID/g respectively for the 10 µg total protein dose, which is 2.3-fold higher compared to 89Zr-PbCtrl. Autoradiography showed 89Zr-CX-072 localization in PD-L1-positive tumor tissue areas on immunohistochemistry. Activated CX-072 was detected by capillary electrophoresis immunoassay mainly in MDA-MB-231 tumor, with limited amounts found in spleen. Flow cytometry confirmed PD-L1 expression in lymphoid tissues of C57BL6/J mice, while 89Zr-CX-072 uptake in these tissues was similar to 89Zr-PbCtrl and significantly lower compared to 89Zr-CX-075.
89Zr-CX-072 accumulates in PD-L1-expressing tumors with minor uptake in murine peripheral lymphoid tissues, confirming that the CX-072 structure limits uptake in non-tumor, PD-L1-expressing tissues. We developed clinical grade 89Zr-CX-072 to study its whole-body distribution in patients.
Dept. of Medical Oncology, University Medical Center Groningen (UMCG), The Netherlands.
CytomX Therapeutics Inc.
I. Popova, B. Howng, O. Vasiljeva: Employee: CytomX Therapeutics Inc. E.G.E. de Vries: Research funding: CytomX was made available to her institution (UMCG); Advisory boards: Pfizer, Daiichi Sankyo; Other funding: Amgen, Bayer, Chugai, G1 Therapeutics, Genentech/Roche, Nordic Nanovector, Regeneron, Synthon, all payments to UMCG. All other authors have declared no conflicts of interest.
CC-90011 is a potent, selective, reversible oral inhibitor of the epigenetic target, lysine-specific demethylase 1A (LSD1) that has demonstrated anti-proliferative activity against cancer cells in vitro and in patient-derived xenograft models.
CC-90011-ST-001 is a phase I, first-in-human study of CC-90011 in patients (pts) with advanced unresectable solid tumors and R/R NHL. Pts received oral CC-90011 once/wk (QW) in 28-d cycles. Primary endpoints included safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objectives were to measure preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD).
As of September 4, 2018, 50 pts were enrolled. All had advanced solid tumors except 1 pt with R/R NHL; 26 pts had neuroendocrine neoplasms (NENs). Pts received escalating doses of CC-90011 at 1.25 (n = 4), 2.5 (n = 5), 5 (n = 6), 10 (n = 4), 20 (n = 5), 40 (n = 6), 60 (n = 6), 80 (n = 10), or 120 mg (n = 4). The non-tolerated dose was established as 120 mg QW, the MTD as 80 mg QW, and the RP2D as 60 mg QW. The median age was 61 y (range, 22–75), 52% were male, and pts had received a median of 3 (range, 1–4) prior systemic anticancer regimens. Thrombocytopenia, an on-target effect, was the only dose-limiting toxicity. The most common grade 3/4 treatment-related adverse events (AEs) were thrombocytopenia (16%) and neutropenia (8%; occurring in the context of thrombocytopenia at the highest doses). Serious AEs occurred in 40% of pts; 6% were treatment-related. Peak plasma concentrations occurred 2-4 h post-dose and average terminal half-life was ∼60 h; exposure was dose proportional. PD analysis showed decreased CgA and MMD in response to CC-90011, correlating with clinical benefit. One pt achieved a complete response (CR) and 22 had stable disease (SD). Prolonged SD ≥ 4 months occurred in 7 pts, 5 with bronchial NEN and 2 with prostate NEN.
CC-90011 is well-tolerated with promising antitumor activity in solid tumors and R/R NHL, including a CR and prolonged SD in pts with NENs. PD and PK data showed sufficient target engagement. Taken together, the preliminary clinical data provides the rationale for dose expansion of CC-90011 in pts with NENs.
Editorial assistance was provided by Johna Van Stelten, Ph.D., of BioConnections LLC, funded by Celgene Corp.
NCT02875223 and EUDRACT 2015-005243-13.
A. Hollebecque: Honoraria: Merck Serono; Consultant or advisor: Gritstone Oncology; Travel funding: Amgen. J.S. de Bono: Advisor: AstraZeneca, Genentech, Pfizer, Merck Sharp & Dohme, Bayer, Merck Serono, Janssen, Astellas, Seattle Genetics; Research funds: AZ, Sanofi, Genentech, GSK, Daiichi Sankyo, Taiho Oncology, Merck Serono, Merck Sharp & Dohme, Sierra Oncology; Speaker bureau: AZ. R. Plummer: Honoraria: Novartis, BristolMyers Squibb; Research funding: Merck, Genmab, AstraZeneca, Menarini; Patents: with Clovis Oncology; Travel funding: Merck Sharp & Dohme, Bristol Myers Squibb. S. Mora: Travel funding: Celgene; Employment and equity ownership: Celgene. E. Filvaroff: Employee: Celgene; Stock or equity ownership: Celgene, Amgen, Gilead, Genentech, Roche; Patents/royalties: Celgene and Genentech. M. Lamba: Employee, equity ownership, research funding: Pfizer, Celgene; Patents/royalties: Pfizer. Z. Nikolova: Employee, equity ownership, travel funding: Celgene. All other authors have declared no conflicts of interest.
Computed tomography textural analysis (CTTA) can be used to quantify intra-tumour heterogeneity, which is linked to adverse tumour biology. We aimed to evaluate if CTTA can predict treatment response in metastatic epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (mNSCLC) with T790M mutations (T790M+) treated with osimertinib, after prior tyrosine kinase inhibitors.
We did a retrospective analysis of 39 consecutive patients with T790M+ mNSCLC on osimertinib. Treatment response was independently assessed on CT scans by RECIST 1.1. Routine contrast-enhanced CT images were acquired for each patient pre-osimertinib. Contiguous regions of interest (ROIs) were drawn by a radiologist around all measurable lesions and encompassing the entire axial tumour volume to assess tumour heterogeneity. Acquired image data was evaluated with an in-house program developed for analysing textures using Matlab (MathWorks, Natick, MA). Four textural variables – skewness, kurtosis, entropy and standard deviation (SD) were computed based on voxel histogram statistics, quantifying the distribution and relationship of voxel gray levels in each CT image. Each variable was assessed for association with objective response rates. Patients who had partial or complete response were “responders” (Rs), those with stable disease or disease progression were “non-responders” (NRs).
There were 23 Rs and 16 NRs (ORR 59%). Patient characteristics were similar between Rs and NRs. SD (which reflects degree of variability) was significantly higher in NRs: average SD was 35.8 (28.67, 38.91) in NRs vs. 31.2 (23.82, 33.28) in Rs; p = 0.04. Except for skewness, there was a trend towards higher entropy (measure of irregularity) and lower kurtosis (peakedness of the histogram) in NRs. Average entropy was 5.93 (5.667, 6.177) in NRs vs. 5.71 (5.434, 5.888) in Rs; p = 0.06, and average kurtosis was 3.27 (2.505, 4.189) in NRs vs. 4.14 (3.043, 5.223) in Rs; p = 0.08. Findings were consistent with greater tumour heterogeneity in NRs compared to Rs.
Texture parameters of SD, entropy and kurtosis derived from pre-treatment CT images of T790M+ mNSCLC may reflect tumour heterogeneity and have potential to predict for response to osimertinib.
Centralised Institutional Review Board - SingHealth Research.
Has not received any funding.
All authors have declared no conflicts of interest.