Publications by authors named "Hui K Gan"

83 Publications

Tumor volumes as a predictor of response to the anti-EGFR antibody drug conjugate depatuxizumab mafadotin.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab102. Epub 2021 Aug 3.

Tumour Targeting Program, Olivia Newton-John Cancer Research Institute, Austin Health, Heidelberg, Melbourne, Australia.

Background: The adverse impact of increasing brain tumor size on the efficacy of antibody-drug conjugates (ADCs) was investigated preclinically then validated with clinical data.

Methods—preclinical Study: The impact of tumor size on ADC tumor delivery and treatment response was evaluated in an -amplified patient-derived glioblastoma (GBM) model following treatment with Depatuxizumab mafadotin (Depatux-M). Biodistribution and imaging studies correlated drug distribution with starting treatment volume and anti-tumor activity.

Methods—clinical Study: M12-356 was a Phase I study of Depatux-M in patients with GBM. Blinded volumetric analysis of baseline tumor volumes of M12-356 patients was undertaken by two reviewers and results correlated with response and survival.

Results: Preclinically, imaging and biodistribution studies showed specific and significantly higher tumor uptake of zirconium-89 labeled Depatux-M (Zr-Depatux-M) in mice with smaller tumor volume (~98 mm) versus those with larger volumes (~365 mm); concordantly, mice with tumor volumes ≤100 mm at treatment commencement had significantly better growth inhibition by Depatux-M (93% vs 27%, < .001) and significantly longer overall survival ( < .0001) compared to tumors ≥400 mm. Clinically, patients with tumor volumes <25 cm had significantly higher response rates (17% vs. 0%, = .009) and longer overall survival (0.5 vs 0.89 years, = .001) than tumors above 25 cm.

Conclusion: Both preclinical and clinical data showed intra-tumoral concentration and efficacy of Depatux-m inversely correlated with tumor size. This finding merit further investigation with pretreatment tumor volume as a predictor for response to ADCs, in both gliomas and other solid tumors.
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http://dx.doi.org/10.1093/noajnl/vdab102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446913PMC
August 2021

Barriers and potential solutions to international collaboration in neuro-oncology clinical trials: Challenges from the Australian perspective.

Asia Pac J Clin Oncol 2021 Jun 24. Epub 2021 Jun 24.

Cooperative Trials Group for Neuro-Oncology, National Health and Medical Research Council Clinical Trials Centre, Sydney, Australia.

Aim: The neuro-oncology community in Australia is well positioned to collaborate internationally, with a motivated trials group, strong regulatory bodies and an attractive fiscal environment. We sought to identify gaps in the Australian neuro-oncology clinical trials landscape and describe strategies to increase international trial access in Australia.

Methods: We searched clinical trial registries to identify active adult primary brain cancer trials. We compared the participation rate and phase of these trials between tumour types and countries. A survey was distributed to the Cooperative Trials Group for Neuro-Oncology membership to identify barriers and solutions to effective international collaboration.

Results: Globally, 307 trials for adult primary brain cancers were identified. These included 50% pharmaceutical agents, 18% cellular therapies and 9% radiation therapy. Twelve adult primary brain cancer trials were actively recruiting in Australia at the time the survey was sent out. There were more early phase brain cancer trials (34%) compared with colorectal and breast cancer (21% and 24%, respectively). In Australia, 92% of brain cancer trials were involving pharmaceutical agents. The most commonly cited barrier was lack of funding for international trials (86%) and insufficient research time (75%). High ranking solutions included increasing the availability of funding for international trials and creating opportunities to develop personal relationships with collaborators. Accreditation of clinical research key performance indicators into practice (88%) and hospital accreditation (73%) also ranked highly.

Conclusions: Participation in international research in Australia could be improved by embedding clinical research targets into institutional funding, provision of funding for early phase studies and streamlining mutual ethics schemes.
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http://dx.doi.org/10.1111/ajco.13606DOI Listing
June 2021

A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors.

Oncologist 2021 Oct 21;26(10):e1844-e1853. Epub 2021 Jul 21.

Department of Medical Oncology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York, USA.

Background: GSK2849330, an anti-HER3 monoclonal antibody that blocks HER3/Neuregulin 1 (NRG1) signaling in cancer cells, is engineered for enhanced antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. This phase I, first-in-human, open-label study assessed the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity of GSK2849330 in patients with HER3-expressing advanced solid tumors.

Patients And Methods: Patients with various tumor types were prospectively selected for HER3 expression by immunohistochemistry; a subset was also screened for NRG1 mRNA expression. In the dose-escalation phase, patients received GSK2849330 1.4-30 mg/kg every 2 weeks, or 3 mg/kg or 30 mg/kg weekly, intravenously (IV). In the dose-expansion phase, patients received 30 mg/kg GSK2849330 IV weekly.

Results: Twenty-nine patients with HER3-expressing cancers, of whom two expressed NRG1, received GSK2849330 (dose escalation: n = 18, dose expansion: n = 11). GSK2849330 was well tolerated. No dose-limiting toxicities were observed. The highest dose, of 30 mg/kg weekly, expected to provide full target engagement, was selected for dose expansion. Treatment-emergent adverse events (AEs) were mostly grade 1 or 2. The most common AEs were diarrhea (66%), fatigue (62%), and decreased appetite (31%). Dose-proportional plasma exposures were achieved, with evidence of HER3 inhibition in paired tissue biopsies. Of 29 patients, only 1 confirmed partial response, lasting 19 months, was noted in a patient with CD74-NRG1-rearranged non-small cell lung cancer (NSCLC).

Conclusion: GSK2849330 demonstrated a favorable safety profile, dose-proportional PK, and evidence of target engagement, but limited antitumor activity in HER3-expressing cancers. The exceptional response seen in a patient with CD74-NRG1-rearranged NSCLC suggests further exploration in NRG1-fusion-positive cancers.

Implications For Practice: This first-in-human study confirms that GSK2849330 is well tolerated. Importantly, across a variety of HER3-expressing advanced tumors, prospective selection by HER3/NRG1 expression alone was insufficient to identify patients who could benefit from treatment with this antibody-dependent cell-mediated cytotoxicity- and complement-dependent cytotoxicity-enhanced anti-HER3 antibody. The only confirmed durable response achieved was in a patient with CD74-NRG1-rearranged lung cancer. This highlights the potential utility of screening for NRG1 fusions prospectively across tumor types to enrich potential responders to anti-HER3 agents in ongoing trials.
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http://dx.doi.org/10.1002/onco.13860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488777PMC
October 2021

Bintrafusp alfa (M7824), a bifunctional fusion protein targeting TGF-β and PD-L1: results from a phase I expansion cohort in patients with recurrent glioblastoma.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab058. Epub 2021 Apr 9.

Austin Brain Tumor Center, Austin, Texas, USA.

Background: For patients with recurrent glioblastoma (rGBM), there are few options following treatment failure with radiotherapy plus temozolomide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor (a TGF-β "trap") fused to a human IgG1 antibody blocking PD-L1.

Methods: In this phase I, open-label expansion cohort (NCT02517398), patients with rGBM that progressed after radiotherapy plus temozolomide received bintrafusp alfa 1200 mg Q2W until disease progression, unacceptable toxicity, or trial withdrawal. Response was assessed per RANO criteria. The primary endpoint was disease control rate (DCR); secondary endpoints included safety.

Results: As of August 24, 2018, 35 patients received bintrafusp alfa for a median of 1.8 (range, 0.5-20.7) months. Eight patients (22.9%) experienced disease control as assessed by an independent review committee: 2 had a partial response, 4 had stable disease, and 2 had non-complete response/non-progressive disease. Median progression-free survival (PFS) was 1.4 (95% confidence interval [CI], 1.2-1.6) months; 6- and 12-month PFS rates were 15.1% and 11.3%, respectively. Median overall survival (OS) was 5.3 (95% CI, 2.6-9.4) months; 6- and 12-month OS rates were 44.5% and 30.8%, respectively. The DCR (95% CI) was 66.7% (22.3-95.7%) for patients with -mutant GBM ( = 6) and 13.8% (3.9-31.7%) for patients with -wild-type GBM ( = 29). Disease control was seen regardless of PD-L1 expression. Twenty-five patients (71.4%) experienced treatment-related adverse events (grade ≥3; 17.1% [ = 6]).

Conclusions: The percentage of patients achieving disease control and the manageable safety profile may warrant further investigation of bintrafusp alfa in GBM.
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http://dx.doi.org/10.1093/noajnl/vdab058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156979PMC
April 2021

EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism.

Cancers (Basel) 2021 Mar 10;13(6). Epub 2021 Mar 10.

Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia.

Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.
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http://dx.doi.org/10.3390/cancers13061198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999088PMC
March 2021

A Phase 1 and Biodistribution Study of ABT-806i, an In-Radiolabeled Conjugate of the Tumor-Specific Anti-EGFR Antibody ABT-806.

J Nucl Med 2021 06 28;62(6):787-794. Epub 2021 Jan 28.

Olivia Newton-John Cancer Research Institute, Austin Health, Melbourne, Australia.

ABT-806 is a tumor-specific antibody targeting the epidermal growth factor receptor (EGFR). This study assessed safety, biodistribution, and pharmacokinetics of In-radiolabeled ABT-806 (ABT-806i) and effects of repeated doses of ABT-806 on receptor occupancy. Eligible patients had advanced tumors likely to express EGFR/EGFRvIII; adequate performance status and organ function; and measurable disease by RECIST 1.1. In cohort 1, 6 patients received a bolus administration of ABT-806i and underwent SPECT followed by whole-body planar scans. In cohort 2, 12 patients were imaged similarly as in 1 initially; thereafter, they received 3 doses of unlabeled ABT-806, before another dose of ABT-806i with associated SPECT and whole-body planar scans. At the end of both cohorts, patients who had stable or responding disease were able to enroll into an extension study (M12-326) in which they received unlabeled ABT-806 every 2 wk until disease progression, withdrawal of consent, or intolerable toxicity. No toxicity related to ABT-806i infusion was observed. ABT-806i showed minimal uptake in normal tissues and cleared gradually from blood with a half-life of 6.0 ± 1.5 d. The mean effective dose of ABT-806i was 0.137 mSv/MBq for males and 0.183 mSv/MBq for females. ABT-806i tumor uptake varied and did not correlate with archived tumor EGFR expression. No change in ABT-806i uptake was observed after interval ABT-806 treatment, indicating stable EGFR expression in tumor. The patient with highest tumor uptake of ABT-806i had advanced head and neck cancer and experienced a partial response. ABT-806i allows for real-time imaging of EGFR conformational expression in tumors, has an acceptable radiation dosimetry, and provides important additional information about antigen expression compared with standard approaches using archival tissue. Its role to assist in patient selection for EGFR-based therapeutics and investigate treatment resistance should be further investigated.
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http://dx.doi.org/10.2967/jnumed.120.253146DOI Listing
June 2021

Sensitization of Cancers Resistant to HER2 Antibodies.

Crit Rev Oncog 2020 ;25(3):175-207

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia.

Human epidermal growth factor receptor 2 (HER2) oncogene addiction has led to the development of anti-HER2 therapies which have revolutionized the management of patients with HER2-positive cancers, with trastuzumab being the cornerstone of treatment of HER2-positive breast cancer. Despite the success of these biologics in breast cancer patients, not all patients with HER2-positive tumors respond to treatment, and many eventually develop resistance to therapy. Developing therapies that that circumvent current resistance mechanisms and improve patient outcomes further remains an area of unmet clinical need. Based on insights gained from established anti-HER2 therapies and our understanding of known resistance mechanisms a number of novel anti-HER2 treatments are being developed. These include novel HER2 antibody-drug conjugates that have shown activity in HER2 high and low tumors, novel HER2 antibodies, T cell bispecific antibodies, and HER2 antibodies in combination with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, immunotherapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. In this article, we review resistance mechanisms to approved HER2 antibodies and provide an overview of emerging therapeutic agents.
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http://dx.doi.org/10.1615/CritRevOncog.2020036080DOI Listing
January 2020

Expression of EGFR and conformational forms of EGFR in malignant pleural mesothelioma and its impact on survival.

Lung Cancer 2021 03 31;153:35-41. Epub 2020 Dec 31.

Department of Medical Oncology, Austin Health, Melbourne, Australia; Olivia-Newton John Cancer Research Institute, Melbourne, Australia; Faculty of Medicine, University of Melbourne, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia.

Aim: Conformational forms of the epidermal growth factor receptor (EGFR) are pro-tumorigenic. The prevalence and impact of conformational forms of EGFR in malignant mesothelioma (MM) is unknown. We investigated expression of EGFR and conformational forms of EGFR by immunohistochemistry using EGFR-targeting monoclonal antibodies (mAb). In addition, EGFR gene amplification was investigated by fluorescent in-situ hybridization (FISH). Findings were correlated with survival.

Methods: Patients treated between 1988 and 2014 were identified from the thoracic surgery database of the Austin Hospital, Melbourne, Australia. Tissue microarrays (TMAs) were constructed, subjected to wild type (wt) EGFR IHC staining and FISH analysis. Conformational and mutation forms of EGFR were detected by IHC using mAb806, and LMH-151 which detects EGFRVIII. `H-scores` were derived and EGFR expression correlated with survival by Kaplan-Meier and log rank analysis.

Results: WtEGFR expression was seen in 93 % (299/321) of cases with overexpression (defined as an H-score ≥200) seen in more than half of cases (64 %). EGFR overexpression in MM was seen more commonly in the epithelioid subtype. EGFR overexpression was not associated with true EGFR amplification, although multiple copies were appreciated in samples with polysomy. EGFR expression did not correlate with survival. A conformational form of EGFR associated with EGFR dysregulation was found in 8.2 % of cases, and patients with these tumors had a trend towards a poorer outcome. No cases of the EGFRVIII mutation were identified.

Conclusion: MM consistently demonstrated high expression of EGFR, with a subset of tumors showing conformational EGFR forms consistent with EGFR dysregulation, but withoutEGFR amplification or EGFR VIII mutation. wtEGFR expression did not influence survival. The impact of EGFR conformation on survival warrants further investigation.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.028DOI Listing
March 2021

Antibody-Drug Conjugates for Cancer Therapy.

Molecules 2020 Oct 16;25(20). Epub 2020 Oct 16.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, VIC 3084, Australia, (U.H.).

Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.
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http://dx.doi.org/10.3390/molecules25204764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587605PMC
October 2020

Prognostic performance of qSOFA in oncology patients admitted to the emergency department with suspected infection.

Asia Pac J Clin Oncol 2021 Feb 20;17(1):94-100. Epub 2020 Oct 20.

Department of Radiation Oncology, Olivia Newton-John Cancer Wellness and Research Centre, Austin Health, Heidelberg, Victoria, Australia.

Aim: We aimed to test the performance of the quick Sequential Organ Failure Assessment score (qSOFA) in predicting the outcomes of oncology patients admitted to the emergency department (ED) with suspected infection.

Methods: Retrospective cohort analysis of all oncology patients presenting to the ED of a tertiary hospital with suspected infection from 1 December 2014 to 1 June 2017. Patients were identified by cross-linkage of ED and Oncology electronic health records. The primary outcome was in-hospital mortality and/or ICU stay ≥ 3 days.

Results: A total of 1655 patients were included in this study--1267 (76.6%) with solid tumor and 388 (23.4%) with hematological malignancies. At presentation, 495 patients had chemotherapy, and 140 had radiotherapy within the preceding 6 months. Four hundred patients received chemotherapy and/or radiotherapy in the previous 4 weeks. Overall, 371 (22.4%) patients had qSOFA ≥ 2. Such patients had a higher likelihood of respiratory infections compared to patients with a qSOFA < 2 (43.9% vs 29%) and were more likely to be admitted to ICU or require mechanical ventilation. In-hospital mortality or in-hospital mortality and/or ICU stay ≥ 3 days were 17.3% and 21%, for qSOFA ≥ 2 patients versus 4.7% and 6.9% for qSOFA < 2 patients (P < .001). qSOFA ≥ 2 had a negative predictive value of 95% for in-hospital mortality and 93% for in-hospital mortality or ICU stay ≥ 3 days.

Conclusion: Among oncology patients presenting to the ED with suspected infection, a qSOFA ≥ 2 is associated with a threefold risk of hospital mortality/prolonged ICU stay. Its absence helps identify low-risk patients.
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http://dx.doi.org/10.1111/ajco.13422DOI Listing
February 2021

First clinical study of a pegylated diabody I-labeled PEG-AVP0458 in patients with tumor-associated glycoprotein 72 positive cancers.

Theranostics 2020 15;10(25):11404-11415. Epub 2020 Sep 15.

Avipep Pty Ltd and the Victorian Cancer Biologics Consortium, Parkville, Victoria 3052, Australia.

Through protein engineering and a novel pegylation strategy, a diabody specific to tumor-associated glycoprotein 72 (TAG-72) (PEG-AVP0458) has been created to optimize pharmacokinetics and bioavailability to tumor. We report the preclinical and clinical translation of PEG-AVP0458 to a first-in-human clinical trial of a diabody. Clinical translation followed characterization of PEG-AVP0458 drug product and preclinical biodistribution and imaging assessments of Iodine-124 trace labeled PEG-AVP0458 (I-PEG-AVP0458). The primary study objective of the first-in-human study was the safety of a single protein dose of 1.0 or 10 mg/mI-PEG-AVP0458 in patients with TAG-72 positive relapsed/ metastatic prostate or ovarian cancer. Secondary study objectives were evaluation of the biodistribution, tumor uptake, pharmacokinetics and immunogenicity. Patients were infused with a single-dose of I labeled PEG-AVP0458 (3-5 mCi (111-185 MBq) for positron emission tomography (PET) imaging, performed sequentially over a one-week period. Safety, pharmacokinetics, biodistribution, and immunogenicity were assessed up to 28 days after infusion. PEG-AVP0458 was radiolabeled with I and shown to retain high TAG-72 affinity and excellent targeting of TAG-72 positive xenografts by biodistribution analysis and PET imaging. In the first-in-human trial, no adverse events or toxicity attributable to I-PEG-AVP0458 were observed. Imaging was evaluable in 5 patients, with rapid and highly specific targeting of tumor and minimal normal organ uptake, leading to high tumor:blood ratios. Serum concentration values of I-PEG-AVP0458 showed consistent values between patients, and there was no significant difference in T½α and T½β between dose levels with mean (± SD) results of T½α = 5.10 ± 4.58 hours, T½β = 46.19 ± 13.06 hours. These data demonstrates the safety and feasibility of using pegylated diabodies for selective tumor imaging and potential delivery of therapeutic payloads in cancer patients.
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http://dx.doi.org/10.7150/thno.49422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545991PMC
June 2021

Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma.

Pharmaceuticals (Basel) 2020 Oct 2;13(10). Epub 2020 Oct 2.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Victoria 3084, Australia.

Epidermal growth factor receptor (EGFR) is highly overexpressed in malignant mesothelioma (MM). MAb806 is a novel anti-EGFR antibody that selectively targets a tumor-selective epitope. MAb806-derived antibody drug conjugates (ADCs), ABT-414, ABBV-221 and ABBV-322, may represent a novel therapeutic strategy in MM. EGFR and mAb806 epitope expressions in mesothelioma cell lines were evaluated using an array of binding assays, and the in vitro cell effects of ABT-414 and ABBV-322 were determined. In vivo therapy studies were conducted in mesothelioma xenograft and patient-derived xenograft (PDX) tumor models. We also performed biodistribution and imaging studies to allow the quantitative targeting of MM by mAb806 using a Zr-labeled immunoconjugate-ch806. A high EGFR expression was present in all mesothelioma cell lines evaluated and mAb806 binding present in all cell lines, except NCIH-2452. ABT-414 and ABBV-322 resulted in significant tumor growth inhibition in MM models with high EGFR and mAb806 epitope expressions. In contrast, in an EGFR-expressing PDX model that was negative for the mAb806 epitope, no growth inhibition was observed. We demonstrated the specific targeting of the mAb806 epitope expressing MM tumors using Zr-based PET imaging. Our data suggest that targeting EGFR in MM using specific ADCs is a valid therapeutic strategy and supports further investigation of the mAb806 epitope expression as a predictive biomarker.
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http://dx.doi.org/10.3390/ph13100289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601847PMC
October 2020

New insights into ErbB3 function and therapeutic targeting in cancer.

Expert Rev Anticancer Ther 2020 12 26;20(12):1057-1074. Epub 2020 Oct 26.

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute , Melbourne, Australia.

Introduction: The importance of ErbB3 receptor tyrosine kinase in cancer progression, primary and acquired drug resistance, has become steadily evident since its discovery in 1989. ErbB3 overexpression in various solid organ malignancies is associated with shorter survival of patients. However, initial strategies to therapeutically target ErbB3 have not been rewarding.

Areas Covered: Here, we provide an overview of ErbB3 biology in carcinogenesis. We outline the role of ErbB3 as a critical pathway for resistance to other anti-cancer drugs. We focus on emerging clinical data, which will steer the potential future development of ErbB3 directed therapies.

Expert Opinion: Initial approaches to ErbB3 targeting have been challenging. However, the lack of success of anti-ErbB3 therapies in ongoing clinical trials may relate more to the complex biology of the receptor and challenges with the biomarkers used to date. Furthermore, it seems certain that the expression of the receptor is necessary but not sufficient for the response to ErbB3 therapies. Emerging data suggest that more sophisticated biomarkers are needed. Nonetheless, it is also likely that ErbB3 therapies may have the most efficacy in combination therapy, and their favorable toxicity profile makes this feasible.
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http://dx.doi.org/10.1080/14737140.2020.1829485DOI Listing
December 2020

Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate.

Mol Cancer Ther 2020 10 26;19(10):2117-2125. Epub 2020 Aug 26.

AbbVie Inc., North Chicago, Illinois.

ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody-drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or amplification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatux-m or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0149DOI Listing
October 2020

Practical Considerations for Treating Patients With Cancer in the COVID-19 Pandemic.

JCO Oncol Pract 2020 08 13;16(8):467-482. Epub 2020 May 13.

Biosecurity Program, Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.

Cancer has become a prevalent disease, affecting millions of new patients globally each year. The COVID-19 pandemic is having far-reaching impacts around the world, causing substantial disruptions to health and health care systems that are likely to last for a prolonged period. Early data have suggested that having cancer is a significant risk factor for mortality from severe COVID-19. A diverse group of medical oncologists met to formulate detailed practical advice on systemic anticancer treatments during this crisis. In the context of broad principles, issues including risks of treatment, principles of prioritizing resources, treatment of elderly patients, and psychosocial impact are discussed. Detailed treatment advice and options are given at a tumor stream level. We must maintain care for patients with cancer as best we can and recognize that COVID-19 poses a significant competing risk for death that changes conventional treatment paradigms.
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http://dx.doi.org/10.1200/OP.20.00229DOI Listing
August 2020

Antibody Targeting of Eph Receptors in Cancer.

Pharmaceuticals (Basel) 2020 May 8;13(5). Epub 2020 May 8.

Olivia Newton-John Cancer Institute and La Trobe University School of Cancer Medicine, Victoria 3084, Australia.

The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with tumor initiation, angiogenesis and metastasis. Eph receptors are thus attractive therapeutic targets, and monoclonal antibodies have been commonly developed and tested for anti-cancer activity in preclinical models, and in some cases in the clinic. This review summarizes 20 years of research on various antibody-based approaches to target Eph receptors in tumors and the tumor microenvironment, including their mode of action, tumor specificity, and efficacy in pre-clinical and clinical testing.
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http://dx.doi.org/10.3390/ph13050088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281212PMC
May 2020

Clinical Development of Molecular Targeted Therapy in Head and Neck Squamous Cell Carcinoma.

JNCI Cancer Spectr 2019 Dec 12;3(4):pkz055. Epub 2019 Nov 12.

Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France.

A better understanding of cancer biology has led to the development of molecular targeted therapy, which has dramatically improved the outcome of some cancer patients, especially when a biomarker of efficacy has been used for patients' selection. In head and neck oncology, cetuximab that targets epidermal growth factor receptor is the only targeted therapy that demonstrated a survival benefit, both in the recurrent and in the locally advanced settings, yet without prior patients' selection. We herein review the clinical development of targeted therapy in head and neck squamous cell carcinoma in light of the molecular landscape and give insights in on how innovative clinical trial designs may speed up biomarker discovery and deployment of new molecular targeted therapies. Given the recent approval of immune checkpoint inhibitors targeting programmed cell death-1 in head and neck squamous cell carcinoma, it remains to be determined how targeted therapy will be incorporated into a global drug development strategy that will inevitably incorporate immunotherapy.
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http://dx.doi.org/10.1093/jncics/pkz055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049986PMC
December 2019

A First-in-Human Dose Finding Study of Camrelizumab in Patients with Advanced or Metastatic Cancer in Australia.

Drug Des Devel Ther 2020 18;14:1177-1189. Epub 2020 Mar 18.

Linear Clinical Research, Nedlands, Western Australia, Australia.

Purpose: Camrelizumab inhibits PD-1 in non-clinical models and showed typical non-clinical pharmacokinetic (PK) and safety profiles for an IgG4 monoclonal antibody. We report results from the First-in-Human Phase 1 trial of camrelizumab in Australian population.

Methods: Camrelizumab was administered to patients with advanced solid tumors who had failed standard therapies. In the dose-escalation phase (n=23), camrelizumab was administered intravenously at 1 mg/kg, 3 mg/kg, 6 mg/kg, and 10 mg/kg every 2 weeks. In dose expansion (n=26), camrelizumab was given at 200 mg or 600 mg every 4 weeks.

Results: Two dose-limiting toxicities were observed during dose escalation: transaminase elevation and diarrhea (both grade 3). Overall, treatment-related adverse events were consistent with the expected toxicity profile of immune checkpoint inhibition, with the striking exception of the dose-related development of angiomatous skin lesions characterized as reactive cutaneous capillary endothelial proliferation. The PK profile showed a dose-progressive increase in half-life from 3 days at 1 mg/kg to 7 days at 10 mg/kg. Moreover, receptor occupancy assays showed a PD-1 occupancy of >50% in most patients out to 28 days post-dose. The objective response rate was 15.2% (95% CI 6.3-28.9).

Conclusion: Camrelizumab has manageable toxicity and encouraging preliminary antitumor activity in advanced solid tumors in Australia.

Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT02492789.
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http://dx.doi.org/10.2147/DDDT.S243787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090185PMC
February 2021

Spatial and quantitative mapping of glycolysis and hypoxia in glioblastoma as a predictor of radiotherapy response and sites of relapse.

Eur J Nucl Med Mol Imaging 2020 06 5;47(6):1476-1485. Epub 2020 Feb 5.

Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Victoria, Australia.

Introduction: Tumor hypoxia is a centerpiece of disease progression mechanisms such as neoangiogenesis or aggressive hypoxia-resistant malignant cells selection that impacts on radiotherapy strategies. Early identification of regions at risk for recurrence and prognostic-based classification of patients is a necessity to devise tailored therapeutic strategies. We developed an image-based algorithm to spatially map areas of aerobic and anaerobic glycolysis (Glyoxia).

Methods: F-FDG and F-FMISO PET studies were used in the algorithm to produce DICOM-co-registered representations and maximum intensity projections combined with quantitative analysis of hypoxic volume (HV), hypoxic glycolytic volume (HGV), and anaerobic glycolytic volume (AGV) with CT/MRI co-registration. This was applied to a prospective clinical trial of 10 glioblastoma patients with post-operative, pre-radiotherapy, and early post-radiotherapy F-FDG and F-FMISO PET and MRI studies.

Results: In the 10 glioblastoma patients (5M:5F; age range 51-69 years), 14/18 F-FMISO PET studies showed detectable hypoxia. Seven patients survived to complete post-radiotherapy studies. The patient with the longest overall survival showed non-detectable hypoxia in both pre-radiotherapy and post-radiotherapy F-FMISO PET. The three patients with increased HV, HGV, and AGV volumes after radiotherapy showed 2.8 months mean progression-free interval vs. 5.9 months for the other 4 patients. These parameters correlated at that time point with progression-free interval. Parameters combining hypoxia and glycolytic information (i.e., HGV and AGV) showed more prominent variation than hypoxia-based information alone (HV). Glyoxia-generated images were consistent with disease relapse topology; in particular, one patient had distant relapse anticipated by HV, HGV, and AGV maps.

Conclusion: Spatial mapping of aerobic and anaerobic glycolysis allows unique information on tumor metabolism and hypoxia to be evaluated with PET, providing a greater understanding of tumor biology and potential response to therapy.
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http://dx.doi.org/10.1007/s00259-020-04706-0DOI Listing
June 2020

Longitudinal molecular trajectories of diffuse glioma in adults.

Nature 2019 12 20;576(7785):112-120. Epub 2019 Nov 20.

Fondazione IRCCS Istituto Neurologico Besta, Milano, Italy.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner.
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http://dx.doi.org/10.1038/s41586-019-1775-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897368PMC
December 2019

Current Development of Monoclonal Antibodies in Cancer Therapy.

Recent Results Cancer Res 2020 ;214:1-70

Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Heidelberg, Melbourne, VIC, 3084, Australia.

Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.
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http://dx.doi.org/10.1007/978-3-030-23765-3_1DOI Listing
September 2019

Young adults diagnosed with high grade gliomas: Patterns of care, outcomes, and impact on employment.

J Clin Neurosci 2019 Oct 29;68:45-50. Epub 2019 Jul 29.

La Trobe University School of Cancer Medicine, Melbourne, Australia; Olivia Newton-John Cancer Wellness and Research Centre, Melbourne, Australia; Monash Health, Melbourne, Australia. Electronic address:

There is limited information on the patterns of care and outcomes of high grade gliomas (HGGs) in young adults, in particular, the impact it has on a person's employment. We retrospectively identified young adult patients (age ≤ 40 years old) with newly diagnosed high grade gliomas treated between January 2013 and June 2018 across four major neuro-oncology centres in Australia. Patient demographics, tumour characteristics and treatment parameters were collected and outcomes determined. A total of 113 patients were identified with a median follow up of 27.0 months (range 1.0-70.2 months). The median age was 31 years, majority were male (65%) and employed (71.6%). IDH mutations were detected in 66 (62%) cases. The median progression-free survival (PFS) was 38.0 months (95% CI 23.3-52.7 months) and median overall survival (OS) was not reached. Patients with IDH wild type anaplastic astrocytoma and glioblastoma had a significantly shorter median PFS (19.3 months vs. NR, p = 0.001) and median OS (43.5 months vs NR, p = 0.007) than those with IDH mutated grade III anaplastic astrocytoma and oligodendroglioma. There was no significant difference in median OS or PFS between patients who underwent gross or subtotal tumour resection. Significantly, after diagnosis only 36 (32%) patients reported being employed. Young patients with IDH wild type astrocytomas and glioblastoma had better outcomes than reported historical controls. Most patients did not continue in employment post diagnosis.
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http://dx.doi.org/10.1016/j.jocn.2019.07.063DOI Listing
October 2019

First-in-Human Phase I Study of the Selective MET Inhibitor, Savolitinib, in Patients with Advanced Solid Tumors: Safety, Pharmacokinetics, and Antitumor Activity.

Clin Cancer Res 2019 08 5;25(16):4924-4932. Epub 2019 Apr 5.

Monash Medical Center, Bentleigh East, Victoria, Australia.

Purpose: Aberrant activation of MET (hepatocyte growth factor receptor) signaling is implicated in the tumorigenesis of human cancers. This phase I study assessed the safety, tolerability, and MTD of the potent and selective MET inhibitor, savolitinib (AZD6094, HMPL-504, volitinib).

Patients And Methods: This open-label, multicenter dose-escalation and -expansion study evaluated oral savolitinib for patients with locally advanced or metastatic solid tumors. A 3 + 3 design assessed repeated daily (QD) and twice daily (BID) dosing schedules. The dose-expansion phase included 12 patients. Primary objectives were to evaluate the safety, tolerability, MTD, and dose-limiting toxicities (DLT) of savolitinib. Secondary and exploratory objectives included pharmacokinetics, biomarker research, and antitumor activity.

Results: Overall, 48 patients were enrolled. Four patients had DLTs following QD savolitinib (600 mg = 1, 800 mg = 1, and 1,000 mg = 2); the MTD was 800 mg QD and not reached for BID dosing. The recommended phase II dose (RP2D) was 600 mg QD. The most frequent adverse events were nausea (30 patients, 63%), vomiting (20 patients, 42%), fatigue (20 patients, 42%), and peripheral edema (15 patients, 31%). At 600 mg QD, was 2,414.8 ng/mL, AUC was 17053.9 h·ng/mL, and there was no apparent drug accumulation. Three patients with papillary renal cell carcinoma (PRCC) and MET aberrations had partial responses with durations from 39 to 147 weeks.

Conclusions: The tolerability profile of savolitinib was acceptable and the RP2D was established as 600 mg QD. Preliminary antitumor activity was demonstrated supporting further study in patients with PRCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1189DOI Listing
August 2019

BI 853520, a FAK-Simile of Prior FAK Inhibitors?

Target Oncol 2019 02;14(1):39-41

Olivia Newton John Cancer Centre, 145 Studley Rd, Heidelberg, VIC, 3084, Australia.

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http://dx.doi.org/10.1007/s11523-019-00621-zDOI Listing
February 2019

Comparison of Biomarker Assays for : Implications for Precision Medicine in Patients with Glioblastoma.

Clin Cancer Res 2019 06 22;25(11):3259-3265. Epub 2019 Feb 22.

Erasmus MC Cancer Center, Rotterdam, the Netherlands.

Purpose: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing amplification by multiple assays. Specifically, we evaluated correlation among fluorescence hybridization (FISH), a standard assay for detecting amplification, with other methods. Formalin-fixed, paraffin-embedded tumor samples were used for all assays. amplification was detected using FISH ( = 206) and whole-exome sequencing (WES, = 74). mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, = 206) and transcriptome profiling (RNAseq, = 64). EGFR protein expression was determined by immunohistochemistry (IHC, = 34). Significant correlations among various methods were determined using Cohen's kappa (κ = 0.61-0.80 defines substantial agreement) or statistics.

Results: mRNA expression levels by RNA sequencing (RNAseq) and RT-PCR were highly correlated with amplification assessed by FISH (κ = 0.702). High concordance was also observed when comparing FISH to WES (κ = 0.739). RNA expression was superior to protein expression in delineating amplification.

Conclusions: Methods for assessing mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapeutic approaches.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291723PMC
June 2019

Changes in the Use of Comprehensive Geriatric Assessment in Clinical Trials for Older Patients with Cancer over Time.

Oncologist 2019 08 1;24(8):1089-1094. Epub 2019 Feb 1.

Medical Oncology Department, Hospices Civils de Lyon (IC-HCL), Pierre-Bénite, France.

Background: The objective of this study was to describe the implementation of comprehensive geriatric assessment (CGA) in clinical trials dedicated to older patients before and after the creation of the International Society of Geriatric Oncology in the early 2000s.

Subjects, Materials, And Methods: All phase I, II, and III trials dedicated to the treatment of cancer among older patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. We considered that a CGA was performed when the authors indicated an intention to do so in the Methods section of the article. We collected each geriatric domain assessed using a validated tool even in the absence of a clear CGA, including nutritional, functional, cognitive, and psychological status, comorbidity, comedication, overmedication, social status and support, and geriatric syndromes.

Results: A total of 260 clinical trials dedicated to older patients were identified over the two time periods: 27 phase I, 193 phase II, and 40 phase III trials. CGA was used in 9% and 8% of phase II and III trials, respectively; it was never used in phase I trials. Performance status was reported in 67%, 79%, and 75% of phase I, II, and III trials, respectively. Functional assessment was reported in 4%, 11%, and 13% of phase I, II, and III trials, respectively. Between the two time periods, use of CGA increased from 1% to 11% ( = .0051) and assessment of functional status increased from 3% to 14% ( = .0094).

Conclusion: The use of CGA in trials dedicated to older patients increased significantly but remained insufficient.

Implications For Practice: This article identifies the areas in which research efforts should be focused in order to offer physicians well-addressed clinical trials with results that can be extrapolated to daily practice.
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http://dx.doi.org/10.1634/theoncologist.2018-0493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693722PMC
August 2019

A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors.

Int J Cancer 2019 08 4;145(3):639-648. Epub 2019 Feb 4.

Department of Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Pierre-Bénite, France.

The advent of immune checkpoint-inhibitors (CPI) has transformed treatment for several cancer types. This review was performed to assess the rate of adverse events (AEs) associated with the use of CPI, alone or in combinations. A review of AEs reporting quality was also performed. All publications of Randomized Clinical Trials (RCTs) assessing CPI published before December 2017 were included. To investigate the quality of AEs reporting, a set of items was defined based on the 2004 CONSORT harms extension statement. Rates of Grade 5, serious, and study-withdrawal related AEs were collected in each treatment category. Specific immune related AEs (irAEs) were also collected when available. Pooled estimates of adverse event rates were calculated by using generalized linear mixed model. A total of 35 RCTs including 16,485 patients were included. The overall quality of AEs reporting was satisfactory, but items pertaining to methods of data collection and analysis were infrequently reported. Grade ≥ 3 AEs were reported for 14% (95% CI 12-16) of patients treated with PD(L)-1 inhibitors, 34% (95% CI 27-42) of patients treated with CTLA-4 inhibitors, 55% (95% CI 51-59) of patients on CPI combinations and 46% (95% CI 40-53) of patients on immunotherapy-chemotherapy combination. The profile of irAEs was different among the treatment categories. The use of CPI, especially in combination, is associated with significant rates of Grade ≥ 3 AEs. Healthcare planning should anticipate the expected high number of patients presenting with irAEs in the future.
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http://dx.doi.org/10.1002/ijc.32132DOI Listing
August 2019

A single-institution prospective evaluation of a neuro-oncology multidisciplinary team meeting.

J Clin Neurosci 2018 Oct 29;56:127-130. Epub 2018 Jun 29.

Austin Hospital, Heidelberg, Victoria, Australia; La Trobe University School of Cancer Medicine, Melbourne, Australia; Department of Medicine, University of Melbourne, 145 Studley Road, Heidelberg, Victoria 3084, Australia. Electronic address:

Multi-disciplinary team meetings (MDTs) are considered essential to quality cancer care. For some malignancies, MDTs have been associated with improved outcomes, but data regarding the neuro-oncology MDT is limited. We prospectively described the MDT at our institution and evaluated its impact on clinical management. Cases were discussed amongst the treating team and a pre-MDT plan and reason for discussion (RFD) was documented before the MDT. Patient specific clinical data was captured prospectively, with further pathological and radiological information captured during the MDT. Subsequently, the MDT consensus decision was recorded. High impact decisions (HID) were those in which the pre-MDT plan was substantially modified. A HID rate of >10% was considered clinically significant. Adherence to MDT recommendations was recorded. Seventy-nine cases were discussed at the MDT. Fifty-two cases (66%) were male. The median age was 53 (17-84). Thirty-three cases were new diagnoses and the remainder were relapsed/progressive disease. Thirty-nine cases were primary brain tumours, 25 were metastatic tumours and 15 were other. Twenty-eight (35%) had HID. No RFDs were statistically significantly associated with a HID (p = 0.265). Adherence data was collected for 95% (75) of cases. Treatment concordance with the MDT plan occurred in 90% (67) of cases. For cases of non-concordance, six out of eight (75%) were due to patient choice. Overall, a clinically significant proportion of treatment modifications are made at the neuro-oncology MDT. There were no case types which did not benefit from MDT discussion. MDT recommendations were largely adhered to, and in cases of non-concordance, were largely due to patient choice.
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http://dx.doi.org/10.1016/j.jocn.2018.06.032DOI Listing
October 2018

Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial.

Neuro Oncol 2019 01;21(1):106-114

NorthShore University Health System, Evanston, Illinois, USA.

Background: Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM.

Methods: M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve.

Results: There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%.

Conclusions: Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).
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http://dx.doi.org/10.1093/neuonc/noy091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303422PMC
January 2019

Clinical correlates of severe thrombocytopenia from temozolomide in glioblastoma patients.

Intern Med J 2018 Oct;48(10):1206-1214

Medical Oncology Department, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, Victoria, Australia.

Background/aim: This study was conducted retrospectively to evaluate rates of thrombocytopenia and their clinical impact during chemo-radiotherapy for glioblastomas and to elucidate associated clinical factors.

Methods: A total of 64 patients who received temozolomide chemotherapy at our institution was included; 35 patients received full-dose chemo-radiotherapy as per the STUPP protocol (Group A), and 9 patients received abbreviated radiotherapy with concurrent chemotherapy (Group B). Twenty patients received temozolomide alone with an intended 12 cycles of therapy for first relapse at least 6 months after completion of adjuvant chemotherapy (Group C).

Results: In Group A, 27 of 35 (77%) patients completed the chemo-radiotherapy phase; 14% had grade 3-4 thrombocytopenia leading to discontinuation. Of 27 patients, 16 (59%) completed adjuvant chemotherapy. There were no grade 3-4 thrombocytopenias, but 4% discontinued due to grade 2 thrombocytopenias. In Group B, four of nine (45%) patients completed the chemo-radiotherapy phase; 11% had grade 3-4 thrombocytopenias and discontinued treatment. Three of four (75%) patients completed adjuvant chemotherapy. Of these, 75% had grade 3-4 thrombocytopenias, but none discontinued. Finally, in Group C, 8 of 20 (40%) patients completed, with 10% discontinuing due to thrombocytopenias and the rest due to disease progression. In exploratory analyses, being female increased the risk of myelosuppresion, and there was a trend noticed in patients having a higher body surface area.

Conclusion: Our toxicity data were within range of the literature. We identified the group of patients that have increased thrombocytopenia risk. Larger pooled retrospective series and prospective studies are required.
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http://dx.doi.org/10.1111/imj.14000DOI Listing
October 2018
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