CNS Progression-free Survival Research Articles

Abstract OT3-01-08: NRG oncology/RTOG 1119: Phase II randomized study of whole brain radiotherapy with concurrent lapatinib in patients with brain met from HER2-positive breast cancer — A collaborative study of RTOG and KROG (NCT01622868)

Abstract Background: The addition of trastuzumab to cytotoxic chemotherapy has improved outcomes for patients with HER2+ breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of trastuzumab may contribute to the increased incidence of brain metastases (mets) in these patients. Half of these patients die of intracranial disease progression rather than extracranial systemic disease. Therefore, strategies to improve survival must include increased CNS disease control. Lapatinib crosses the BBB & demonstrates modest activity against intracranial mets. Based upon preclinical data & phase I study results, it's hypothesized that lapatinib plus WBRT can improve the intracranial disease control compared to whole brain radiotherapy (WBRT) alone. Trial design : RTOG 1119 is a randomized phase II trial that will evaluate if there is a sufficient enough signal in improved 12-week complete response (CR) rate following WBRT with the addition of lapatinib versus WBRT alone in patients with brain met from HER2+ breast cancer to warrant a future phase III trial. Eligibility criteria: Eligibility includes HER2+ breast cancer with at least one measurable, unirradiated parenchymal brain met (≥10 mm if solitary, & > 5 mm if multiple on enhanced MRI). The two populations targeted for accrual include patients with 1) newly diagnosed, multiple brain mets or 2) progressive brain mets after stereotactic radiosurgery (SRS) or surgical resection of 1-3 mets. Patients are stratified by breast-specific graded prognostic assessment; use of non-CNS penetrating HER2 targeted therapy; & prior SRS or surgical resection. Non-CNS penetrating HER2 targeted therapy is permitted throughout the study, but patients not on trastuzumab, pertuzumab or any other breast cancer therapy at study entry are not permitted to begin this therapy while on protocol treatment, but may begin it 24 hours after its completion. Prior lapatinib is allowed, last dose > 21 days prior to study entry. Specific aims: Primary objective is to determine if there is an increase in CR rate in the brain at 12 weeks post WBRT as determined by MRI scan of the brain, with the addition of lapatinib to WBRT compared to WBRT alone. Secondary objectives includes: CR rate at 4 weeks on MRI post WBRT, objective response rate on MRI at 4 & 12 weeks, evaluation of lesion specific MRI response rates; CNS progression-free survival rate, overall survival rate, & adverse event rates. Statistical methods: The randomization of experimental & control arms is set as 1:1. With 114 eligible subjects there will be 86% power to detect a 15% absolute increase in CR rate at a significance level of 0.10, using a 1-sided Z-test for 2 proportions. Targeted accrual is 143 accounting for up to a 5% ineligibility rate, 15% patients not evaluable for the primary endpoint due to death, patient withdrawal, or other reasons. Present accrual (6-1-2015): 52. Targeted accrual: 143. Contact Information: Protocol: CTSU member web site https://www.ctsu.org. Enrollment: OPEN at https://open.ctsu.org. Supported by NCI U10 grants CA21661, CA180868, CA180822, CA37422 & UG1CA189867. Citation Format: White JR, Moughan J, Kim IA, Peereboom DM, De Los Santos JF, Sperduto PW, Mehta MP. NRG oncology/RTOG 1119: Phase II randomized study of whole brain radiotherapy with concurrent lapatinib in patients with brain met from HER2-positive breast cancer — A collaborative study of RTOG and KROG (NCT01622868). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-01-08.

Low Rate of Subsequent Whole Brain Radiotherapy Following a Policy of Local Therapy with MRI Surveillance for Central Nervous System Oligometastases

Background: Palliative Whole Brain Radiotherapy (WBRT) for cerebral metastases has potential morbidity and in large randomized studies has not shown a clear survival benefit. This study audits the outcome of patients with cerebral oligometastatic disease (which we defined as 1-4 lesions on MRI) who were managed with an active policy avoiding WBRT utilising local therapies and MRI surveillance. Methods: A clinical audit was performed of 31 patients with cerebral oligometastases referred for radiation therapy at the Northern Sydney Cancer Centre between July 2009 and December 2012. Patients were offered management with a programme of local therapy (neurosurgery, stereotactic radiosurgery or intensity modulated radiotherapy, or combined modality therapy) followed by protocol based MRI surveillance. Systemic therapy was delivered as indicated for extra-cranial disease. Data on patient, tumour and treatment factors was collected using a prospective database. Results: Median follow-up for surviving patients is 23 months. Compliance with MRI surveillance was good (87%). 21 patients had CNS progression, of which 12 were detected by MRI surveillance without symptoms. Median CNS progression free survival was 11 months (95% CI: 4.9 - 17.1 months). Only 5 patients (16%) received WBRT at relapse. 16 patients died during follow-up with a median survival of 20 months (95% CI: 10.6 – 29.4 months), with cause of death attributable to CNS disease in 6 patients. Conclusion: WBRT Avoidance with MRI surveillance is an acceptable management policy after local therapy for patients diagnosed with cerebral oligometastases. In our study, the rate of CNS progression was acceptable, it was not associated with increased mortality due to uncontrolled CNS disease and WBRT was avoided in the majority of these patients.

BMET-20RTOG1119 PHASE II RANDOMIZED STUDY OF WHOLE BRAIN RADIOTHERAPY WITH CONCURRENT LAPATINIB IN PATIENTS WITH BRAIN METASTASIS FROM Her2-POSITIVE BREAST CANCER: A COLLABORATIVE STUDY OF NRG AND KROG (NCT01622868)

BACKGROUND: The addition of trastuzumab to cytotoxic chemotherapy has improved outcomes for patients with HER2 positive breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of trastuzumab may contribute to the increased incidence of brain metastasis in these patients. Half of these patients die of intracranial disease progression rather than extracranial disease. Therefore, strategies to improve survival must include increased CNS disease control in these patients. Lapatinib crosses the BBB and demonstrates modest activity against intracranial metastases. Based upon preclinical data and results of a phase I study, it's hypothesized that lapatinib plus WBRT can improve the intracranial disease control compared to WBRT alone. METHODS: A randomized phase II trial of WBRT (37.5 Gy/3 weeks) plus or minus concurrent lapatinib (1000 mg qd x 21 during WBRT and for 21 days after) was initiated. Non-CNS penetrating HER2 targeted therapy is permitted throughout the study, but patients not on trastuzumab, pertuzumab or any other breast cancer therapy at study entry are not permitted to begin this therapy while on protocol treatment, but may begin it 24 hours after completion of protocol treatment. Eligibility includes HER2+ breast cancer with at least one measurable, unirradiated parenchymal brain metastasis. The two populations targeted for accrual include patients with 1) newly diagnosed, multiple brain metastases or 2) progressive brain metastases after stereotactic radiosurgery (SRS) or surgical resection of 1-3 metastases. Prior lapatinib is allowed. Patients are stratified by breast-specific graded prognostic assessment; use of non-CNS penetrating HER2 targeted therapy; and prior SRS or surgical resection. The primary endpoint is complete response rate in the brain 12 weeks after WBRT. Secondary endpoints include objective response rate, lesion-specific response rate, CNS progression-free survival, and overall survival. 52 of 143 target accrual have enrolled (6/1/2015). Supported by NCI grants U10CA21661, U10CA180868, U10CA180822, U10CA37422 and UG1CA189867.

Correlation of Imaging Characteristics With Histopathological WHO Grade in Meningiomas

0.7, pZ 0.01).Within the BRAF-mutated subgroup, therewas no difference in tumor LC based on exposure to a BRAF inhibitor. There was also a trend towards improved CNS progression free survival (PFS) at 1 year (26% vs. 0%, pZ0.06), favoring BRAF-mutated patients. There was no difference in overall survival between the groups. Conclusion: In this retrospective study we found that BRAF mutation was associated with an improvement in local control for melanoma brain metastases treated with SRS compared to those without the mutation. There was also a trend for improved CNS PFS. Our data suggest that BRAF mutation may sensitize tumors to radiosurgery, and that BRAF wild-type tumors may be more radioresistant. Additional studies will be required to fully characterize the role of BRAF mutation in LC of brain metastases treated with SRS. Author Disclosure: I.S. Gallaher: None. Y. Watanabe: None. K.E. Dusenbery: None. C.K. Lee: None. H. Lin: None. T.E. DeFor: None. J. Yuan: None.

Epidermal Growth Factor Receptor (EGFR)-Mediated Adverse Events (AEs) in Patients (pts) With EGFR-Mutation Positive (EGFR M+) Non-Small Cell Lung Cancer (NSCLC) Treated With Afatinib (A): Metastatic Non-Small Cell Lung Cancer

performance status, T and N stage, number of metastatic lesions, and EGFR mutation type were included in univariate analysis (UVA). Candidate factors on UVAwere incorporated into a multivariate analysis (MVA) to identify factors independently associated with BMFS. Results: Of 112 patients, 33 (29%) were male, median age at diagnosis was 60 years, and 35 (31%) had a history of smoking. Seventy-three (65%) and 34 (30%) carried exon 19 deletions and exon 21 (L858R) mutations, respectively; 5 patients had other mutations. In total, 38 patients developed BM, for a crude incidence of 33.9%. Median survival was 25.2 months, and among patients with BM, the median time to BM was 28.9 months. The cumulative incidence of BM at 2 and 3 years was 14.7% and 30.3%, respectively. On UVA, the only factor significantly associated with BM was L858R (exon 21) mutation (hazard ratio [HR] 1.93 vs exon 19 deletion, PZ.035). Older age was nonsignificantly associated with less BM (PZ.11). On MVA, L858R retained borderline significance (HR: 1.82, PZ.054). The cumulative incidence of BM at 2 years was 23.2% in the exon 21 group vs 10.4% in the exon 19 group. Conclusion: Brain metastasis is a significant pattern of failure in EGFRmutant metastatic NSCLC patients maintained on erlotinib therapy, occurring in approximately a third of such patients. Contrary to previous reports, we found that patients with L858R mutations may be at particularly greater risk of BM compared to patients with exon 19 mutations. These results suggest a potential role for PCI in this select group of patients as a means of improving CNS-progression free survival. Author Disclosure: S. Patel: None. A. Rimner: E. Research Grant; Varian Medical Systems. G. Consultant; General Electric. A. Foster: None. Z. Zhang: None. K.M. Woo: None. H.A. Yu: None. G.J. Riely: None. A.J. Wu: G. Consultant; Pfizer, Inc.

Improved Locoregional Control for Patients With T1-2N1 Triple-Negative Breast Cancer Treated With Radiation Therapy Following Modified Radical Mastectomy

HER 2 positive) and HER 2-discordant (HER 2-positive primary breast tumors had HER 2 negative) tumors were compared. Results: The median follow-up time was 24 months (0.75-74 months). Receptor status was available in 226 patients: 31.8% Luminal A, 17.7% Luminal B, 29.6% HER 2, 20.8% Basal. Median survival from brain metastases in Luminal A, Luminal B, HER 2, Basal subtype was 11 months (95% CI Z 9.34-12.65), 9.4 months (95% CI Z 6.44-12.09), 10 months (95% CI Z 6.57-13.42) and 5 months (95% CI Z 2.61-7.39), respectively (p Z 0.01). In HER 2-positive patients (Luminal B and HER 2 subgroups), survival after WBRT (40 vs 32 weeks; P Z 0.029), and CNS progression free survival after WBRT (24 vs 20 weeks; P Z 0.037) was significantly longer compared with HER 2negative patients. For the 44 cases receiving repeat brain radiation therapy, HER 2-positive patients also had longer survival and CNS disease free survival after brain irradiation. Thirtyseven of 108 HER 2-positive patients had metastatic tumor biopsy results available for review. Twelve (32%) of the 37 patients had HER 2-discordant metastatic tumors. Patients with discordant HER 2 status had shorter survival after WBRT than did patients with concordant HER 2 status (P Z 0.046). Conclusions: Our findings indicate that HER 2-positive breast cancer patients with brain metastasis had better prognosis after brain radiation therapy. Loss of HER 2-positive status in metastatic tumors can occur in patients with primary HER 2-positive breast cancer. The need for biopsies of metastatic lesions to accurately determine patient prognosis and appropriate use of tailored brain radiation therapy for brain metastases, and target systemic therapy after WBRT based on molecular subtypes should be considered. Author Disclosure: S. Lai: None. C. Huang: None. C. Wang: None. Y. Chen: None. K. Lan: None. A. Cheng: None. S. Kuo: None.

Prognostic Significance of Internal Mammary Node Involvement in Patients With Clinical Stage IIIC Breast Cancer Who Received Neoadjuvant Chemotherapy, Surgery, and Radiation Therapy

HER 2 positive) and HER 2-discordant (HER 2-positive primary breast tumors had HER 2 negative) tumors were compared. Results: The median follow-up time was 24 months (0.75-74 months). Receptor status was available in 226 patients: 31.8% Luminal A, 17.7% Luminal B, 29.6% HER 2, 20.8% Basal. Median survival from brain metastases in Luminal A, Luminal B, HER 2, Basal subtype was 11 months (95% CI Z 9.34-12.65), 9.4 months (95% CI Z 6.44-12.09), 10 months (95% CI Z 6.57-13.42) and 5 months (95% CI Z 2.61-7.39), respectively (p Z 0.01). In HER 2-positive patients (Luminal B and HER 2 subgroups), survival after WBRT (40 vs 32 weeks; P Z 0.029), and CNS progression free survival after WBRT (24 vs 20 weeks; P Z 0.037) was significantly longer compared with HER 2negative patients. For the 44 cases receiving repeat brain radiation therapy, HER 2-positive patients also had longer survival and CNS disease free survival after brain irradiation. Thirtyseven of 108 HER 2-positive patients had metastatic tumor biopsy results available for review. Twelve (32%) of the 37 patients had HER 2-discordant metastatic tumors. Patients with discordant HER 2 status had shorter survival after WBRT than did patients with concordant HER 2 status (P Z 0.046). Conclusions: Our findings indicate that HER 2-positive breast cancer patients with brain metastasis had better prognosis after brain radiation therapy. Loss of HER 2-positive status in metastatic tumors can occur in patients with primary HER 2-positive breast cancer. The need for biopsies of metastatic lesions to accurately determine patient prognosis and appropriate use of tailored brain radiation therapy for brain metastases, and target systemic therapy after WBRT based on molecular subtypes should be considered. Author Disclosure: S. Lai: None. C. Huang: None. C. Wang: None. Y. Chen: None. K. Lan: None. A. Cheng: None. S. Kuo: None.

Phase II trial of patupilone in patients with brain metastases from breast cancer

For patients with progressive breast cancer brain metastasis (BCBM) after whole brain radiotherapy (WBRT), few options exist. Patupilone is an epothilone that crosses the blood-brain barrier. We hypothesized that patupilone would produce a 35% 3-month CNS progression-free survival in women with BCBM after WBRT. This multicenter phase II trial included 2 cohorts. Group A included women with progressive BCBM after WBRT. Group B was an exploratory cohort of patients with either leptomeningeal metastases or untreated brain metastases. The primary goal was to observe a 35% 3-month CNS progression-free survival in Group A. The sample size was 45 for Group A and 10 for Group B. Patients received patupilone 10 mg/m(2) once every 3 weeks until progression. Responses were scored according to the Macdonald criteria. Fifty-five patients (45 in Group A, 10 in Group B) enrolled. In Group A, the 3-month CNS progression-free survival was 27%, the median overall survival was 12.7 months, and the overall response rate was 9%. In Group B, which enrolled 5 patients with leptomeningeal disease and 5 with no prior WBRT, no responses occurred and 8 patients had CNS progression before 3 months. Systemic responses occurred in 15% of patients, including a complete response in liver metastases. Diarrhea occurred in 87% of patients; 25% had grade 3 and 4 adverse events. Patupilone in patients with BCBM did not meet the efficacy criteria and had significant gastrointestinal toxicity. Further study of brain-penetrant agents is warranted for patients with CNS metastases from breast cancer.

Bevacizumab, etoposide, and cisplatin (BEEP) in brain metastases of breast cancer progressing from radiotherapy: Results of the first stage of a multicenter phase II study.

1079 Background: With a general prolongation of survival, brain metastasis (BM) has become a common complication of breast cancer. However, management of BM remains a severe challenge. We hypothesized that bevacizumab (BE) could significantly enhance drug delivery of etoposide (E) and cisplatin (P), two of the cytotoxic agents that have moderate activity in BM of breast cancer, to brain tumors and thereby improve the efficacy. Methods: Breast cancer patients (pts) with BM progression after whole brain radiotherapy (WBRT) were enrolled. Pts received BE 15 mg/kg day 1, and E 70 mg/m2/day, days 2-4, P 70 mg/m2/day, day 2, every 21 days for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS objective response (CNS-OR) defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. Using a Simon’s optimal two-stage design with 15% as a minimum interest in CNS-OR rate (by intent to treat analysis), 11 pts were needed at the first stage; and a total of 31 evaluable for the whole study. Results: Among 16 pts enrolled from Jan 2011 to Jan 2012, 12 pts were evaluable for treatment response at the time of abstract submission. Median age was 55 (range 34-66); 1 pt was ER+HER2-, 5 pts were HER2+, and 6 pts were ER-HER2-. The median treatment cycles were 4.5 (range 1-6). Nine of 12 pts (75%; 95%CI 42.8-94.5) achieved CNS-OR including 6 pts (50%) with ≥80% and 3 pts (25%) with 50-80% CNS volumetric reduction, respectively. Two pts had non-CNS disease progression while CNS tumors remained under control. The median CNS progression free survival was 6.6 months (95% CI 0.8-12.4). Grade 3 /4 toxicities included neutropenia, leukopenia, anemia, and platelet in 13 (25.5%), 6 (11.8%), 2 (3.9%), and 2 (3.9%) cycles, respectively. Seven pts (58.3%) had received dose reduction to E 60 mg/m2 and P 60 mg/m2. Early reporting of this study was approved by Data and Safety Monitoring Committeedue to an extremely promising result. Conclusions: BEEP regimen has a significant anti-tumor effect for BM of breast cancer which progresses after WBRT.

Salvage stereotactic radiosurgery (SRS) after previous whole-brain radiation therapy (WBRT) for breast cancer brain metastases: Outcomes and prognostic factors including tumor phenotype.

581 Background: Salvage SRS is often considered in breast cancer patients (pts) previously treated with WBRT for brain metastases. The goal of this study was to analyze clinical outcomes and prognostic factors for survival in the salvage setting. Methods: We retrospectively examined all breast cancer pts who underwent SRS at DF/BWCC between 2000 and 2010. We identified 79 consecutive female pts who received salvage SRS (interval of > 3 months after initial therapy), 76 of whom (96%) received prior WBRT. Overall survival (OS) and CNS progression-free survival was calculated from the date of SRS using the Kaplan-Meier method. Prognostic factors were evaluated using the Cox proportional hazards model. Results: Median age was 50.5 years. Subtype distribution was: ER+, 46; HER2+, 27; triple negative, 8). 97% had a KPS ≥70%. 95% had extracranial metastases at the time of SRS, 81% at other visceral sites (lung/pleura/liver). 48% had stable extracranial disease at the time of SRS. Median interval from WBRT to SRS was 8.4 months. Median follow-up for survivors was 16.7 months. Median CNS progression-free survival was 5.7 months (IQR 3.6-11 months) and median OS was 9.8 months (IQR 3.8-18 months). 82% of evaluable pts received further systemic therapy after SRS. 92% of patients were in RPA class II. RPA class was not found to be a useful prognostic index in this population. Median OS in RPA class II pts was 10.4 months. HER2 status (adjusted HR 2.4, p=0.008) and extracranial disease status (adjusted HR 2.7, p=0.004) were significant prognostic factors for survival on multivariate analysis. Conclusions: In patients with good KPS, salvage SRS at the time of CNS recurrence should be strongly considered. HER2 positivity and status of extracranial disease are prognostic factors for survival following SRS in the salvage setting after prior WBRT. Prognostic factors for OS. Univariate Multivariate HR P value HR P value Age >65 y 3.4 0.02 1.8 0.3 Extracranial disease Progessing 2.9 <0.001 2.7 0.004 Stable 1 HER2+ Yes 1 No 2.3 0.002 2.4 0.008 ER+ Yes 0.73 0.2 No 1 Triple-negative Yes 3.8 0.001 1.6 0.3 No 1 KPS <80% 4.2 <0.001 1.9 0.11 N lesions treated SRS 1.1 0.76 Time to SRS 1.0 0.77

A multicenter phase II trial of intrathecal topotecan in patients with meningeal malignancies

To determine the therapeutic efficacy (13-week and 26-week CNS progression-free survival [PFS], response rate, and overall survival) and safety of intraventricular (IVent) topotecan in patients with neoplastic meningitis (NM), we conducted a phase II, open-label, nonrandomized, single-arm trial of IVent topotecan in patients with NM using 400 mug of topotecan IVent twice weekly for 6 weeks, followed by evaluation with imaging, cerebrospinal fluid (CSF), and physical examinations. In the absence of disease progression, patients were then treated with IVent topotecan weekly for 6 weeks, twice monthly for 4 months, and monthly thereafter. Sixty-two patients (23 males and 39 females) were enrolled from April 2001 through March 2006. Median age and KPS at enrollment were 56 (range 5-83) and 80 (range 60-100), respectively. Primary cancers included breast (19), lung (13), CNS (14), and others (16). Forty patients (65%) completed the 6-week induction period, among whom 13 (21%) had CSF clearance of malignant cells. Kaplan-Meier estimates of PFS at 13 and 26 weeks were 30% (95% confidence interval [CI], 20%-45%) and 19% (95% CI, 11%-34%). Overall median survival (50 deaths) was 15 weeks (95% CI, 13-24 weeks). The most common side effect was chemical meningitis in 32% of patients (5% grade 3); 32% experienced no drug side effects. IVent topotecan is well tolerated, but provides no added benefit over other IVent therapies. Because of its modest side effect profile, combining IVent topotecan with other IVent or systemic interventions should be considered.