Gondi, Vinai

Abstract BACKGROUND Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The objective of the METIS study [NCT02831959] is evaluation of the efficacy and safety of TTFields in NSCLC patients with brain metastases. METHODS NSCLC patients (N=270) with 1–10 brain metastases were randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The portable device delivered TTFields to the brain using 4 transducer arrays, while patients received the best standard-of-care for systemic disease. Patients were followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT, surgical resection of metastases, or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. On September, 2019, an independent Data Monitoring Committee (DMC) reviewed METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.

Abstract The incidence of brain metastasis is increasing as improvements in systemic therapy lead to increased survival. This provides new and challenging clinical decisions for patients who are trying to balance the risk of recurrence or progression with treatment-related side effects, and it requires appropriate management strategies from multidisciplinary teams. Improvements in prognostic assessment and systemic therapy with increasing activity in the brain allow for individualized care to better guide the use of local therapies and/or systemic therapy. Here, we review the current landscape of brain-directed therapy for the treatment of brain metastasis in the context of recent improved systemic treatment options. We also discuss emerging treatment strategies including targeted therapies for patients with actionable mutations, immunotherapy, modern whole-brain radiation therapy, radiosurgery, surgery, and clinical trials.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Abstract BACKGROUND: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The METIS study [NCT02831959] investigates the efficacy and safety of TTFields in NSCLC patients with brain metastases. Study Design: NSCLC patients (N=270) with 1–10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, > 18 hours/day) within 7 days of SRS or supportive care. The portable device delivers TTFields to the brain using 4 transducer arrays, while patients receive the best standard-of-care for systemic disease. Patients are followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. In August 2018, an independent Data Monitoring Committee (DMC) performed a review of the METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.

Abstract BACKGROUND NRG-CC001 sought to evaluate the neuro-protective effects of avoiding the peri-hippocampal stem cell niche using intensity-modulated radiotherapy during WBRT. METHODS Patients with brain metastasis were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+ Memantine (M) (30Gy in 10 fractions). Standardized NCF tests and the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) were obtained at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure defined using the reliable change index. Pre-specified secondary endpoints included patient-reported symptoms using the MDASI-BT. Time to NCF was reported as cumulative incidence (with death without NCF failure as a competing risk); between-arms differences were tested using Gray’s test. Deterioration at discrete time-points were tested using chi-square tests. MDASI-BT symptom burden, interference, and cognitive and neurologic burden were analyzed using mixed effects models and t-tests within the model using Hochberg’s multiplicity adjustment. RESULTS A total of 518 patients were randomized from 7/2016 to 3/2018. Median follow-up for alive patients was 12.1 mos, with no difference between arms in terms of toxicity, overall survival or intracranial progression-free survival. HA-WBRT+M was associated with lower risk of NCF failure (adjusted HR=0.739, 95% CI: 0.577–0.945, p=0.0.016), with differences first noted at 4 mos in Trail Making Test Part-B (23.3% vs. 40.4% deteriorated, p=0.012). Age did not dilute treatment effect. HA-WBRT+M was associated with reduced cognitive symptom burden in an imputed model (estimate=-0.29, p=0.0425), and also reduced overall symptom burden (p< 0.0001) and interference (p< 0.0016) at 6 mos. CONCLUSIONS The addition of HA to WBRT+M preserved NCF and reduced patient reported cognitive symptom burden, overall symptom burden and symptom interference and should be considered standard of care for any patient fit enough to have WBRT. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.

Abstract Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment comprising alternating electric fields that have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The METIS study [NCT02831959] investigates the efficacy and safety of TTFields in NSCLC patients with brain metastases. NSCLC patients (N=270) with 1–10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, &gt; 18 hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays, while patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. In August 2018, an independent Data Monitoring Committee (DMC) performed a review of the METIS trial data collected to that point. The DMC concluded that no unexpected safety issues have emerged on the study, and recommended to continue the METIS study as planned.

Abstract PURPOSE: RTOG 0933 demonstrated benefits to memory following HA-WBRT, supporting the hypothesis of hippocampal radiosensitivity and associated memory specificity. However, some patients demonstrated cognitive decline, suggesting mechanisms outside hippocampal radiosensitivity playing a role. WMI has been implicated in RT-induced cognitive decline. This secondary analysis explored the relationship between pre-treatment WMI and memory following HA-WBRT. METHODS AND MATERIALS: 113 patients received HA-WBRT. Standardized cognitive assessments were performed at baseline, 2, 4, and 6 months. The primary endpoint was Hopkins Verbal Learning Test Delayed Recall (HVLT-DR) at 4 mos. Secondary endpoints included HVLT Total Recall (HVLT-TR) and Recognition (HVLT-Recog). Of 113 patients, 34 underwent pre-treatment and 4-month post-treatment HVLT testing and pre-treatment post-contrast volumetric T1 and axial T2/FLAIR MRI. Volumetric analysis of metastatic disease burden and disease-unrelated WMI was conducted on the pre-treatment MRI. Correlational analyses were performed examining the relationship between pre-treatment WMI and HVLT outcomes following HA-WBRT. RESULTS: Correlation was found between larger volumes of pre-treatment WMI and decline in HVLT-Recog (r=.54, p&lt; .05) and a correlational trend was observed between larger volume of pre-treatment WMI and decline in HVLT-DR (r=.31, p=.08). Patients with higher pre-treatment disease burden experienced a greater magnitude of stability or positive shift in HVLT-recall and –delayed recall following HA-WBRT. (r=-.36 and r=-.36, p’s &lt; .05), compared to the magnitude of stability/positive shift in those with lesser disease burden. CONCLUSION: In patients receiving HA-WBRT, pre-treatment-WMI predicts memory decline, suggesting white matter integrity pre-treatment contributes to the pathogenesis of post-WBRT cognitive toxicity independent of hippocampal stem cell radiosensitivity. Less decline or improvement in HVLT following HA-WBRT for patients with higher pre-treatment intracranial metastatic burden supports the importance of WBRT-induced intracranial control on cognition. These imaging biomarkers for cognitive toxicity will be further explored on NRG CC001 and CC003, phase III trials of WBRT with or without HA.

Abstract BACKGROUND: NRG CC001, a phase III trial of WBRT+memantine (WBRT+M) with or without Hippocampal Avoidance (HA), sought to assess the neuro-protective effects of lowering the radiation dose received by the hippocampus. METHODS: Patients (pts) with brain metastases were stratified by RPA class and prior radiosurgery/surgery and randomized to either WBRT+M or HA-WBRT+M (30Gy/10 fractions). Standardized neurocognitive function (NCF) tests were performed at baseline, 2, 4, 6, and 12 months (mos.). The primary endpoint was NCF failure, defined as decline using the reliable change index on Hopkins Verbal Learning Test-Revised, Trail Making Test, or Controlled Oral Word Association. Cumulative incidence estimated NCF failure (death without NCF failure was competing risk); between-arms differences tested using Gray’s test. Deterioration at each collection time point was tested using a chi-square test. Patient-reported symptoms were assessed using the MD Anderson Symptom Inventory with Brain Tumor module and analyzed using mixed effects models and t-tests. RESULTS: From 7/2016 to 3/2018, 518 patients were randomized. Median follow-up was 7.9 mos. HA-WBRT+M was associated with lower NCF failure risk (adjusted HR=0.74, p=0.02) due to lower risk of deterioration in executive function at 4 mos. (p=0.01); and encoding (p=0.049) and consolidation (p=0.02) at 6 mos. Age≤61 predicted for lower NCF failure risk (HR=0.60, p=0.0002); non-significant test for interaction indicated independent effects of HA and age. Patient-reported fatigue (p=0.036); difficulty speaking (p=0.049); and problems remembering things (p=0.013) at 6 mos. favored the HA-WBRT+M arm. Imputation models accounting for missing data also favored the HA-WBRT+M arm for patient-reported cognition (p=0.011) and symptom interference (p=0.008) at 6 mos. Treatment arms did not significantly differ in toxicity; intracranial progression or overall survival. CONCLUSIONS: While achieving similar intracranial control and survival; Hippocampal Avoidance during WBRT+M for brain metastases better preserves NCF and patient-reported symptoms. Supported by UG1CA189867 (NCORP) and DCP from the NCI.

Abstract Background: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising low intensity alternating electric fields. TTFields has demonstrated efficacy in non-small cell lung cancer (NSCLC) in in vitro and in vivo models, and in a Phase I/II clinical study. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. This prospective, multicenter study [NCT02831959] investigated the efficacy, safety and neurocognitive outcomes of TTFields in NSCLC patients with brain metastases. Methods: NSCLC patients (N=270) with 1-10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, &gt; 18 hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays and allows normal daily activities. Patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Patients in the control arm are allowed to cross over to TTFields arm at the time of second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2-10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1-4 and 5-10 brain metastases; bi-monthly intracranial progression rate from 2-12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57. Citation Format: Minish P Mehta, Vinai Gondi, Manmeet Ahluwalia, Paul D. Brown. Phase III METIS study: Tumor Treating Fields (150 kHz) and radiosurgery for supra- and/or infratentorial brain metastases (1-10) from non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT172.