Mustafa Khasraw

Overview:

I am a professor of medicine and neurooncology, a medical oncologist at Duke's Preston Robert Tisch Brain Tumor Center as well as the Deputy Director of the Center for Cancer Immunotherapy, Duke Cancer Institute, where are tasked to speed up clinical research and translation for scientists across all departments and across all tumor types at Duke, who have made discoveries that show promise for developing new immunotherapies.

Prior to joining Duke in September, 2019, I worked as a medical oncologist in Sydney, Australia and I was also as a Clinical Lead at the Australian National Health & Medical Research Council Clinical Trial Centre at The University of Sydney. 

I am leading several clinical and translational programs with significant laboratory collaborations. I am interested in innovative trials designed to improve outcome of cancer patients. I am lead principal investigator on phase I, II and III multi-center clinical trials for a number of pharmaceutical and academic groups. 

I serve as an advisor and grant reviewer for a number of non-profits and patient advocacy groups and I am a Fellow of the Royal Australasian College of Physicians as well as an Elected Fellow of the Royal College of Physicians (Lon, UK). 

Positions:

Professor of Neurosurgery

Neurosurgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2001

Rijksuniversiteit Groningen (Netherlands)

Publications:

Anti-epidermal growth factor receptor therapy for glioblastoma in adults.

BACKGROUND: Glioblastoma is an uncommon but highly aggressive type of brain tumour. Significant gains have been achieved in the molecular understanding and the pathogenesis of glioblastomas, however clinical improvements are difficult to obtain for many reasons. The current standard of care involves maximal safe surgical resection followed by chemoradiation and then adjuvant chemotherapy European Organisation for Research and Treatment of Cancer and the NCIC Clinical Trials Group (EORTC-NCIC) protocol with a median survival of 14.6 months. Successive phase III international randomised controlled studies have failed to significantly demonstrate survival advantage with newer drugs. Epidermal growth factor receptor (EGFR) is observed to be aberrant in 30% to 60% of glioblastomas. The receptor aberrancy is driven by abnormal gene amplification, receptor mutation, or both, in particular the extracellular vIII domain. EGFR abnormalities are common in solid tumours, and the advent of anti-EGFR therapies in non-small cell lung cancer and colorectal adenocarcinomas have greatly improved clinical outcomes. Anti-EGFR therapies have been investigated amongst glioblastomas, however questions remain about its ongoing role in glioblastoma management. This review aimed to report on the available evidence to date and perform a systematic analysis on the risks and benefits of use of anti-EGFR therapies in glioblastomas. OBJECTIVES: To evaluate the efficacy and harms of anti-EGFR therapies for glioblastoma in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, EBM Reviews databases, with supplementary handsearches to identify all available and relevant studies to 20 April 2020. SELECTION CRITERIA: All randomised controlled trials (RCTs) using anti-EGFR therapies in adults with glioblastoma were eligible for inclusion. Anti-EGFR therapies included tyrosine kinase inhibitors, monoclonal antibodies, or vaccines. The comparison included investigational product added to standard of care versus standard of care or placebo, or investigational product against standard of care or placebo. DATA COLLECTION AND ANALYSIS: The authorship team screened the search results and recorded the extracted data for analysis. We used standard Cochrane methodology to performed quantitative meta-analysis if two or more studies had appropriate and available data. Otherwise, we conducted a qualitative and descriptive analysis. We used the GRADE system to rate the certainty of the evidence. The analysis was performed along the two clinical settings: first-line (after surgery) and recurrent disease (after failure of first line treatment). Where information was available, we documented overall survival, progression-free survival, adverse events, and quality of life data from eligible studies. MAIN RESULTS: The combined searches initially identified 912 records (after removal of duplicates), and further screening resulted in 19 records for full consideration. We identified nine eligible studies for inclusion in the review. There were three first-line studies and six recurrent studies. Five studies used tyrosine kinase inhibitors (TKIs); two studies used monoclonal antibodies; and two studies used targeted vaccines. More recent studies presented greater detail in the conduct of their studies and thus had a lower risk of bias. We observed no evidence benefit in overall survival with the use of anti-EGFR therapy in the first-line or recurrent setting (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76 to 1.04; 3 RCTs, 1000 participants, moderate-certainty evidence; and HR 0.79, 95% CI 0.51 to 1.21, 4 RCTs, 489 participants, low-certainty evidence, respectively). All the interventions were generally well tolerated with low-certainty evidence for lymphopenia (odds ratio (OR) 0.97, 95% CI 0.19 to 4.81; 4 RCTs, 1146 participants), neutropenia (OR 1.29, 95% CI 0.82 to 2.03; 4 RCTs, 1146 participants), and thrombocytopenia (OR 3.69, 95% CI 0.51 to 26.51; 4 RCTs, 1146 participants). A notable toxicity relates to ABT-414, where significant ocular issues were detected. The addition of anti-EGFR therapy showed no evidence of an increase in progression-free survival (PFS) in the first-line setting (HR 0.94, 95% CI 0.81 to 1.10; 2 RCTs, 894 participants, low-certainty evidence). In the recurrent setting, there was an increase in PFS with the use of anti-EGFR therapy (HR 0.75, 95% CI 0.58 to 0.96, 3 RCTs, 275 participants, low-certainty evidence). The available quality of life assessment data showed that anti-EGFR therapies were neither detrimental or beneficial when compared to standard care (not estimable). AUTHORS' CONCLUSIONS: In summary, there is no evidence of a demonstrable overall survival benefit with the addition of anti-EGFR therapy in first-line and recurrent glioblastomas. Newer drugs that are specially designed for glioblastoma targets may raise the possibility of success in this population, but data are lacking at present. Future studies should be more selective in pursuing people displaying specific EGFR targets.
Authors
Lee, A; Arasaratnam, M; Chan, DLH; Khasraw, M; Howell, VM; Wheeler, H
MLA Citation
Lee, Adrian, et al. “Anti-epidermal growth factor receptor therapy for glioblastoma in adults.Cochrane Database Syst Rev, vol. 5, May 2020, p. CD013238. Pubmed, doi:10.1002/14651858.CD013238.pub2.
URI
https://scholars.duke.edu/individual/pub1441548
PMID
32395825
Source
pubmed
Published In
The Cochrane Database of Systematic Reviews
Volume
5
Published Date
Start Page
CD013238
DOI
10.1002/14651858.CD013238.pub2

ATIM-16. PHASE 1 STUDY RESULTS OF M7824 (MSB0011359C), A BIFUNCTIONAL FUSION PROTEIN TARGETING TGF- AND PD-L1, AMONG PATIENTS WITH RECURRENT GLIOBLASTOMA (rGBM).

AbstractBACKGROUNDTGF- signaling promotes tumor immunosuppression; TGF- inhibition in the tumor microenvironment may enhance the response to antiPD-L1 treatment. M7824 is an innovative, first-in-class, bifunctional fusion protein composed of a human antiPD-L1 IgG1 monoclonal antibody fused with two extracellular domains of TGF RII to function as a TGF- trap. We report safety and efficacy of M7824 in patients with rGBM.METHODSIn this efficacy expansion cohort of the ongoing, phase 1 trial NCT02517398, patients with rGBM who progressed after chemoradiation received M7824 1200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal. The primary objective was disease control rate (DCR) per RANO; secondary objectives included safety/tolerability.RESULTSAmong 35 patients, median age was 57 years, 68.6% were male, and 91.4% were at first recurrence. At 15 months minimum follow-up, median treatment duration was 8.1 (range, 2.0–72.1) weeks; four patients remained on treatment at >1 year, and one additional patient decided to stop treatment per protocol at 12 months. Two patients had a partial response, and nine had stable disease (DCR, 31.4% [95% CI, 16.9–49.3]), of which two exhibited early progressive disease and subsequent durable stable disease ongoing for >12 months per investigators assessment. The most common treatment-related adverse events (TRAEs) were gingival bleeding (17.1%), asthenia (14.3%), pruritus, and rash (each 11.4%). Grade 3 TRAEs (6 patients, 17.1%) included diarrhea, eczema, increased liver/pancreatic enzymes, papular rash, papules, one grade 4 asymptomatic increased lipase, and one grade 5 intratumoral hemorrhage (investigator-assessed) coterminous with disease progression.CONCLUSIONSM7824 demonstrated a manageable safety profile and encouraging efficacy in rGBM, including two durable partial responses and a DCR of 31.4%. Further investigation of M7824 in GBM is warranted; future development aims to define molecular characteristics of responders.
Authors
Khasraw, M; Weller, M; Estelles, DL; Kolibaba, K; Lee, C; Gedye, C; De La Fuente, M; Vicente, D; Reardon, D; Ojalvo, L; Helwig, C; Gourmelon, C; Groves, M
MLA Citation
Khasraw, Mustafa, et al. “ATIM-16. PHASE 1 STUDY RESULTS OF M7824 (MSB0011359C), A BIFUNCTIONAL FUSION PROTEIN TARGETING TGF- AND PD-L1, AMONG PATIENTS WITH RECURRENT GLIOBLASTOMA (rGBM).Neuro Oncology, vol. 20, no. Suppl 6, Nov. 2018, pp. vi4–vi4. Epmc, doi:10.1093/neuonc/noy148.011.
URI
https://scholars.duke.edu/individual/pub1428890
Source
epmc
Published In
Neuro Oncology
Volume
20
Published Date
Start Page
vi4
End Page
vi4
DOI
10.1093/neuonc/noy148.011

The role of large volume re-irradiation with Bevacizumab in chemorefractory high grade glioma.

Background and purpose: Current practice in re-irradiation (reRT) of previously treated high-grade gliomas (HGG) has generally been limited to small volume reRT with stereotactic procedures. Less evidence exists for large volume reRT involving treatment volumes equivalent to that used at initial diagnosis. The primary aim of this study was to investigate the outcome of large volume reRT delivered in combination with Bevacizumab (BEV) in patients with recurrent chemorefractory HGG. Methods and materials: Patients with HGG managed with reRT were entered prospectively into a database. Clinicopathological features were recorded including timing of reRT, use of BEV and Dosimetric data. Median survival following reRT was the primary endpoint and association with clinicopathological factors was assessed with cox regression models. Results: Sixty seven patients in total were managed with reRT, 51 patients had glioblastoma and 16 had anaplastic glioma. The median PTV was 145.3 cm3. Median OS post reRT was 7.8 months (95% CI 6.3-9.2 months) in the total cohort and 7.5 months (95% CI: 6.6-8.3 months) for GBM patients. In multivariate analysis of the whole cohort, IDH1 mutation status (p = 0.041) and ECOG status prior to reRT (<0.001) were significantly associated with OS. In terms of safety and toxicity, the majority of patients (66.5%) were ECOG 0-2 three months after treatment. In total, four episodes of suspected radiation necrosis occurred, all in patients treated without upfront BEV. Conclusion: Large volume reRT with bevacizumab is a feasible late salvage option in patients with recurrent HGG and offers meaningful prolongation of survival with low toxicity.
Authors
Chan, J; Jayamanne, D; Wheeler, H; Khasraw, M; Wong, M; Kastelan, M; Guo, L; Back, M
MLA Citation
Chan, Joseph, et al. “The role of large volume re-irradiation with Bevacizumab in chemorefractory high grade glioma.Clin Transl Radiat Oncol, vol. 22, May 2020, pp. 33–39. Pubmed, doi:10.1016/j.ctro.2020.03.005.
URI
https://scholars.duke.edu/individual/pub1434802
PMID
32195378
Source
pubmed
Published In
Clinical and Translational Radiation Oncology
Volume
22
Published Date
Start Page
33
End Page
39
DOI
10.1016/j.ctro.2020.03.005

Adapting to a Pandemic - Conducting Oncology Trials during the SARS-CoV-2 Pandemic.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic has necessitated changes in cancer care delivery as resources are reallocated. Clinical trials and other research activities are inevitably impacted. Start-up activities for new trials may be deferred and recruitment suspended. For patients already enrolled however, there are challenges in continuing treatment on trial. Regulatory bodies have issued guidance on managing clinical trials during the pandemic, including contingency measures for remote study visits, delivery of investigational product, and site monitoring visits. New cancer clinical trial practices during the SARS-CoV-2 pandemic include new risk assessment strategies, decentralized and remote trial coordination, data collection, and delegation of specific therapeutic activities. This experience could provide evidence of more feasible and cost-effective methods for future clinical trial conduct.
Authors
MLA Citation
Tan, Aaron C., et al. “Adapting to a Pandemic - Conducting Oncology Trials during the SARS-CoV-2 Pandemic.Clin Cancer Res, Apr. 2020. Pubmed, doi:10.1158/1078-0432.CCR-20-1364.
URI
https://scholars.duke.edu/individual/pub1437984
PMID
32312892
Source
pubmed
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Published Date
DOI
10.1158/1078-0432.CCR-20-1364

Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers.

The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or rearrangements form a unique sub-class, with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (NTRK), rearrangement during transfection (RET), and neuregulin 1 (NRG1) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (EGFR) mutant and ALK-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases.
Authors
Tan, AC; Itchins, M; Khasraw, M
MLA Citation
Tan, Aaron C., et al. “Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers.Int J Mol Sci, vol. 21, no. 4, Feb. 2020. Pubmed, doi:10.3390/ijms21041416.
URI
https://scholars.duke.edu/individual/pub1432987
PMID
32093103
Source
pubmed
Published In
International Journal of Molecular Sciences
Volume
21
Published Date
DOI
10.3390/ijms21041416

Research Areas:

Anti-cancer
Cancer
Cancer Therapy Resistance
Cancer Vaccines
Cancer genes