Median Central Nervous System Research Articles

DDDR-20. CLINICAL EFFICACY OF PYROTINIB COMBINING WITH STEREOTACTIC RADIOSURGERY IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES

Abstract BACKGROUND Up to 50% of patients with breast cancer (BC) and human epidermal growth factor receptor 2 (HER2) positive present with disease progression in brain metastases (BM). Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase inhibitor, has shown efficacy in active central nervous system (CNS) metastases. However, clinical efficacy of pyrotinib combining with stereotactic radiosurgery (SRS) in BCBM is unclear. METHODS This retrospective, observational study collected data from 52 HER2+ BC patients with brain metastasis who received pyrotinib-based therapy in Guang dong Sanjiu brain hospital from 2019 to 2023. Among these patients, 36 received pyrotinib-based therapy combining with SRS concurrently, or within 1 months. Age, stage at diagnosis, dates of BM, primary tumor subtypes, prior systemic therapy, CNS-directed local therapy, the objective response and survival status were collected. The assessment of adverse effects was based on CTCAE 4.0. RESULTS 34 patients were evaluable for efficacy (median age: 51.5). With a median follow-up duration of 19.6 months, 1 patient (0.3%) achieved CR, while 27 patients (79.4%) had PR, resulting in an ORR of 82.3%. The median CNS PFS was 13.2 months (95% CI, 4.9-21.7). Median overall survival (OS) was 22.6 months (95% CI, 17.5-27.6). The most common grade 3 or worse treatment-emergent adverse event was diarrhea (6 [17.6%]). CONCLUSIONS Our results suggest that pyrotinib combining with SRS is associated with promising efficacy and a satisfactory safety profile for Her2+ breast cancer brain metastases.

Efficacy and safety of anlotinib for triple-negative breast cancer with brain metastases.

The anti-angiogenic agent anlotinib offers a new treatment option for triple-negative breast cancer (TNBC) patients with brain metastases. This study aimed to evaluate the efficacy and safety of anlotinib in the treatment of TNBC patients with brain metastases. Between October 2019 and April 2024, 29 TNBC patients with brain metastases who had failed prior therapy and were treated with anlotinib were retrospectively analyzed. The primary endpoint was central nervous system (CNS) progression-free survival (PFS), and secondary endpoints included overall survival (OS), intracranial disease control rate (iDCR), intracranial objective response rate (iORR), and safety. The median CNS PFS of 29 patients was 7.2 months (95% confidence interval [CI], 3.5-10.9 months), and the median OS was 10.2 months (95% CI, 5.6-14.8 months). The iORR and iDCR were 31.0% and 86.2%, respectively. Five patients (17.2%) experienced grade 3-4 adverse events (AEs), with bone marrow suppression (2/29, 6.9%) being the most common. Most AEs were clinically manageable, and no treatment-related death was observed. Anlotinib demonstrated encouraging efficacy and manageable toxicity in the treatment of TNBC patients with brain metastases who had failed standard treatment.

Osimertinib after definitive chemoradiotherapy in unresectable stage III epidermal growth factor receptor-mutated non-small-cell lung cancer: analyses of central nervous system efficacy and distant progression from the phase III LAURA study

Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here. Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints. Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo. Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. ClinicalTrials.gov number, NCT03849768.

Clinical efficacy of pyrotinib combined with stereotactic radiosurgery in HER2-positive breast cancer brain metastases.

e13017 Background: Up to 50% of patients with breast cancer (BC) and human epidermal growth factor receptor 2 (HER2) positive present with disease progression in brain metastases (BM). Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase inhibitor, has shown efficacy in active central nervous system(CNS) metastases. However, clinical efficacy of pyrotinib combining with stereotactic radiosurgery (SRS) in BCBM is unclear. Methods: This retrospective, observational study collected data from 52 HER2+ BC patients with brain metastasis who received pyrotinib-based therapy in Guangdong Sanjiu brain hospital from 2019 to 2023. Among these patients, 36 received pyrotinib-based therapy combining with SRS concurrently, or within 1 months. Age, stage at diagnosis, dates of BM, primary tumor subtypes, prior systemic therapy, CNS-directed local therapy, the objective response and survival status were collected. The assessment of adverse effects was based on CTCAE 4.0. Results: 34 patients were evaluable for efficacy (median age: 51.5). With a median follow-up duration of 19.6 months, 1 patient (0.3%) achieved CR, while 27 patients (79.4%) had PR, resulting in an ORR of 82.3%. The median CNS PFS was 13.2 months (95% CI, 4.9-21.7). Median overall survival (OS) was 22.6 months (95% CI, 17.5-27.6). The most common grade 3 or worse treatment-emergent adverse event was diarrhea (6 [17.6%]). Conclusions: Our results suggest that pyrotinib combining with SRS is associated with promising efficacy and a satisfactory safety profile for Her2+ breast cancer brain metastases.

CNS efficacy of trastuzumab deruxtecan in metastatic breast cancer: A single-institution, real-world analysis.

e13117 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that revolutionized the management of patients with HER2+ (HER2 FISH+, IHC 3+) and HER2low (HER2 FISH-, IHC 1+/2+) metastatic breast cancer (MBC). Studies have shown that T-DXd may induce antitumor activity in HER2+ MBC with brain metastases (BM). However, data is limited on the central nervous system (CNS) efficacy of T-DXd in HER2low disease. The only report thus far is from the HER2low cohorts in the DEBBRAH study with 12 patients showing an intracranial overall response rate (ORR-IC) of 50% and progression free survival (PFS) of 5.7 months. Here, we provide a real-world, retrospective analysis of the CNS efficacy of T-DXd in HER2+, HER2low, and HER2null MBC with BM. Methods: This is a single institution, retrospective analysis of patients with MBC with BM who received T-DXd between January 2020 and November 2023. Patients with HER2+, HER2low, or HER2null MBC and BM, treated or untreated at the time of T-DXd initiation, were included. All patients had baseline brain magnetic resonance imaging before T-DXd initiation. Efficacy analyses were performed using the RECIST 1.1 criteria to CNS target lesions by investigator assessment. ORR-IC and intracranial clinical benefit rate (CBR-IC) were reported. CNS PFS, defined as time until CNS progression or death of any cause, and overall survival (OS) were also evaluated. Results: 29 patients were included in the study: 10 (35%) had HER2+, 16 (55%) had HER2low, and 3 (10%) had HER2null disease. The patients had ECOG performance status ranging from 0 to 3, and received a median of 3 prior lines of therapy (range 1-8). At baseline, 3 patients (10%) had untreated BM, 6 (21%) had prior surgery, and 23 (79%) had prior radiation. 28 (97%) had concurrent extra-cranial metastases. Best CNS response and duration of response are listed in the table below. ORR-IC was 10% overall and 6% in HER2low group. CBR-IC was 58% overall and 50% in HER2low group. Median OS in all patients was 65 weeks. Median CNS PFS was not statistically different in the overall group (24 weeks) compared to the HER2low group (21 weeks) with p=0.4661 via log rank test. Conclusions: This is the first real-world study reporting the CNS efficacy of T-DXd in patients with MBC across HER2 expression levels. The CNS efficacy of T-DXd in our institutional experience was similar in HER2+ and HER2low MBC, and was much lower than previously reported in prospective clinical trials. Performance status, extent of prior treatment, and systemic disease burden likely contributed to this difference. Larger cohort and prospective studies on patients with HER2low MBC with BM are warranted. [Table: see text]

Brain Radiotherapy With Pyrotinib and Capecitabine in Patients With ERBB2-Positive Advanced Breast Cancer and Brain Metastases

The potential benefit of combining intracranial effective systemic therapy with radiotherapy for patients with breast cancer with brain metastases remains unclear. To assess the activity and safety of combining radiotherapy with pyrotinib and capecitabine in patients with ERBB2-positive breast cancer and brain metastases. This was a single-arm, single-center, phase 2 nonrandomized clinical trial with a safety run-in phase. Between January 2020 and August 2022, patients with ERBB2-positive breast cancer and brain metastases were enrolled. The data cutoff date was February 1, 2023. Patients received either fractionated stereotactic radiotherapy or whole-brain radiotherapy. Treatment with pyrotinib (400 mg, once daily) and capecitabine (1000 mg/m2, twice daily, on days 1-14 of each 21-day cycle) was initiated from the first day of radiotherapy to the seventh day after the completion of radiotherapy and continued until disease progression or unacceptable toxic effects. The primary end point was 1-year central nervous system (CNS) progression-free survival (PFS) rate. Secondary end points included CNS objective response rate (ORR), PFS, overall survival (OS), safety, and changes in neurocognitive function. A total of 40 female patients (median age, 50.5 years [IQR, 46-59 years]) were enrolled and received treatment, including 3 patients in safety run-in phase. With a median follow-up of 17.3 months (IQR, 10.3-26.9), the 1-year CNS PFS rate was 74.9% (95% CI, 61.9%-90.7%), and the median CNS PFS was 18.0 months (95% CI, 15.5 to not reached). The 1-year PFS rate was 66.9% (95% CI, 53.1%-84.2%), and the median PFS was 17.6 months (95% CI, 12.8-34.1). The CNS objective response rate was 85% (34 of 40). Median overall survival was not reached. The most common grade 3 or 4 treatment-related adverse event was diarrhea (7.5%). Asymptomatic radiation necrosis was identified in 4 of 67 lesions (6.0%) treated with fractionated stereotactic radiotherapy. Most patients maintained neurocognitive function, as evaluated by the Mini-Mental State Examination at different points. The results of this trial suggest that radiotherapy combined with pyrotinib and capecitabine is associated with long intracranial survival benefit in patients with ERBB2-positive advanced breast cancer and brain metastases with an acceptable safety profile. This combination deserves further validation. ClinicalTrials.gov Identifier: NCT04582968.

CNS Control after First-Line Osimertinib in Patients with Metastatic EGFR-Mutant NSCLC

Although osimertinib (osi) has excellent intracranial activity in EGFR-mutant metastatic non-small cell lung cancer (NSCLC), there is no consensus regarding whether to continue osi for central nervous system (CNS) control with second-line chemotherapy (chemo) at the time of systemic progression. We aimed to compare CNS outcomes after first-line osi in patients receiving second-line chemo with or without continuation of osi. We retrospectively reviewed patients with EGFR-mutant NSCLC with brain metastases (BrM) at the time of initiating first-line osi who experienced progression and started second-line chemo. Cumulative incidence of local and distant CNS progression, and extracranial (EC) progression was calculated from time of second-line chemo initiation with death as a competing risk. Overall survival (OS) was analyzed using Kaplan-Meier. We included 52 patients with a median follow up of 9.6 months (range 0.4-36.4). Median OS and CNS progression-free survival (PFS) from the time of starting second-line chemo was 12.5 months (95% CI 8.1-16.9), and 5.3 months (95% CI 3.35-7.26), respectively. The 1-year cumulative incidence of local, distant CNS progression, any CNS progression, and EC progression was 14.4% (95% CI 4.5-24.2), 42.8% (95% CI 22.8-56.8), 42.8% (95% CI 22.8-56.8) and 66.8% (95% CI 53.5-80.2), respectively. After progression on first-line osi, 25 (48.1%) and 27 patients (51.9%) continued and discontinued osi, respectively. Patients who continued osi had significantly higher BrM burden than those who did not, with 17 (68%), 3 (12%), and 5 (20%) versus 26 (96%), 0, and 1 (3.7%) patient having <10 or >11 parenchymal brain lesions, or leptomeningeal disease (LMD) at the time of second line therapy, respectively (p<0.01). In those who continued osi vs those who did not, median OS (10.8 vs 12.5 months; p = 0.37), median intracranial PFS (5.3 vs 4.8 months; p = 0.99), 1-year cumulative incidence of local (8.4% versus 20 % p = 0.26), and 1-year distant CNS progression (24.8% vs 60%; p = 0.08) was not significantly different. CNS complications such as symptomatic, hospitalizations, and steroid initiation for CNS disease, and progression of LMD were not significantly different between the two groups. Eventually, 10 patients underwent salvage RT post first-line osi and median time to salvage RT was 7.8 months (range 2-9.4). Of patients who underwent salvage RT, 2 patients (20%) had continued osi with second-line chemo. Twelve patients (44.4%) who did not continue osi eventually re-started osi for progressive disease. Patients who continued osi had significantly higher BrM tumor burden. Despite these patients being at higher risk for CNS progression, time to CNS progression and incidence of CNS complications were not significantly different in the two cohorts. Patients who discontinued osi were more likely to undergo salvage RT. Continuation of osi may allow patients to defer salvage RT.

Efficacy and safety of dose-escalated alectinib in patients with metastatic ALK-positive NSCLC and CNS relapse on standard dose alectinib.

e21079 Background: Central nervous system (CNS) metastases represent a common cause of morbidity and mortality in patients (pts) with ALK-positive (ALK+) non-small cell lung cancer (NSCLC), with limited therapeutic options. We previously reported re-induction of CNS responses using dose intensification of alectinib in two pts with metastatic ALK+ NSCLC who had experienced CNS progression on standard dose alectinib. However, this strategy has not been assessed in larger cohorts. Methods: In this retrospective study, pts were eligible if they had advanced ALK+ NSCLC with CNS relapse on standard dose alectinib (600 mg twice daily) and subsequently received dose-escalated alectinib (900 mg twice daily). Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events (trAEs) were graded per the CTCAE version 5.0. Results: 27 pts were eligible [male, 67%; median age at diagnosis, 53 (range, 31-69)]. Pts had previously received median 3 lines of systemic therapy (range, 1-12) and median 2 ALK TKIs (range, 1-4); all had received standard dose alectinib with CNS progression. 19 pts (70%) had received prior CNS-directed radiotherapy (RT) [median time from most recent RT to dose-escalated alectinib, 13.9 months (mos) (range, 0.2-52.3)]. The median duration of dose-escalated alectinib therapy in this cohort was 7.7 mos (95% CI, 4.8-10.9), with median overall progression-free survival (PFS) of 7.8 mos (95% CI, 4.9-13.7). Among 25 response-evaluable pts with baseline measurable or non-measurable CNS metastases, the CNS objective response rate (ORR) was 8.0% (95% CI, 1.0-26.0), with 2 pts having intracranial complete responses. CNS disease control rate (DCR) was 92.0% (95% CI, 74.0-99.0), with median CNS duration of response (DoR) of 5.3 mos (95% CI, 3.4-8.3) and median CNS PFS of 7.1 mos (95% CI, 4.4-13.7). Of 3 patients with baseline measurable CNS disease, all 3 had best intracranial response of SD, and median CNS PFS was 6.7 mos (95% CI, 6.2-not reached). Dose-escalated alectinib was well tolerated with no drug discontinuation due to trAE and no grade 3 or higher trAEs. One pt required dose reduction to 750 mg twice daily due to intolerable grade 2 fatigue. 23 pts (85%) experienced grade 1-2 trAEs. Grade 1-2 trAEs that occurred in 10% of pts were anemia (52%), fatigue (37%), constipation (26%), bilirubin increase (15%), alkaline phosphatase increase (15%), and peripheral neuropathy (11%). Conclusions: Dose intensification of alectinib demonstrated meaningful efficacy and tolerability in pts with metastatic ALK+ NSCLC who had experienced CNS disease relapse on standard dose alectinib, and may represent a viable therapeutic option for re-establishing CNS disease control.

Radiotherapy combined with pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and brain metastases: A single-arm, exploratory trial.

e13024 Background: Previous researches indicated the enhanced radiosensitivity in HER2-positive cancer cells by pyrotinib. For patients with treatment-naive brain metastases and central nervous system (CNS) symptoms, whether radiotherapy (current mainstay treatment) combined with pyrotinib-based systemic regimen is more beneficial remains unclear. This study explored radiotherapy combined with pyrotinib plus capecitabine in this population. Methods: In this exploratory trial (NCT04767828), patients aged 18-75 years who had HER2-positive metastatic breast cancer and untreated symptomatic brain metastases with an Eastern Cooperative Oncology Group performance status of 0-2 were included. Patients with meningeal metastases or without measurable CNS lesions were excluded. Eligible patients received whole-brain radiotherapy (WBRT) or stereotactic radiotherapy (SRT). The irradiation sites, total radiation dose, and fractions were decided by investigator based on the number of CNS lesions and size. Pyrotinib (400 mg, once a day) and capecitabine (1000 mg/m2, twice a day, on days 1-14 of each 21-day cycle) were given since the start of radiotherapy until disease progression or intolerable toxicity. The primary endpoint was CNS progression-free survival (PFS), assessed by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Extracranial lesions were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Between May 5, 2020 and November 25, 2022, a total of 19 patients were enrolled. Thirteen (68%) patients had other visceral metastases, and 18 (95%) had prior trastuzumab treatment (5 for early breast cancer, 12 for advanced breast cancer, and 1 for both). Fifteen (79%) patients received WBRT and 4 (21%) received SRT. By the data cutoff date on January 16, 2023, the median follow-up duration was 15.0 months (range, 1.7-24.8). Median CNS PFS was 10.0 months (95% CI, 5.3-14.7). CNS objective response rate was 100%, including two (11%) patients with CNS complete response. Median overall PFS was 8.5 months (95% CI, 4.8-12.2). Median overall survival was 19.0 months (95% CI, 13.1-24.9). The most common grade 3 or 4 adverse events were vomiting (16%) and nausea (11%). For 11 patients with available results of Mini-Mental State Examination (MMSE), 10 (91%) had normal cognitive function during study period or recovered to normal level within 6 months after radiotherapy. Conclusions: Radiotherapy combined with pyrotinib plus capecitabine shows favorable CNS response and promising survival outcomes in patients with HER2-positive metastatic breast cancer and untreated symptomatic brain metastases, with an acceptable safety profile. This combination strategy warrants further validation in large samples. Clinical trial information: NCT04767828 .

A multicenter study of central nervous system (CNS) metastasis in EGFR-mutated advanced non–small-cell lung cancer in Thailand: CNS progression-free survival analysis.

e14002 Background: Central Nervous System (CNS) metastasis is common in patients with advanced stage non-small cell lung cancer (NSCLC), which impacts their survival and quality of life. Nearly Half of NSCLCs in Thailand are EGFR (Epidermal Growth Factor Receptor) mutated NSCLCs. The aim of this study was to define the prevalence of CNS metastasis in EGFR mutated advanced NSCLC in Thai patients and their survival during the year 2013-2019.Now we reported CNS progression free survival data in subgroup with evidence of CNS progression. Methods: We retrospectively conducted a multicenter study of EGFR mutated advanced NSCLC from 9 government hospitals in Thailand from January 2013 to December2019. Demographic data and cancer treatments were recorded with previous reports of overall survival data in all cohorts. Brain imaging was performed upon neurologic signs and symptoms. Treatment of CNS metastasis, CNS progression date and overall survival data were collected. The analysis of CNS progression free survival and overall survival was performed and the effect of Osimertinib was defined. Results: There were 254 patients with advanced EGFR mutated NSCLCs. The prevalence of CNS metastasis was 32.28% (82 patients). There were 25.6% (21) of patients with definite evidence of CNS progression by imaging or clinical. In this group, Brain metastasis at first diagnosis was 61.9% (13 patients). EGFR TKIs was given as first line 42.9% (9 patients), second line 33.3% (7 patients), third line 19% (4 patients). Whereas one patient did not received EGFR TKIs. Most of EGFR TKIs treatment was first generation for 95% (19 patients). Osimertinib was given in 23.8% (5) of patients as second line, third line and fourth line for 2, 1 and 2 patients, respectively. The onset of CNS metastasis before EGFR TKIs was 76.2% when compared to 4.8%, 19% during EGFR TKIs and after EGFR TKIs, respectively. Treatment of brain metastasis was whole brain radiation for 85.7% (18 patients), followed by surgery with whole brain radiation for 14.3% (3 patients). The median CNS progression free survival was 14.00 (9.51,18.48) months. The median CNS progression free survival between no Osimertinib treatment and Osimertinib treatment was 13 (10.38,15.61) months and 21 (17.49,24.5) months, respectively. The median survival was 30.03 (19.6,40.45) months. The median survival between no Osimertinib treatment and Osimertinib treatment was 26.58 (18.96,34.20) months and NR (NR, NR), respectively. Conclusions: The prevalence of CNS progression was 25.6% in patients with EGFR mutated NSCLC in Thailand. Treatment with EGFR TKIs improved CNS progression free survival better than historical data.3rd generation EGFR TKIs Osimertinib in later line prolong clinical benefit of CNS Progression free survival and overall survival better than 1st generation EGFR TKIs alone.

Central nervous system efficacy of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small cell lung cancer: a pooled analysis from two phase 2 studies

BackgroundFurmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies.MethodsThis was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4–8.3), 11.6 months (95% CI 8.3–13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively.ConclusionsFurmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC.Trial registrationBoth studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.

Phase II Randomized Trial Comparing Proton Craniospinal Irradiation with Photon Involved-Field Radiotherapy for Patients with Solid Tumor Leptomeningeal Metastasis

<h3>Purpose/Objective(s)</h3> Solid tumor leptomeningeal metastasis (LM) is associated with limited survival and treatments. Photon involved-field radiotherapy (IFRT) is the standard of care radiotherapy (RT) but lacks durability in disease and symptom control. We hypothesized that proton craniospinal irradiation (pCSI) encompassing the central nervous system (CNS) would result in superior disease control. <h3>Materials/Methods</h3> We conducted a randomized phase 2 study comparing pCSI vs. IFRT in patients with non-small cell lung cancer (NSCLC) or breast cancer LM. Eligibility criteria included radiographic and/or cytologic LM and Karnofsky performance status (KPS)≥ 60. Patients were stratified by histology and systemic disease (active vs. stable) and were randomized in a 2:1 ratio favoring pCSI. For all other solid tumor histologies, patients were enrolled on an exploratory cohort and all received pCSI. RT was 3Gy x 10 fractions for all patients. The primary objective is CNS progression-free survival (CNS PFS), defined as time from randomization to CNS progression (POD); the secondary objectives include overall survival (OS) and treatment-related adverse events (TAEs). A target of 81 patients to compare pCSI and IFRT was designed with a one-sided alpha of 0.025 and power of 0.8 based on stratified log-rank test. Analysis is based on intent-to-treat. <h3>Results</h3> From 4/2020-10/2021, 42 and 21 patients were randomized to pCSI and IFRT, respectively. Baseline factors were not different: median age was 56 vs. 61 years (p=0.5), both cohorts included 57% NSCLC and 52% patients with active systemic disease. At median follow up of 7.1 months, 25 patients had CNS POD and 28 died. At planned interim analysis, significant benefit in CNS PFS was observed with pCSI (median=7.5 months, 95% CI: 6.6-NA) vs. IFRT (median=2.0. 95% CI: 1.0-5.1, p<0.001). As a result, the Data and Safety Monitoring Committee recommended early discontinuation of the trial. In addition, OS benefit with pCSI (median= 8.2 months, 95% CI: 7.4-NA) vs. IFRT (median= 4.9 months, 95% CI: 3.1-NA, p=0.04) was observed. In a multivariable analysis including age, KPS and stratification factors, pCSI remained significantly associated with improved CNS PFS (HR=13, 95% CI: 5-33, p<0.001) and OS (HR=2, 95% CI: 1-5, p=0.04). Grade 3 non-heme TAEs occurred in 3 patients with pCSI and 5 with IFRT. The only Grade 4 TAE was lymphopenia (4 patients in each cohort). For the exploratory pCSI cohort, 35 patients enrolled, the median age was 61, 20 (57%) had active systemic disease and ovarian (7 [20%]) was the most common histology. At median follow up of 9.6 months, 7 (20%) had CNS POD and 20 (57%) died. Median CNS PFS was 5.4 months (95% CI: 4.8-9.1), OS was 6.6 months (95% CI: 5.4-12.1), 4 patients had Grade 3 non-heme TAEs and 4 had Grade 4 lymphopenia. <h3>Conclusion</h3> In this pre-planned interim analysis of the first randomized trial of RT for LM, we demonstrated improved CNS PFS of pCSI compared to IFRT, meeting the primary endpoint. pCSI also had a significant OS benefit. Toxicities were comparable.

Efficacy and Safety of Rezivertinib (BPI-7711) in Patients With Locally Advanced or Metastatic/Recurrent EGFR T790M-Mutated NSCLC: A Phase 2b Study

IntroductionRezivertinib (BPI-7711) is a novel third-generation EGFR tyrosine kinase inhibitor (TKI) targeting both EGFR-sensitizing mutations and EGFR T790M mutation. This study aimed to evaluate the efficacy and safety of rezivertinib in patients with locally advanced or metastatic/recurrent EGFR T790M-mutated NSCLC. MethodsPatients with locally advanced or metastatic/recurrent NSCLC with confirmed EGFR T790M mutation who progressed after first-/second-generation EGFR TKI therapy or primary EGFR T790M mutation were enrolled. Patients received rezivertinib at 180 mg orally once daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary end point was objective response rate (ORR) assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival, and safety. This study is registered with Clinical Trials.gov (NCT03812809). ResultsA total of 226 patients were enrolled from July 5, 2019, to January 22, 2020. By the data cutoff date on January 24, 2022, the median duration of follow-up was 23.3 months (95% confidence interval [CI]: 22.8–24.0). The ORR by blinded independent central review was 64.6% (95% CI: 58.0%–70.8%), and DCR was 89.8% (95% CI: 85.1%–93.4%). The median duration of response was 12.5 months (95% CI: 10.0–13.9), and median PFS was 12.2 months (95% CI: 9.6–13.9). The median overall survival was 23.9 months (95% CI: 20.0–not calculated [NC]). Among 91 (40.3%) patients with central nervous system (CNS) metastases, the median CNS PFS was 16.6 months (95% CI: 11.1–NC). In 29 patients with more than or equal to one brain target lesion at baseline, the CNS ORR and CNS DCR were 69.0% (95% CI: 49.2%–84.7%) and 100% (95% CI: 88.1%–100%), respectively. Time to progression of CNS was 16.5 months (95% CI: 9.7–NC). Of 226 patients, 188 (83.2%) had at least one treatment-related adverse event, whereas grade more than or equal to 3 occurred in 45 (19.9%) patients. No interstitial lung disease was reported. ConclusionsRezivertinib was found to have promising efficacy and favorable safety profile for patients with locally advanced or metastatic/recurrent NSCLC with EGFR T790M mutation.

Phase II randomized study comparing proton craniospinal irradiation with photon involved-field radiotherapy for patients with solid tumor leptomeningeal metastasis.

2000 Background: Leptomeningeal metastasis (LM) is associated with limited survival and treatments. Photon involved-field radiotherapy (IFRT) is the standard of care radiotherapy (RT) but benefits are limited. We hypothesized that proton craniospinal irradiation (pCSI) encompassing the central nervous system (CNS) compartment would result in superior CNS disease control compared to IFRT. Methods: We conducted a randomized phase 2 study comparing pCSI vs. IFRT in patients with non-small cell lung cancer (NSCLC) or breast cancer LM. Eligibility criteria included radiographic and/or cytologic LM and Karnofsky performance status (KPS) ≥ 60. Patients were stratified by histology (breast vs. NSCLC) and systemic disease (active vs. stable) and were randomized in a 2:1 ratio of pCSI:IFRT. Patients with all other solid tumor histologies were enrolled to an exploratory pCSI arm. RT was 3Gy x 10 fractions for all patients. The primary endpoint is CNS progression-free survival (CNS PFS), defined as time from randomization to CNS progression (POD); secondary endpoints include overall survival (OS) and treatment-related adverse events (TAEs). A target of 81 patients to compare pCSI and IFRT was designed with a one-sided alpha of 0.025 and a power of 0.8 based on stratified log-rank test. Analysis is based on intent-to-treat. Results: From 4/2020-10/2021, 42 and 21 patients were randomized to pCSI and IFRT, respectively. Baseline factors were not different: median age was 56 vs. 61 years (p = 0.5); both cohorts included 57% NSCLC and 52% with active systemic disease. At median follow up of 7.1 months, 25 patients had CNS POD (pCSI = 9 [21%], IFRT = 16 [76%]) and 28 died (pCSI = 15 [36%], IFRT = 13 [62%]). At planned interim analysis, significant benefit in CNS PFS was observed with pCSI (median = 7.5 months, 95% CI: 6.6-NA) vs. IFRT (median = 2.0, 95% CI: 1.0-5.1, p &lt; 0.001). As a result, the Data and Safety Monitoring Committee recommended early discontinuation of the trial. In addition, OS benefit with pCSI (median = 8.2 months, 95% CI: 7.4-NA) vs. IFRT (median = 4.9 months, 95% CI: 3.1-NA, p = 0.04) was observed. In a multivariable analysis including age, KPS and stratification factors, CNS PFS and OS benefit for pCSI remained significant. Grade 3 non-heme TAEs occurred in 3 patients with pCSI and 5 with IFRT. For the exploratory pCSI cohort, 35 patients enrolled, the median age was 61, 20 (57%) had active systemic disease and ovarian (7 [20%]) was the most common histology. At median follow up of 9.6 months, 7 (20%) had CNS POD and 20 (57%) died. Median CNS PFS was 5.4 months (95% CI: 4.8-9.1), OS was 6.6 months (95% CI: 5.4-12.1) and 4 patients had Grade 3 TAEs. Conclusions: In this trial, the first randomized study of RT for LM, we demonstrated improved CNS PFS of pCSI compared to IFRT, meeting the primary endpoint. pCSI also had a significant OS benefit. Grade 3 toxicities were comparable. Clinical trial information: NCT04343573.

Long-Term Outcomes of a Prospective Clinical Trial of Proton Craniospinal Irradiation for Leptomeningeal Metastasis

Leptomeningeal metastasis (LM) is associated with limited survival and treatment options for patients with solid tumor malignancies. While photon involved-field radiotherapy (IFRT) is effective for local palliation, it lacks durability. Craniospinal irradiation (CSI), in contrast, treats the entire central nervous system (CNS) compartment, thus potentially improving disease control. We previously reported the safety and tolerability of proton CSI (pCSI) in a completed phase IB study, and we are now reporting the mature survival outcomes of these patients.We enrolled 24 patients with solid tumor LM to receive hypofractionated pCSI of 30 Gy (RBE) in 10 fractions in this phase I prospective trial between June 2018 and May 2019 (NCT03520504). The primary endpoint is dose-liming toxicity (DLT) within 1 month of treatment. Secondary endpoints, including time to CNS progression (CNS TTP), CNS progression-free survival (PFS), and overall survival (OS), were assessed using Kaplan-Meier analysis with median survival estimates and 95% confidence intervals (CI) reported. Correlations between cerebrospinal fluid (CSF) circulating tumor cells (CTCs) and survival outcomes were evaluated using Kaplan-Meier analysis. An optimal cutoff for CTCs was determined through maximally selected rank statistics using CNS PFS.Of the 24 patients enrolled, 3 did not complete treatment due to systemic disease progression and were excluded from this analysis. The majority of patients had metastatic lung (52%) and breast (33%) malignancies. The median age was 52 years (range 30-67 years) and the median Karnofsky performance status was 70 (range 60-90). The majority of patients had LM that progressed on other therapies prior to enrollment (57% vs. 43% of patients with newly diagnosed LM), and all patients with molecularly driven disease had CNS progression on small-molecule tyrosine kinase inhibitors prior to enrollment. Only 1 patient was censored at 24 months of follow-up, while 20 patients were followed until death with a median OS of 9 months (95% CI 6-22 months). The median CNS TTP was 8 months (95% CI 7-18 months), with 5 (24%) patients with durable CNS control for > 12 months after pCSI. The median CNS PFS was 7 months (95% CI 5-13 months). In the 18 patients with CSF CTCs evaluation at baseline, having a pre-pCSI CSF CTCs < 41/3mL was associated with improved CNS TTP (19 vs. 8 months, P < 0.01), CNS PFS (18 vs. 6 months, P < 0.01), and a trend toward improved OS (21 vs. 8 months, P = 0.06).We reported that pCSI is a safe treatment for patients with solid tumor LM. In this analysis, we demonstrated durable disease control and prolonged survival in some patients. Lower CSF CTCs at baseline, a potential biomarker of response, was associated with improved survival outcomes. An ongoing randomized phase II trial will determine the efficacy of pCSI compared to photon IFRT in patients with solid tumor LM.

Yield of Surveillance Imaging in Long-Term Survivors of Brain Metastasis Treated With Stereotactic Radiosurgery

Although patients with brain metastasis treated with stereotactic radiosurgery (SRS) in the definitive or post-operative setting have high rates of local control, surveillance imaging is necessary to assess for central nervous system (CNS) recurrence. Guidelines recommend magnetic resonance imaging (MRI) of the brain every three months for surveillance in asymptomatic patients post-SRS. However, optimal frequency and duration of surveillance imaging in long-term survivors is unknown. Our objective is to define the yield and cost of surveillance MRIs in long-term (> 1 year) survivors following SRS.We identified a cohort of patients with brain metastases treated with SRS in the definitive or postoperative setting at a single institution from 8/2014 to 9/2019. Eligible patients had at least one-year of follow-up with absence of CNS disease failure up to and including the first MRI of the brain after 12 months from SRS. Each post-treatment MRI of the brain was assessed for disease progression or new lesions. CNS disease-free survival was time from SRS to last follow-up, death or CNS failure. Delay to diagnosis and cost per patient were estimated using hypothetical MRI schedules of 2, 3, 4 and 6 months from 1-year post-treatment while CNS disease-free. Delay to diagnosis was calculated as time from actual CNS progression to hypothetical imaging date. Medicare reimbursement median cost of $498 per MRI brain with and without contrast was used for this analysis.A total of 373 patients treated with SRS for brain metastasis were identified at our institution. 61 patients met eligibility criteria for inclusion in this study (median follow-up 2.50 years, median age at treatment 60 years). The median CNS disease-free survival in this population was 2.37 years from date of SRS. 15 patients (24.6%) had CNS progression at median time of 2.26 years. Of the 15 patients, 3 patients were symptomatic at recurrence. Median frequency of MRI after one year post SRS was 5.9 months. Per patient, $1156 was spent annually on MRIs of the brain after 12 months with average annual yield of 17.0%. The cost per diagnosis of CNS progression was $6806. A 2-month, 3-month, 4-month and 6-month MRI schedule had a respective estimated delay to diagnosis of 0.69 months, 1.13 months, 1.44 months and 3.19 months. The respective mean total cost of each MRI schedule per patient from one-year post-treatment while CNS disease-free was $4662, $3053, $2229 and $1380.Patients with metastatic disease to the brain treated definitively or postoperatively with SRS without evidence of CNS recurrence at one year have a low rate of CNS failure and relatively good prognosis. Based strictly on limiting delay of diagnosis, a 2-month MRI Brain schedule is optimal in this population, albeit with a relatively small increase in financial cost over the patient's lifespan. We propose a multi-institutional study of long-term survivors with brain metastasis to strengthen these findings.B.J. Rich: None. D. Kwon: None. Y.S. Soni: None. D.L. John: None. J.B. Bell: None. G. Azzam: None. E.A. Mellon: None. R. Yechieli: Support and guide school in strategic and management related matters; Toras Chaim Toras Emes, Miami FL.C. Benjamin: None. R. Benveniste: None. R.J. Komotar: None. M. Ivan: None. J. Morcos: None. T. Diwanji: None.

Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: efficacy, safety, and cerebrospinal fluid biomarkers

BackgroundThe benefit of immune checkpoint inhibitors (ICIs) in patients with leptomeningeal metastases (LMM) is unknown.MethodsWe undertook a phase II trial of pembrolizumab in patients with LMM from solid tumors. Eligible...

356MO Osimertinib adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) NSCLC (ADAURA): Central nervous system (CNS) disease recurrence

CNS relapse is common in NSCLC, and is a poor prognostic factor. In the resected EGFRm NSCLC setting, the impact of treatment on sites of recurrence, including the CNS, is a key consideration. Osimertinib is a 3rd-generation EGFR-TKI with demonstrated efficacy in NSCLC CNS metastases. In ADAURA, osimertinib demonstrated a highly statistically significant and clinically meaningful improvement in disease-free survival vs placebo (PBO; DFS, hazard ratio [HR]: 0.20 [99.12% CI 0.14, 0.30; p<0.001) in resected stage IB–IIIA EGFRm (ex19del/L858R) NSCLC (Ph III ADAURA; NCT02511106). We report an exploratory analysis of recurrence patterns. Pts with resected stage IB–IIIA EGFRm NSCLC, with/without adjuvant chemotherapy, were randomised 1:1 to receive osimertinib 80 mg once-daily or PBO until recurrence/discontinuation/3 years. Patterns of recurrence and CNS DFS (time to CNS recurrence/death) were exploratory endpoints. An MRI/CT brain scan was mandated at baseline either before surgery or upon enrolment, but was not required in absence of symptoms. Recurrence was categorised as local/regional and/or distant, with sites of relapse recorded. Data cutoff: 17/01/20. Overall, 682 pts were randomised (osimertinib: 339; PBO: 343). Pts treated with osimertinib had fewer recurrence events vs PBO (Table); 45 pts had CNS DFS events (osimertinib: 6; PBO: 39; median follow-up 22 months [mo]). Conditional probability of CNS recurrence at 12 mo (95% CI): <1% (0%, 2%) with osimertinib vs 7% (4%, 10%) with PBO. Median CNS DFS: not reached (95% CI 39.0 mo, not calculable [NC]) with osimertinib vs 48.2 (NC, NC) mo with PBO. CNS DFS HR: 0.18 (95% CI 0.10, 0.33); p<0.0001.Table: 356MOOsimertinib n=339PBO n=343CNS DFS events, pts (%):6 (2)39 (11)CNS recurrence4 (1)33 (10)Death*2 (1)6 (2)DFS events, pts (%):37 (11)159 (46)Disease recurrence37 (11)157 (46)—— Non-CNS recurrence33 (10)123 (36)—— CNS recurrence4 (1)33 (10)—— Disease recurrence with missing location01 (0)Death†02 (1)*Death in absence of CNS disease recurrence, or death within two visits of baseline where the patient has no evaluable assessments or no baseline data. †Death in the absence of disease recurrence (any site), or death within two visits of baseline where the patient has no evaluable assessments or no baseline data. Open table in a new tab *Death in absence of CNS disease recurrence, or death within two visits of baseline where the patient has no evaluable assessments or no baseline data. †Death in the absence of disease recurrence (any site), or death within two visits of baseline where the patient has no evaluable assessments or no baseline data. There was a clinically meaningful improvement in CNS DFS with osimertinib: 82% reduction in risk of CNS disease recurrence or death. Results support that osimertinib reduces risk of CNS recurrence in the resected EGFRm NSCLC setting.

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases

Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. SRS and WBRT for small cell lung cancer brain metastases. Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses. In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results. Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.