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1. Re-irradiation of recurrent IDH-wildtype glioblastoma in the bevacizumab and immunotherapy era: Target delineation, outcomes and patterns of recurrence

Author

Sebastian M. Christ, Gilbert Youssef, Shyam K. Tanguturi, Daniel Cagney, Diana Shi, J. Ricardo McFaline-Figueroa, Ugonma Chukwueke, Eudocia Q. Lee, Caroline Hertler, Nicolaus Andratschke, Michael Weller, David A. Reardon, Daphne Haas-Kogan, Matthias Guckenberger, Patrick Y. Wen, and Rifaquat Rahman

Subjects
Re-irradiation, Recurrent glioblastoma, New systemic therapies, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Introduction and background: While recurrent glioblastoma patients are often treated with re-irradiation, there is limited data on the use of re-irradiation in the setting of bevacizumab (BEV), temozolomide (TMZ) re-challenge, or immune checkpoint inhibition (ICI). We describe target delineation in patients with prior anti-angiogenic therapy, assess safety and efficacy of re-irradiation, and evaluate patterns of recurrence. Materials and methods: Patients with a histologically confirmed diagnosis of glioblastoma treated at a single institution between 2013 and 2021 with re-irradiation were included. Tumor, treatment and clinical data were collected. Logistic and Cox regression analysis were used for statistical analysis. Results: One hundred and seventeen recurrent glioblastoma patients were identified, receiving 129 courses of re-irradiation. In 66 % (85/129) of cases, patients had prior BEV. In the 80 patients (62 %) with available re-irradiation plans, 20 (25 %) had all T2/FLAIR abnormality included in the gross tumor volume (GTV). Median overall survival (OS) for the cohort was 7.3 months, and median progression-free survival (PFS) was 3.6 months. Acute CTCAE grade ≥ 3 toxicity occurred in 8 % of cases. Concurrent use of TMZ or ICI was not associated with improved OS nor PFS. On multivariable analysis, higher KPS was significantly associated with longer OS (p

Published
2024
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2. Less Time Is Less Motion: Analysis of Practical Efficiencies Gained With a Modified Workflow Integrating Planar kV Midimaging With CBCT for Spine Stereotactic Body Radiation Therapy

Author

David Y. Hu, PhD, Yiwen Xu, PhD, Yu-Hui Chen, PhD, Marjan Khosravi, MS, Yulia Lyatskaya, PhD, Jeremy S. Bredfeldt, PhD, Fred L. Hacker, PhD, Tracy A. Balboni, MD, Alexander Spektor, MD, PhD, Daniel Cagney, MD, Raymond Mak, MD, and Mai Anh Huynh, MD, PhD

Subjects
Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Purpose: Our purpose was to optimize an image guided radiation therapy (IGRT) workflow to achieve practical setup accuracy in spine stereotactic body radiation therapy (SBRT). We assessed the time-saving efficiencies gained from incorporating planar kV midimaging as a surrogate for cone beam computed tomography (CBCT) for intrafraction motion monitoring. Methods and Materials: We selected 5 thoracic spine SBRT patients treated in 5 fractions and analyzed patient shifts captured by a modified IGRT workflow using planar kV midimaging integrated with CBCT to maintain a tolerance of 1 mm and 1°. We determined the frequency at which kV midimaging captured intrafraction motion as validated on repeat CBCT and assessed the potential time and dosimetric advantages of our modified IGRT workflow. Results: Patient motion, detected as out-of-tolerance shifts on planar kV midimaging, occurred during 6 of 25 fractions (24%) and were validated on repeat CBCT 100% of the time. Observed intrafraction absolute shifts (mean ± standard deviation) for the 25 fractions were 0.39 ± 0.21, 0.56 ± 0.22, and 0.45 ± 0.21 mm for lateral-longitude-vertical translations and 0.38 ± 0.12°, 0.32 ± 0.09°, and 0.47 ± 0.14° for pitch-roll-yaw rotation, which if uncorrected, could have significantly affected target coverage and increased spinal cord dose. The average times for pretreatment imaging, midtreatment verification, and total treatment time were 8.94, 2.81, and 16.21 minutes. Our modified IGRT workflow reduced the total number of CBCTs required from 120 to 35 (70%) and imaging dose from 126.2 to 43.4 cGy (65.6%) while maintaining high fidelity for our patient population. Conclusions: Accurate patient positioning was effectively achieved with use of multiple 2-dimensional-3-dimensional kV images and an average of 1 verification CBCT scan per fraction. Integration of planar kV midimaging can effectively reduce treatment time associated with spine SBRT delivery and minimize the potential dosimetric effect of intrafraction motion on target coverage and spinal cord dose.

Published
2022
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3. Use of a healthy volunteer imaging program to optimize clinical implementation of stereotactic MR-guided adaptive radiotherapy

Author

Patrick J. Boyle, Elizabeth Huynh, Sara Boyle, Jennifer Campbell, Jessica Penney, Iquan Usta, Emily Neubauer Sugar, Fred Hacker, Christopher Williams, Daniel Cagney, Raymond Mak, and Lisa Singer

Subjects
MR-linac, Magnetic resonance imaging, Adaptive radiotherapy, Training, Workflow, Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Purpose: MR-linacs (MRLs) have enabled the use of stereotactic magnetic resonance (MR) guided online adaptive radiotherapy (SMART) across many cancers. As data emerges to support SMART, uncertainty remains regarding optimal technical parameters, such as optimal patient positioning, immobilization, image quality, and contouring protocols. Prior to clinical implementation of SMART, we conducted a prospective study in healthy volunteers (HVs) to determine optimal technical parameters and to develop and practice a multidisciplinary SMART workflow. Methods: HVs 18 years or older were eligible to participate in this IRB-approved study. Using a 0.35 T MRL, simulated adaptive treatments were performed by a multi-disciplinary treatment team in HVs. For each scan, image quality parameters were assessed on a 5-point scale (5 = extremely high, 1 = extremely poor). Adaptive recontouring times were compared between HVs and subsequent clinical cases with a t-test. Results: 18 simulated treatments were performed in HVs on MRL. Mean parameters for visibility of target, visibility of nearby organs, and overall image quality were 4.58, 4.62, and 4.62, respectively (range of 4–5 for all measures). In HVs, mean ART was 15.7 min (range 4–35), comparable to mean of 16.1 (range 7–33) in the clinical cases (p = 0.8963). Using HV cases, optimal simulation and contouring guidelines were developed across a range of disease sites and have since been implemented clinically. Conclusions: Prior to clinical implementation of SMART, scans of HVs on an MRL resulted in acceptable image quality and target visibility across a range of organs with similar ARTs to clinical SMART. We continue to utilize HV scans prior to clinical implementation of SMART in new disease sites and to further optimize target tracking and immobilization. Further study is needed to determine the optimal duration of HV scanning prior to clinical implementation.

Published
2020
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4. Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA)

Author

Paul W. Sperduto, Penny Fang, Jing Li, William Breen, Paul D. Brown, Daniel Cagney, Ayal Aizer, James B. Yu, Veronica Chiang, Supriya Jain, Laurie E. Gaspar, Sten Myrehaug, Arjun Sahgal, Steve Braunstein, Penny Sneed, Brent Cameron, Albert Attia, Jason Molitoris, Cheng-Chia Wu, Tony J.C. Wang, Natalie A. Lockney, Kathryn Beal, Jessica Parkhurst, John M. Buatti, Ryan Shanley, Emil Lou, Daniel D. Tandberg, John P. Kirkpatrick, Diana Shi, Helen A. Shih, Michael Chuong, Hirotake Saito, Hidefumi Aoyama, Laura Masucci, David Roberge, and Minesh P. Mehta

Subjects
Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background: Patients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985–2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database. Methods: An IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA. Results: Median survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0–1, 1.5–2, 2.5–3.0 and 3.5–4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0). Conclusions: Brain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com. Keywords: Gastrointestinal cancers, Brain metastases, Prognosis, End-of-life

Published
2019
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5. Phase I study of a novel glioblastoma radiation therapy schedule exploiting cell-state plasticity

Author

Jamie A Dean, Shyam K Tanguturi, Daniel Cagney, Kee-Young Shin, Gilbert Youssef, Ayal Aizer, Rifaquat Rahman, Lubna Hammoudeh, David Reardon, Eudocia Lee, Jorg Dietrich, Kaoru Tamura, Masaru Aoyagi, Lacey Wickersham, Patrick Y Wen, Paul Catalano, Daphne Haas-Kogan, Brian M Alexander, and Franziska Michor

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

Background Glioblastomas comprise heterogeneous cell populations with dynamic, bidirectional plasticity between treatment-resistant stem-like and treatment-sensitive differentiated states, with treatment influencing this process. However, current treatment protocols do not account for this plasticity. Previously, we generated a mathematical model based on preclinical experiments to describe this process and optimize a radiation therapy fractionation schedule that substantially increased survival relative to standard fractionation in a murine glioblastoma model. Methods We developed statistical models to predict the survival benefit of interventions to glioblastoma patients based on the corresponding survival benefit in the mouse model used in our preclinical study. We applied our mathematical model of glioblastoma radiation response to optimize a radiation therapy fractionation schedule for patients undergoing re-irradiation for glioblastoma and developed a first-in-human trial (NCT03557372) to assess the feasibility and safety of administering our schedule. Results Our statistical modeling predicted that the hazard ratio when comparing our novel radiation schedule with a standard schedule would be 0.74. Our mathematical modeling suggested that a practical, near-optimal schedule for re-irradiation of recurrent glioblastoma patients was 3.96 Gy × 7 (1 fraction/day) followed by 1.0 Gy × 9 (3 fractions/day). Our optimized schedule was successfully administered to 14/14 (100%) patients. Conclusions A novel radiation therapy schedule based on mathematical modeling of cell-state plasticity is feasible and safe to administer to glioblastoma patients.

Published
2022

6. Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors

Author

Paul W. Sperduto, Brian De, Jing Li, David Carpenter, John Kirkpatrick, Michael Milligan, Helen A. Shih, Tugce Kutuk, Rupesh Kotecha, Hajime Higaki, Manami Otsuka, Hidefumi Aoyama, Malie Bourgoin, David Roberge, Salah Dajani, Sean Sachdev, Jordan Gainey, John M. Buatti, William Breen, Paul D. Brown, Lisa Ni, Steve Braunstein, Matthew Gallitto, Tony J.C. Wang, Ryan Shanley, Emil Lou, Jay Shiao, Laurie E. Gaspar, Satoshi Tanabe, Toshimichi Nakano, Yi An, Veronica Chiang, Liang Zeng, Hany Soliman, Hesham Elhalawani, Daniel Cagney, Evan Thomas, Drexell H. Boggs, Manmeet S. Ahluwalia, and Minesh P. Mehta

Subjects
Cancer Research, Radiation, Lung Neoplasms, Brain Neoplasms, Adenocarcinoma of Lung, Adenocarcinoma, Prognosis, Small Cell Lung Carcinoma, B7-H1 Antigen, ErbB Receptors, Oncology, Carcinoma, Non-Small-Cell Lung, Humans, Radiology, Nuclear Medicine and imaging, Anaplastic Lymphoma Kinase, Retrospective Studies
Abstract

Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly.A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA.Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P.01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies.Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

Published
2021

7. NIMG-59. EVALUATION OF THE RESPONSE ASSESSMENT CRITERIA IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA

Author

Gilbert Youssef, Rifaquat Rahman, Camden Bay, Wei Wang, Mary Jane Lim-Fat, Omar Arnaout, Wenya Linda Bi, Daniel Cagney, Yuh-Shin Chang, Timothy Cloughesy, Matthew DeSalvo, Benjamin Ellingson, Elizabeth Gerstner, Luis Nicolas Gonzalez Castro, Jeffrey Guenette, Albert Kim, Eudocia Lee, J Ricardo McFaline-Figueroa, Christopher Potter, David A Reardon, Raymond Huang, and Patrick Y Wen

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

BACKGROUND We sought to compare the Response Assessment in Neuro-Oncology (RANO), modified RANO (mRANO), and immunotherapy RANO (iRANO) in a large population of patients with newly diagnosed (nGBM) and recurrent (rGBM) glioblastoma. METHODS Bidimensional measurements of enhancing disease and FLAIR sequence evaluation were performed by two independent readers on brain MRIs of consecutive patients with IDH-wildtype nGBM and rGBM treated at a single institution. Discrepancies were evaluated by a third reader. Dates of disease progression (PD) were identified using RANO, mRANO, iRANO, and other response assessment criteria variations. Spearman’s correlations between PFS and OS were calculated using iterative multiple imputations for censored observations. RESULTS 526 nGBM and 580 rGBM cases were included. Spearman’s correlations were not significantly different between RANO and mRANO in nGBM (0.69 [95% CI 0.62 to 0.75] vs. 0.67 [0.60, 0.73]) and rGBM (0.48 [0.40, 0.55] vs. 0.50 [0.42, 0.57]). Evaluation of FLAIR did not improve the correlation in patients who received antiangiogenic therapy. Acquisition of confirmation scans was associated with increased correlation only when PD was identified within 12 weeks of completion of radiation in nGBM. The use of the post-radiation MRI as a baseline was associated with increased correlation compared to use of the pre-radiation MRI in nGBM (0.67 [0.60, 0.73] vs. 0.53 [0.42, 0.62]). The correlation with iRANO was similar to RANO and mRANO among 98 patients with nGBM and 175 patients with rGBM who received immunotherapy. CONCLUSIONS RANO and mRANO demonstrated similar correlations between PFS and OS. The evaluation of FLAIR can be omitted, while confirmation scans were only beneficial in nGBM in the first 12 weeks after completion of radiation. There was a trend in favor of the post-radiation MRI as the baseline scan in nGBM. The use of iRANO criteria did not add a significant benefit in patients who received immunotherapy.

Published
2022

8. Evaluation of the response assessment criteria in newly diagnosed and recurrent glioblastoma

Author

Gilbert Youssef, Rifaquat Rahman, Mary Jane Lim-Fat, Camden Bay, Wenya Linda L. Bi, Daniel Cagney, YuhShin Chang, Matthew Nicholas Desalvo, Thomas Flood, Elizabeth R. Gerstner, Luis Nicolas Gonzalez Castro, Jeffrey Guenette, Albert Eusik Kim, Eudocia Quant Lee, J. Ricardo Ricardo McFaline Figueroa, Christopher Potter, David A. Reardon, Benjamin M. Ellingson, Raymond Yi-kun Huang, and Patrick Y. Wen

Subjects
Cancer Research, Oncology
Abstract

2020 Background: The Response Assessment in Neuro-Oncology (RANO) and modified RANO (mRANO) criteria are the two most widely used criteria to evaluate treatment response in glioblastoma (GBM) clinical trials. Unlike RANO, mRANO omits the evaluation of FLAIR sequence and requires a repeat scan to confirm responses. It also uses the post-radiation (RT) MRI as a baseline MRI in the newly diagnosed setting instead of the pre-RT MRI used in RANO. We sought to compare the 2 response assessment criteria and evaluate the differences between them in a large patient population. We also sought to compare them to immunotherapy RANO (iRANO) in patients who received immunotherapy. Methods: We conducted a retrospective review of consecutive patients with newly diagnosed (nGBM) and recurrent (rGBM) IDH wild-type GBM treated at Dana-Farber Cancer Institute from 2014 to 2020. Bidimensional measurements of enhancing disease and evaluation of FLAIR sequences were performed by two independent readers on patients’ brain MRIs obtained before change of treatment, and discrepancies were evaluated by a third reader. Dates of disease progression (PD) were identified using RANO, mRANO, iRANO, and other response assessment criteria variations. Spearman’s correlations between PFS and OS were calculated using an iterative multiple imputation method to account for any right-censoring. Results: 526 and 580 patients were included in the newly diagnosed and recurrent cohorts, respectively. Spearman’s correlations were not significantly different between RANO and mRANO in the nGBM (0.69 [95% CI 0.62 to 0.75] vs. 0.67 [0.60, 0.73]) and rGBM (0.45 [0.37, 0.52] vs. 0.50 [0.42, 0.57]) cohorts. Evaluation of FLAIR sequences did not improve the correlation between PFS and OS in patients who received antiangiogenic therapy. Addition of confirmation scans was associated with stronger Spearman’s correlations only when PD was identified within 12 weeks of completion of RT in the nGBM cohort, but did not affect the Spearman’s correlations in the rGBM cohort. The use of the post-RT MRI as a baseline was associated with a higher Spearman’s correlation in nGBM than the use of pre-RT MRI (0.67 [0.60, 0.73] vs. 0.53 [0.42, 0.62]). Among 98 patients with nGBM and 175 patients with rGBM who received immunotherapy, the Spearman’s correlations (nGBM and rGBM) with iRANO (0.63 [0.44, 0.76] and 0.34 [0.17, 0.49]) were similar to RANO (0.73 [0.60, 0.82] and 0.42 [0.28, 0.54]) and mRANO (0.65 [0.48, 0.77] and 0.43 [0.28, 0.56]). Conclusions: RANO and mRANO demonstrated similar correlation between PFS and OS. The evaluation of FLAIR can be omitted, while confirmation scans appear to be only beneficial in the nGBM settings during the first 12 weeks of completion of RT. There was a nonsignificant trend in favor of the use of post-RT MRI as the baseline scan in the nGBM setting. The application of iRANO criteria did not add significant benefit in patients who received immunotherapy.

Published
2022

9. CTNI-12. PRELIMINARY RESULTS OF THE ABEMACICLIB ARM IN THE INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT): A PHASE II PLATFORM TRIAL USING BAYESIAN ADAPTIVE RANDOMIZATION

Author

Lakshmi Nayak, Shanna Dowling, Brian M. Alexander, David Meredith, Sandro Santagata, E. Antonio Chiocca, Omar Arnaout, Brittany Fisher-Longden, Daphne H. Haas-Kogan, Geffrey Fell, Jack Geduldig, Rifaquat Rahman, Daniel Cagney, Ayal Aizer, Howard Colman, Christine Lu-Emerson, Tracy T. Batchelor, Thomas Kaley, Jan Drappatz, Patrick Y. Wen, Andrew B. Lassman, Maria Lavallee, Mehdi Touat, Ingo K. Mellinghoff, David Schiff, Manmeet Ahluwalia, Rameen Beroukhim, Shyam Tanguturi, Lisa Doherty, Lorenzo Trippa, Jaroslaw T. Hepel, Wenya Linda Bi, David A. Reardon, Jennifer Bruno, Sarah Gaffey, Keith L. Ligon, Ugonma Chukwueke, Christine McCluskey, Heinrich Elinzano, Evanthia Galanis, Mary Welch, Isabel Arrillaga-Romany, Fiona Watkinson, Pierpaolo Peruzzi, J Ricardo McFaline-Figueroa, Eudocia Q. Lee, and L. Burt Nabors

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Temozolomide, business.industry, Screening Trial, Bayesian probability, Clinical Trials: Non-Immunologic, Adaptive randomization, medicine.disease, chemistry.chemical_compound, Pharmaceutical Adjuvants, chemistry, Internal medicine, medicine, Neurology (clinical), business, Abemaciclib, neoplasms, medicine.drug, Glioblastoma
Abstract

BACKGROUND The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for ER/PR/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150–200 mg orally BID) without temozolomide. Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. RESULTS There were 123 patients (50 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (p=0.03, logrank test) with abemaciclib (median 6.31 months 95% CI [5.29, 8.18]) compared to the control arm (5.16 months 95% CI [4.37, 6.28]). 28/50 control and 36/73 abemaciclib patients remain alive. CONCLUSION Preliminary analysis suggests that abemaciclib increases PFS compared to control. Updated toxicity, PFS and survival data and potential genomic biomarker associations will be presented.

Published
2020

10. CTNI-05. PRELIMINARY RESULTS OF THE NERATINIB ARM IN THE INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT): A PHASE II PLATFORM TRIAL USING BAYESIAN ADAPTIVE RANDOMIZATION

Author

Isabel Arrillaga-Romany, Lorenzo Trippa, Geffrey Fell, Eudocia Quant Lee, Rifaquat Rahman, Mehdi Touat, Christine McCluskey, Jennifer Bruno, Sarah Gaffey, Jan Drappatz, Andrew Lassman, Evanthia Galanis, Manmeet Ahluwalia, Howard Colman, L Burt Nabors, Jaroslaw Hepel, Heinrich Elinzano, Thomas Kaley, Ingo K Mellinghoff, David Schiff, Ugonma Chukwueke, Rameen Beroukhim, Lakshmi Nayak, J Ricardo McFaline-Figueroa, Tracy Batchelor, Christine Lu-Emerson, Wenya Linda Bi, Omar Arnaout, Pierpaolo Peruzzi, Daphne Haas-Kogan, Shyam Tanguturi, Daniel Cagney, Ayal Aizer, Mary Welch, Lisa Doherty, Maria Lavallee, Brittany Fisher-Longden, Shanna Dowling, Jack Geduldig, Fiona Watkinson, Sandro Santagata, David Meredith, E Antonio Chiocca, David Reardon, Keith Ligon, Brian Alexander, and Patrick Wen

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

BACKGROUND EGFR is amplified in over 50% of glioblastoma and 20-30% have EGFRvIII mutations. Neratinib is a potent inhibitor of EGFR/HER2 approved for metastatic HER2+ breast cancer. To efficiently evaluate the potential impact of neratinib on overall survival (OS) in newly-diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, neratinib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and accelerate identification of novel therapies for phase III testing. Initial randomization was equal between neratinib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). We report preliminary results for the neratinib arm. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide or standard radiochemotherapy followed by adjuvant neratinib (240 mg daily). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between neratinib efficacy and EGFR amplification was also investigated. RESULTS There were 144 patients (70 control; 74 neratinib). Neratinib was reasonably well-tolerated with no new toxicity signals identified. PFS was compared (HR 0.84; p=0.38, logrank test – not significant) between the neratinib (median 6.05 months) and control (median 5.82 months) arms. For patients EGFR pathway activation the PFS HR was 0.53 (p-value=0.03 – significant, median PFS: neratinib, 6.21 months, control, 5.26 months). However, there was no significant improvement in OS in EGFR amplified/mutated patients (HR 1.05; p-value 0.87) between neratinib (median 14.2) compared to the control arm (median 14.6). CONCLUSION Neratinib prolonged PFS in the EGFR positive subpopulation but there was no overall PFS benefit, or any OS improvement.

Published
2021

11. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part two

Author

Casey Ager, Matthew Reilley, Courtney Nicholas, Todd Bartkowiak, Ashvin Jaiswal, Michael Curran, Tina C. Albershardt, Anshika Bajaj, Jacob F. Archer, Rebecca S. Reeves, Lisa Y. Ngo, Peter Berglund, Jan ter Meulen, Caroline Denis, Hormas Ghadially, Thomas Arnoux, Fabien Chanuc, Nicolas Fuseri, Robert W. Wilkinson, Nicolai Wagtmann, Yannis Morel, Pascale Andre, Michael B. Atkins, Matteo S. Carlino, Antoni Ribas, John A. Thompson, Toni K. Choueiri, F. Stephen Hodi, Wen-Jen Hwu, David F. McDermott, Victoria Atkinson, Jonathan S. Cebon, Bernie Fitzharris, Michael B. Jameson, Catriona McNeil, Andrew G. Hill, Eric Mangin, Malidi Ahamadi, Marianne van Vugt, Mariëlle van Zutphen, Nageatte Ibrahim, Georgina V. Long, Robyn Gartrell, Zoe Blake, Ines Simoes, Yichun Fu, Takuro Saito, Yingzhi Qian, Yan Lu, Yvonne M. Saenger, Sadna Budhu, Olivier De Henau, Roberta Zappasodi, Kyle Schlunegger, Bruce Freimark, Jeff Hutchins, Christopher A. Barker, Jedd D. Wolchok, Taha Merghoub, Elena Burova, Omaira Allbritton, Peter Hong, Jie Dai, Jerry Pei, Matt Liu, Joel Kantrowitz, Venus Lai, William Poueymirou, Douglas MacDonald, Ella Ioffe, Markus Mohrs, William Olson, Gavin Thurston, Cristian Capasso, Federica Frascaro, Sara Carpi, Siri Tähtinen, Sara Feola, Manlio Fusciello, Karita Peltonen, Beatriz Martins, Madeleine Sjöberg, Sari Pesonen, Tuuli Ranki, Lukasz Kyruk, Erkko Ylösmäki, Vincenzo Cerullo, Fabio Cerignoli, Biao Xi, Garret Guenther, Naichen Yu, Lincoln Muir, Leyna Zhao, Yama Abassi, Víctor Cervera-Carrascón, Mikko Siurala, João Santos, Riikka Havunen, Suvi Parviainen, Akseli Hemminki, Angus Dalgleish, Satvinder Mudan, Mark DeBenedette, Ana Plachco, Alicia Gamble, Elizabeth W. Grogan, John Krisko, Irina Tcherepanova, Charles Nicolette, Pooja Dhupkar, Ling Yu, Eugenie S. Kleinerman, Nancy Gordon, Italia Grenga, Lauren Lepone, Sofia Gameiro, Karin M. 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Ostrowski, Madhuri Koti, Katrina Au, Nichole Peterson, Peter Truesdell, Gillian Reid-Schachter, Charles Graham, Andrew Craig, Julie-Ann Francis, Beatrix Kotlan, Timea Balatoni, Emil Farkas, Laszlo Toth, Mihaly Ujhelyi, Akos Savolt, Zoltan Doleschall, Szabolcs Horvath, Klara Eles, Judit Olasz, Orsolya Csuka, Miklos Kasler, Gabriella Liszkay, Eytan Barnea, Collin Blakely, Patrick Flynn, Reid Goodman, Raphael Bueno, David Sugarbaker, David Jablons, V. Courtney Broaddus, Brian West, Paul R. Kunk, Joseph M. Obeid, Kevin Winters, Patcharin Pramoonjago, Edward B. Stelow, Todd W. Bauer, Osama E. Rahma, Adam Lamble, Yoko Kosaka, Fei Huang, Kate A. Saser, Homer Adams, Christina E. Tognon, Ted Laderas, Shannon McWeeney, Marc Loriaux, Jeffery W. Tyner, Brian J. Druker, Evan F. Lind, Zhuqing Liu, Shanhong Lu, Lawrence P. Kane, Gulidanna Shayan, Julia Femel, Ryan Lane, Jamie Booth, Amanda W. Lund, Anthony Rodriguez, Victor H. Engelhard, Alessandra Metelli, Bill X. Wu, Caroline W. Fugle, Rachidi Saleh, Shaoli Sun, Jennifer Wu, Bei Liu, Zihai Li, Zachary S. Morris, Emily I. Guy, Clinton Heinze, Jasdeep Kler, Monica M. Gressett, Lauryn R. Werner, Stephen D. Gillies, Alan J. Korman, Hans Loibner, Jacquelyn A. Hank, Alexander L. Rakhmilevich, Paul M. Harari, Paul M. Sondel, Erica Huelsmann, Joseph Broucek, Dorothee Brech, Tobias Straub, Martin Irmler, Johannes Beckers, Florian Buettner, Elke Schaeffeler, Matthias Schwab, Elfriede Noessner, Alison Wolfreys, Andre Da Costa, John Silva, Andrea Crosby, Ludovicus Staelens, Graham Craggs, Annick Cauvin, Sean Mason, Alison M. Paterson, Andrew C. Lake, Caroline M. Armet, Rachel W. O’Connor, Jonathan A. Hill, Emmanuel Normant, Ammar Adam, Detlev M. Biniszkiewicz, Scott C. Chappel, Vito J. Palombella, Pamela M. Holland, Annette Becker, Manmohan R. Leleti, Eric Newcomb, Joanne B. L. Tan, Suthee Rapisuwon, Arash Radfar, Kellie Gardner, Geoffrey Gibney, Michael Atkins, Keith R. Rennier, Robert Crowder, Ping Wang, Russell K. Pachynski, Rosa M. Santana Carrero, Sarai Rivas, Figen Beceren-Braun, Scott Anthony, Kimberly S. Schluns, Deepali Sawant, Maria Chikina, Hiroshi Yano, Creg Workman, Elise Salerno, Ileana Mauldin, Donna Deacon, Sofia Shea, Joel Pinczewski, Thomas Gajewski, Stefani Spranger, Brendan Horton, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Raj K. Puri, Randy F. Sweis, Riyue Bao, Jason Luke, Marie-Nicole Theodoraki, Frances-Mary Mogundo, Haejung Won, Dayson Moreira, Chan Gao, Xingli Zhao, Priyanka Duttagupta, Jeremy Jones, Massimo D’Apuzzo, and Sumanta Pal

Subjects
0301 basic medicine, Pharmacology, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Immunology, Cancer, Immunotherapy, medicine.disease, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Family medicine, Molecular Medicine, Immunology and Allergy, Medicine, business
Abstract

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

Published
2016

Catalog

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