Prior Brain Radiotherapy Research Articles

Intracranial response pattern, tolerability and biomarkers associated with brain metastases in non-small cell lung cancer treated by tislelizumab plus chemotherapy.

Programmed cell death protein-1/programmed cell death protein-ligand 1 (PD-1/PD-L1) inhibitor and chemotherapy are the standard treatment for advanced non-small cell lung cancer (NSCLC) without sensitizing mutations. However, patients with untreated, symptomatic or recently-irradiated brain metastases (BMs) are mostly excluded from immunochemotherapy trials. This study aims to evaluate the intracranial response pattern, tolerability and biomarkers of tislelizumab plus chemotherapy in NSCLC with untreated, symptomatic or recently-irradiated BM. This multicenter, single-arm, phase 2 trial enrolled patients with treatment-naïve, brain-metastasized NSCLC. BM could be untreated or irradiated. Symptomatic or recently-irradiated BMs that were deemed clinically stable were allowed. Patients received tislelizumab (200 mg) plus pemetrexed (500 mg/m2) and carboplatin (AUC =5) on day 1 every 3 weeks for 4 cycles, followed by maintenance with tislelizumab plus pemetrexed. Primary endpoint was 1-year progression-free survival (PFS) rate. Secondary endpoints included intracranial efficacy and tolerability. PD-L1 expression, tumor mutational burden (TMB) and genomic alterations were evaluated as potential biomarkers. A total of 36 patients were enrolled, 19.2% had prior brain radiotherapy, 8.3% had symptomatic BMs that required corticosteroids ≤10 mg/d or antiepileptics. Confirmed systemic and intracranial ORR (iORR) was 43.8% and 46.7%, respectively. One-year systematic PFS rate and One-year iPFS rate was 36.8% and 55.8%, respectively. About 41.7% patients had neurological adverse events, 90% patients had concordant intracranial-extracranial responses. No intracranial pseudoprogression or hyperprogression occurred. Patients with prior brain radiation trended towards higher systemic (83.3% vs. 34.6%) and iORR (75.0% vs. 42.3%). Similar intracranial efficacy was observed in tumors with different PD-L1 and TMB levels, while alterations in cytokine receptors pathway predicted higher iORR (P=0.081), prolonged systematic PFS [hazard ratio (HR) =0.16, P=0.021] and overall survival (OS) (HR =0.71, P=0.029). Untreated or irradiated BMs in NSCLC follows a conventional response and progression pattern under immunochemotherapy with altered cytokine receptors pathway being a potential biomarker for systemic and intracranial outcomes.

Efficacy of Chemoimmunotherapy in NSCLC Patients With Brain Metastasis With or Without Prior Brain Radiotherapy.

Many patients with advanced lung cancer develop brain metastasis (BM); however, few reports confirming the efficacy of immune checkpoint inhibitors (ICIs) plus chemotherapy in non-small cell lung cancer (NSCLC) patients with symptomatic BM have been published. Therefore, we retrospectively evaluated the effects of chemoimmunotherapy in NSCLC patients who did or did not receive prior brain radiotherapy. A total of 103 patients with advanced NSCLC who received ICIs plus chemotherapy at our hospital from January 2019 to July 2021 were retrospectively enrolled. Patients with BM tended to have shorter progression-free survival (PFS) and overall survival (OS) compared with patients without BM. The maximum size of BM and the proportion of patients with symptomatic BM were greater among patients who received brain radiotherapy before chemoimmunotherapy. However, patients who received prior brain radiotherapy had better PFS and OS compared with patients who did not receive prior brain radiotherapy. Patients who received prior brain radiotherapy experienced a superior therapeutic benefit of ICIs plus chemotherapy, including those with larger and more symptomatic BM.

A randomized phase 3 study of entrectinib versus crizotinib in patients (pts) with locally advanced/metastatic ROS1 fusion-positive (fp) NSCLC with or without baseline CNS metastases (mets).

TPS9141 Background: ROS proto-oncogene 1 ( ROS1) fusions are found in 1–2% of NSCLC cases. As CNS mets are common in pts with ROS1-fp NSCLC and associated with poor prognosis, CNS-active treatments are needed for these pts. Entrectinib and crizotinib are tyrosine kinase inhibitors (TKIs) of ROS1, recommended as first-line treatments for ROS1-fp NSCLC. Both drugs have shown robust systemic efficacy and good tolerability in pts with ROS1-fp NSCLC. While crizotinib may have suboptimal CNS activity, entrectinib has shown intracranial efficacy in pts with baseline CNS mets by blinded independent central review (BICR, PMIDs 30215676; 33646820). We hypothesized that entrectinib may have greater CNS activity than crizotinib, potentially addressing the unmet need for pts with ROS1-fp NSCLC with CNS mets. Methods: This randomized, open-label, multicenter, phase 3 trial (NCT04603807) aims to compare the efficacy and safety of entrectinib vs crizotinib in adult pts with TKI-naïve advanced/metastatic ROS1-fp NSCLC, with or without CNS mets. Key eligibility criteria: advanced/recurrent/metastatic NSCLC with ROS1 fusion determined locally by certified clinical laboratory testing; measurable systemic disease (RECIST 1.1); age ≥18 years; ECOG PS ≤2; no prior ROS1 TKI or systemic treatment for advanced/metastatic disease; adequate hematologic, renal and hepatic functions; prior radiotherapy ≥14 days before randomization and neurologically stable CNS mets per RECIST 1.1 are permitted. Pts will be randomized 1:1 to receive 600 mg entrectinib once a day or 250 mg crizotinib twice a day. Stratification factors are baseline CNS mets (none/measurable/non-measurable) and prior brain radiotherapy ≤2 months (yes/no); to allow sufficient power, ≥30% of randomized pts will have baseline CNS mets. Study treatment will continue until progressive disease, unacceptable toxicity, death or withdrawal from the study. Pts with radiographic disease progression or isolated asymptomatic CNS progression may continue treatment at the investigator’s discretion. Tumor assessments (brain MRI and chest, abdomen and pelvis CT/MRI) will occur at screening, Wk 4, Wk 8 and every 8 wks thereafter. Blood samples will be collected at every visit. Primary endpoint: progression-free survival (PFS) by BICR in pts with baseline CNS mets (CNS population, target HR = 0.57). Secondary endpoints: CNS-PFS by BICR and ORR, duration of response (DoR) and PFS (by BICR and investigator) in the intent-to-treat (ITT) population; overall survival in the CNS and ITT populations; CNS-ORR and CNS-DoR by BICR in the CNS population. Impact on quality of life, functioning and lung cancer-specific symptoms will be evaluated via questionnaires in the ITT population. Safety endpoints and biomarkers will also be evaluated. As of 12 Jan 2022, 8 pts are enrolled (first pt enrolled in Oct 2021). Clinical trial information: NCT04603807.

Clinical data from the real world: Efficacy analysis of ceritinib (450mg) in ALK-rearrangement non-small-cell lung cancer patients with brain metastases in China.

The real-world intracranial efficacy data of ceritinib at a dose of 450 mg quaque die (QD) are currently unavailable. Therefore, we evaluated the intracranial efficacy of ceritinib (450 mg QD) in anaplastic lymphoma kinase (ALK)-rearrangement NSCLC patients in China. In total, 57 ALK-rearrangement NSCLC patients with brain metastases (BM) were enrolled retrospectively in this real-world study. Of these, 53 patients experienced progression at baseline during or after prior crizotinib administration, and 24 patients received prior brain radiotherapy. Patients received ceritinib (450 mg QD) treatment. Intracranial efficacy [objective response rate (ORR) and disease control rate (DCR)] was evaluated according to the Response Assessment in Neuro-Oncology (RANO) standard; progression-free survival (PFS) and adverse events (AEs) data were obtained through follow-ups. The intracranial ORR and DCR of ceritinib were 73.7% and 93.0%, respectively. The median intracranial PFS in patients reaching the endpoint was 8.75 months, whereas the median intracranial PFS in all patients was not reached and predicted to be not evaluable (NE) (95% CI: 12.9-NE). The estimated 12-month event-free probability (EFP) of intracranial lesions was 68.1%. A subgroup analysis revealed that the estimated 12-month EFP of intracranial lesions was relatively higher in patients with prior brain radiotherapy (93.8% vs. 47.1%, P = 0.0006). Ceritinib administered at 450 mg QD to ALK-rearrangement NSCLC patients with BM in China exhibited superior ORR and DCR, as well as PFS and event free probability. The estimated 12-month EFP for intracranial lesions improved in patients with prior brain radiotherapy.

FP14.12 Quality of Life and Subgroup Analysis in a Phase 3 Randomized Study of Ensartinib vs Crizotinib in ALK–Positive NSCLC Patients: eXalt3.

Ensartinib (X-396) is a novel second-generation ALK tyrosine kinase inhibitor (TKI). In a phase 3 study interim analysis, ensartinib showed statistically significant improvement of median PFS over crizotinib in patients with ALK+ NSCLC who were ALK TKI naive or received up to one prior chemotherapy line, including higher efficacy against brain metastases. Ensartinib was well tolerated, with low grade rash, pruritus, edema, and transaminitis as the most frequent treatment-related AEs. Here we plan to present subgroups analyses and the quality of life outputs of the phase 3 eXalt3 study (NCT02767804). Patients with locally tested ALK+ NSCLC (ITT population) were randomized 1:1 to ensartinib (225 mg QD orally) or crizotinib (250 mg BID orally). No crossover was allowed. Patients were stratified by prior chemotherapy, ECOG PS, brain metastases, and geographic region. The modified ITT (mITT) population was prespecified to include all centrally ALK+ patients by Abbott FISH test. The primary endpoint was blinded independent review committee (BIRC)–assessed progression-free survival (PFS; RECIST v.1.1). Secondary endpoints included overall survival (OS), overall response rate (ORR), and time to treatment failure (TTF) in the brain and patients reported outcomes (PRO). PRO data collection included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ-C30). A linear mixed model for repeated measures was used to analyze change from baseline in the Global Health Status/Quality of Life subscale (GHS/QOL), with a change of greater than or equal to ten points deemed meaningful. Time to symptom deterioration will be presented. In total, 290 patients were randomized (ensartinib [n=143]; crizotinib [n=147]).Median age was 54.1 y, 26% of patients had prior chemotherapy, and 36% of patients had baseline CNS metastases (5% had prior brain radiotherapy). The mITT population included 247 patients (ensartinib [n=121]; crizotinib [n=126]). At the July 1, 2020, data cutoff, 139 BIRC-assessed PFS events (73%) occurred in the ITT population and 119 (63%) in the mITT population. Median PFS was 25.8 months with ensartinib vs 12.7 months with crizotinib (HR, 0.52; P=.0003 by log-rank test) with a median follow-up of 23.8 and 20.2 months in the ITT population. Median PFS was not reached with ensartinib vs 12.7 months with crizotinib in the mITT population (HR, 0.48; P=.0002 by log-rank test). New subgroup analyses in mITT for ensartinib showed a trend for higher efficacy by prior chemotherapy vs no chemotherapy (mPFS NR vs 25.8). Both global health status (GHS) as well as 5 functional and 9 symptom domains within EORTC QLQ-C30 had clinical meaningful improvement over time for ensartinib. Ensartinib delays the time to worsening of GHS with HR =0.83 (95% CI [0.57, 1.20]) vs crizotinib. Complete subgroup analyses (forest plot and multivariate analyisis) will be presented at the conference as well as OS updates. Comprehenive EORTC QLQ-C30 and Lung Cancer Symptom Scale scores will also be reported at the conference. In ALK+ NSCLC patients ensartinib represents a new option in first-line setting. QOLs data support its favorable safety profile. Relevant subgroups analyses to evaluate its clinical impact will be presented at the meeting.

Peri-SRS Administration Of Bevacizumab Offers Promising Efficacy For Large Brain Metastases With Tolerable Toxicity: A Prospective Case Series

Brain metastases (BM) are the most common brain tumors in adults. It is estimated that around 10-30% of cancer patients would develop brain metastases during the course of their illness. Stereotactic radiosurgery (SRS) is the treatment of choice to achieve intracranial control while sparing neurocognitive function. However, the risk of radionecrosis (RN) after single-fraction SRS could be as high as 38% at 12 months if treated brain metastases were larger than 1.5 cm. Therefore, radiation dose is often compromised to avoid excessive toxicities. Herein, we propose a new combined treatment strategy to evaluate the efficacy and safety of SRS with concurrent bevacizumab for large brain metastases. Patients with the diameter of the largest BM ≥ 2 cm were enrolled for combined therapy. Bevacizumab with 5 to 10 mg/kg was given one day before the first fraction of radiosurgery and 2 weeks after the first dose. SRS was given in 1 to 5 fractions depending on tumor size. Radiographic response was assessed by RANO criteria. Intracranial (IC) metastasis progression-free survival (PFS), and overall survival (OS) were calculated by Kaplan-Meier analysis. Forty-eight patients were enrolled in this prospective case series. Nine patients (19%) had prior brain radiotherapy. The median number of BM per patient was 3 (range 1–22). The largest tumor diameter ranged from 20 to 54 mm (median 27.4 mm; 46% were ≥ 3 cm) and the median prescribed biological equivalent dose was 51.3 Gy10 (18.3 Gy single fraction equivalent). With a median follow-up of 18 months, the estimated median OS was 22.6 months (95% CI, 6.9 to 38.3 months) and the median ICPFS was 13.9 months (95% CI, 9 to 18.9 months). Only 4 patients developed local failure (LF). Significant radiographic response (complete and partial response, CR+PR) was achieved in 40 patients (83.3%). No grade 4 or 5 toxicities were observed. Eight patients (16.7%) developed ≥ grade 2 RN, and two of them required surgical intervention. After adjusting death as a competing risk, the cumulative incidence of LF, IC progression and RN at 12 months were 2.5% (95% CI, 0.3% to 17.9%), 39.4% (95% CI, 27.2% to 57.1%), and 14.4% (95% CI, 6.8% to 30.4%), respectively. Four patients (8.3%) had grade 3 hypertension. One patient experienced tumor hemorrhage without significant neurological deficit or need for intervention. Stereotactic radiosurgery with peri-radiosurgical Bevacizumab for large brain metastases is highly effective with low incidence of radionecrosis and low risk of excessive treatment-related toxicities. The combination strategy warrants further evaluation.Abstract 3723; TableMaximum relative tumor reduction and response rate observed as best response by RANO criteria among different tumor sizesLargest tumor diameterNumber of patientsMaximum relative tumor reduction (median, range)Response rate (CR+PR)2-2.5 cm1451% (7-100%)85.7%2.5-3 cm1354% (16-100%)92.3%3-3.5 cm838% (24-55%)75%>3.5 cm1335% (2-63%)76.9% Open table in a new tab

Abstract CT082: Capmatinib in METex14-mutated (mut) advanced non-small cell lung cancer (NSCLC): Results from the phase II GEOMETRY mono-1 study, including efficacy in patients (pts) with brain metastases (BM)

Abstract Background: Capmatinib is a highly selective and potent MET inhibitor that crosses the blood-brain barrier. In the GEOMETRY mono-1 study, capmatinib showed clinically meaningful response rates in pts with advanced NSCLC harboring METex14 skipping mutations, including activity in pts with baseline BM, and also demonstrated manageable safety. Here, we present efficacy and safety data, including an efficacy analysis in METex14 skipping mutated NSCLC pts with baseline BM. Methods: The phase 2, multi-cohort, multicenter GEOMETRY mono-1 study (NCT02414139) is evaluating capmatinib in adult pts with ECOG PS 0-1, ALK and EGFR-wt, METex14-mut/MET-amplified stage IIIB/IV NSCLC, including pts with neurologically stable/asymptomatic BM. Pts were assigned to Cohorts 4 (pretreated, 2/3L) and 5b (treatment-naive) and received capmatinib 400 mg BID. Primary endpoint: overall response rate (ORR) by BIRC per RECIST v1.1. Key secondary endpoint: duration of response (DOR) by BIRC. The retrospective analyses on brain lesions were based on modified RECIST v1.1 as assessed by BIRC neuro-radiologic assessments of all Cohorts 4 and 5b pts with baseline BM. Results: As of April 15, 2019, 97 pts (Cohort 4: 69 pts; Cohort 5b: 28 pts) were evaluable for efficacy. BIRC results for cohorts 4 and 5b, respectively, were (i) ORR (95%CI): 40.6% (28.9-53.1) and 67.9% (47.6-84.1), (ii) median DOR (95%CI): 9.72 (5.55-12.98) and 11.14 (5.55-NE) months (mos), and (iii) median progression-free survival (95%CI): 5.42 (4.17-6.97) and 9.69 (5.52-13.86) mos. There were 13 pts with evaluable baseline BM by BIRC [3.3 brain lesions/pt (range 1−8)]. 7 of the 13 pts (54%) had intracranial response of which 4 pts had complete resolution of all brain lesions. The other 3 responders had (i) complete resolution in 3 lesions, −50% reduction in 1 lesion, stabilization in remaining 4 lesions (total 7 lesions), (ii) complete resolution in 2 lesions, stabilization in 1 remaining lesion (total 3 lesions), and (iii) complete resolution in 1 lesion, stabilization in 3 remaining lesions (total 4 lesions). Intracranial disease control was achieved in 12/13 pts. Intracranial responses were as fast as systemic responses. 3/7 responders had prior brain radiotherapy; 5/7 responders had either signs of progression in the existing brain lesion(s) or new BM at study entry. Most common tx-related adverse events (≥15%, all grades) across all cohorts (N=334) were peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%). Conclusion: BIRC neuro-radiologist review of 13 pts with evaluable baseline BM suggested that capmatinib has anti-tumor efficacy in the brain. Capmatinib also showed deep and durable responses in pts with METex14-mut advanced NSCLC regardless of line of therapy and demonstrated a manageable safety profile. Citation Format: Edward B. Garon, Rebecca S. Heist, Takashi Seto, Ji-Youn Han, Noemi Reguart, Harry J. Groen, Daniel SW Tan, Toyoaki Hida, Maja J. de Jonge, Sergey V. Orlov, Egbert F. Smit, Pierre-Jean Souquet, Johan Vansteenkiste, Sylvie Le Mouhaer, Anna Robeva, Maeve Waldron-Lynch, Monica Giovannini, Juergen Wolf. Capmatinib in METex14-mutated (mut) advanced non-small cell lung cancer (NSCLC): Results from the phase II GEOMETRY mono-1 study, including efficacy in patients (pts) with brain metastases (BM) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT082.

390O - Efficacy and safety of ceritinib in ALK-positive non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM): Results from the phase II, ASCEND-7 study

390O - Efficacy and safety of ceritinib in ALK-positive non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM): Results from the phase II, ASCEND-7 study

MA 07.04 Clinical Impact of Crizotinib on Brain Metastases in Patients with Advanced ROS1-Rearranged Non-Small Cell Lung Cancer

Brain metastases are common in patients with advanced non–small cell lung cancer (NSCLC). Approximately 1% of NSCLC patients have ROS1-rearranged, and these patients achieved prolonged survival when treated with crizotinib, which is approved for the treatment of ROS1-rearranged NSCLC. However, this efficacy might not translate to intracranial control of disease. Herein, we evaluated the clinical impact of crizotinib on brain metastases in patients with advanced ROS1-rearranged NSCLC. Between April 2014 and October 2016, 53 ROS1-rearranged NSCLC patients treated with crizotinib were retrospectively evaluated for baseline characteristics, brain metastases status, progression patterns and the overall prognosis. Of the 53 ROS1-rearranged NSCLC patients who received crizotinib as treatment, 13 (24.5%) patients had baseline brain metastases before crizotinib treatment. Among patients without baseline brain metastases who developed progressive disease after initiation of crizotinib (n=27), 22.2% were diagnosed with brain metastases. Among patients without baseline brain metastases, systemic progression-free survival (PFS) and overall survival (OS) after initiation of crizotinib was significantly longer than that of patients with brain metastases (median PFS: 20.4 months vs. 11.0 months, p = 0.003; median OS: not reached vs. 16.5 months, p = 0.027). There was no significant difference in systemic PFS and OS between patients developing brain metastases before and after crizotinib treatment (median PFS: 11.0 months vs. 6.4 months, p = 0.469; median OS: 16.5 months vs. not reached, p = 0.605). Among the patients with baseline brain metastases, 6 had received prior brain radiotherapy and 7 had received no prior radiotherapy. A total of 2 patients in the treated group had an event of brain metastases progression, as compared with 4 patients in the untreated group (33.3% vs 57.1%, p = 0.592). There was no significant difference in intracranial PFS in the previously brain treated patients versus the untreated patients before crizotinib treatment (median intracranial PFS: 12.5 months vs. 11.0 months, p = 0.790). Brain metastases status before crizotinib treatment was significantly associated with both PFS and OS in crizotinib-treated ROS1-rearranged NSCLC patients. Patients with brain metastases received prior radiotherapy have not prolonged survival compared with the patients treated with crizotinib alone.

Local Control Among Gross and Subtotally Resected Atypical Meningiomas Followed With Adjuvant Radiation or Observation

Atypical meningiomas carry increased local recurrence (LR) rates and may benefit from adjuvant radiotherapy (RT) following both gross and subtotal resection. We hypothesize that subtotally resected (STR) atypical meningiomas treated with adjuvant RT and gross totally resected (GTR) atypical meningiomas followed by observation do not have different LR rates. We hypothesize that STR atypical meningiomas followed with observation experience unacceptably high local progression, which is significantly increased compared to those treated with adjuvant RT. All atypical meningiomas definitively resected with meeting 2016 World Health Organization (WHO) II criteria were included in this single institution retrospective analysis. Patients with prior brain RT or less than one year of radiographic follow up with MRI were excluded. GTR was defined as absence of clear enhancing tumor on post-operative MRI concordant with surgeon’s findings as dictated in the operative note, and STR was defined as residual enhancing tumor as noted on post-operative MRI or operative note. Adjuvant RT included both traditionally fractionated and stereotactic focal RT and defined as any RT delivered post operatively before progression noted on serial MRI. The primary end points of LR and PFS were estimated using the Kaplan Meier method. Cox proportional hazards model was used to evaluate differences in local control rates according to extent of resection and adjuvant RT. A tumor registry query of 2386 patients was reviewed, and 155 patients met inclusion criteria with median radiographic follow-up of 53.1 months (12-208 months). 115 (74.2%) patients were GTR while 40 (25.8%) were STR. Of the STR patients 24 (60%) were observed and 16 (40%) received adjuvant RT. Of those who received adjuvant RT, 16 were traditionally fractionated with median dose of 57.6 Gy (50.4, 60) and 4 received stereotactic focal RT with median dose of 13 (12, 27.5). The Kaplan-Meier estimate of LR at 5 years was 28.9% for patients with a GTR, 57.6% for patients with STR, and 34% for patients with STR followed by adjuvant RT. There was not a significant difference in LR rates between GTR patients followed by observation and STR patients treated with adjuvant RT (p= .667). STR patients followed with observation had significantly increased LR rate compared to those treated with adjuvant RT (p= .018). Observation of STR atypical meningiomas results in unacceptably high LR rates while STR followed by adjuvant RT significantly decreases the LR rate. The LR rate of STR patients who received adjuvant RT was not significantly different than GTR patients followed with observation.

Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases.

Crizotinib is an oral kinase inhibitor approved for the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). The clinical benefits of crizotinib in patients with brain metastases have not been previously studied. Patients with advanced ALK-rearranged NSCLC enrolled onto clinical trial PROFILE 1005 or 1007 (randomly assigned to crizotinib) were included in this retrospective analysis. Patients with asymptomatic brain metastases (nontarget or target lesions) were allowed to enroll. Tumor assessments were evaluated every 6 weeks using RECIST (version 1.1). At baseline, 31% of patients (275 of 888) had asymptomatic brain metastases; 109 had received no prior and 166 had received prior brain radiotherapy as treatment. Among patients with previously untreated asymptomatic brain metastases, the systemic disease control rate (DCR) at 12 weeks was 63% (95% CI, 54% to 72%), the intracranial DCR was 56% (95% CI, 46% to 66%), and the median intracranial time to progression (TTP) was 7 months (95% CI, 6.7 to 16.4). Among patients with previously treated brain metastases, the systemic DCR was 65% (95% CI, 57% to 72%), the intracranial DCR was 62% (95% CI, 54% to 70%), and the median intracranial TTP was 13.2 months (95% CI, 9.9 to not reached). Patients with systemic disease control were also likely to experience intracranial disease control at 12 weeks (correlation coefficient, 0.7652; P < .001). Among patients without baseline brain metastases who developed progressive disease (n = 253) after initiation of crizotinib, 20% were diagnosed with brain metastases. Crizotinib was associated with systemic and intracranial disease control in patients with ALK-rearranged NSCLC who were ALK inhibitor naive and had brain metastases. However, progression of preexisting or development of new intracranial lesions while receiving therapy was a common manifestation of acquired resistance to crizotinib.

SU‐C‐18A‐05: Registration Accuracy of MR‐Based Images to On‐Board Megavoltage Cone‐Beam CT for Brain Patient Setup

Purpose:To quantify the difference in isocenter shifts when co‐registering MR and MR‐based pseudo CTs (pCT) with on‐board megavoltage conebeam CT (CBCT) images.Methods:Fast Spoiled Gradient Echo MRs were used to generate pCTs (research version of Advantage Sim MD™, GE Healthcare) for ten patients who had prior brain radiotherapy. The planning CT (rCT) for each was co‐registered with the MR, and the plan isocenter and two other reference points were transferred to the MR and pCT. CBCT images (with the machine isocenter) from a single treatment day were coregistered with the 3 test images (MR, pCT and rCT), by two observers and by an automated registration algorithm. The reference points were used to calculate patient shifts and rotations from the registrations. The shifts calculated from the test image registrations were compared to each other and to the shifts performed by the therapists who treated the patients on that day.Results:The average difference in absolute value between the isocenter shifts from the MR‐, pCT‐ and rCT‐CBCT registrations, and the therapist shifts, were 2.02, 3.01 and 0.89 mm (craniocaudal), 1.14, 1.34 and 0.46 mm (lateral), and 1.37, 3.43 and 1.43 mm (vertical), respectively. The MR‐ and pCT‐CBCT registrations differed by 1.99, and 2.53 mm (craniocaudal), 1.36, and 1.37 mm (lateral), and 0.74 and 2.34 mm (vertical), respectively, from the average rCT‐CBCT shifts. On average, differences of 2.39 (craniocaudal), 1.28 (lateral) and 2.84 mm (vertical) were seen between the MR and pCT shifts. Rotations relative to the CBCT coordinate system were on average &lt;2° for the MR and rCT, and &lt;6° for the pCT.Conclusion:In this study, FSPGR MR‐CBCT registrations were more precise compared to the pCT‐CBCT registrations. For improved accuracy, MR sequences that are optimal for bony anatomy visualization are necessary.GE healthcare has provided a research version of Advantage Sim MD to UCSF. No financial support was provided.

Clinical outcomes for a novel 6 degrees of freedom image guided localization method for frameless radiosurgery for intracranial brain metastases

Stereotactic radiosurgery (SRS) is an accepted method of treatment for intracranial brain metastases with sub-millimeter accuracy. Frameless radiosurgery (FRS) is becoming an alternative to framed SRS due to its less invasive requirements. The purpose of this study is to describe the clinical outcomes and local patterns of failure for a novel 6 degrees of freedom CT guided method of localization for FRS of intracranial brain metastases. 42 patients underwent linear accelerator-based FRS to 94 intracranial brain metastases between 01/2009 and 07/2011. 78 and 22 % of treated sites were intact metastases and resection cavities, respectively. 55 % of patients had undergone prior brain radiotherapy (45 % SRS, 26 % whole brain radiation therapy). The 1 year actuarial local recurrence rate was 18 %, with a median imaging follow-up period of 13.2 months. Single fraction equivalent dose was the most important predictor of local recurrence. The 1 year actuarial first distant brain recurrence and total intracranial recurrence rate was 58 and 69 %, respectively. The crude radiographic radiation necrosis rate was 3 %. Of the 10 local recurrence events, 8 (80 %) were in-field only, 1 (10 %) was marginal only, and 1 (10 %) was both. The preponderance of in-field only patterns of failure suggests that geographic miss is not a major contributor to local recurrence using this novel localization method for FRS. The 1 year local control rate is comparable to other similar published series of framed and frameless radiosurgery.