Central Nervous System Progression-free Survival Research Articles

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.

Safety and efficacy of osimertinib plus bevacizumab as first-line treatment in EGFR-mutant NSCLC with brain metastases: A dynamic ctDNA-guided study.

e20606 Background: Non-small cell lung cancer (NSCLC) patients with positive driver genes had a higher incidence of brain metastasis. This study evaluates the efficacy and safety of Osimertinib combined with Bevacizumab as first line treatment in EGFR-mutant NSCLC with brain metastases, utilizing liquid biopsy and dynamic molecular detection to guide treatment strategies. This approach is anticipated to bring progression-free survival (PFS) benefits and shows different resistant mechanisms. Methods: We enrolled EGFR-mutant NSCLC patients with brain metastases receiving Osimertinib and Bevacizumab as first-line therapy. Paired plasma and cerebrospinal fluid (CSF) samples were collected at baseline, during stable disease, and at disease progression for Next-Generation Sequencing (NGS) analysis. The study's primary endpoints were central nervous system (CNS) PFS and objective response rate (ORR). Secondary endpoints included overall PFS, ORR, disease control rate (DCR), and safety. We also investigated resistance mechanisms to the combination therapy. Results: A total of 28 patients from Beijing TianTan Hospital (May 2020 - July 2023) were retrospectively enrolled. The average Bevacizumab treatment duration was 8.21 months (range: 1-27 months). CNS PFS was 26.73 months (95% CI, not reached), and overall PFS was 21.93 months (95% CI, 18.84-25.02 months). The CNS PFS for patients with 19del and L858R mutations were not reached and 26.73 months (95% CI, 15.11-38.35 months), respectively (p = 0.25). Patients undergoing intracranial local treatment showed a CNS PFS not reached, compared to 23.33 months (95% CI, 16.21-30.45 months) for those who did not (p = 0.417). The CNS ORR was 88%, ORR was 76%, and DCR was 100%. At the time of data cutoff (Dec 15th, 2023), 1 patient progressed in both lung and CNS metastases, 8 patients only progressed in lung, 8 patients only progressed in CNS metastases .EGFR C797S mutation was detected in 2 plasma sample, Met amplification in 1 tumor tissue, EGFR C719S mutation in 1 paired plasma-tumor tissue and PIK3CA in 2 plasma sample. Increasing abundance in TP53 and CDKN2A were detected in 2 paired plasma-tumor tissue. Adverse events of grade 3 or higher included one case (3.6%) of severe ulcerative colitis leading to Osimertinib discontinuation and two cases (7.1%) of bevacizumab discontinuation due to bleeding events. Conclusions: Osimertinib combined with Bevacizumab as a first-line treatment significantly prolonged CNS PFS in EGFR-mutant NSCLC patients with brain metastases, offering superior control over intracranial lesions compared to Osimertinib monotherapy (15.2 months, FLAURA study). This study underscores the potential of dynamic ctDNA monitoring in guiding effective treatment strategies for this patient population. Further research is warranted to explore the broader clinical implications of these findings.

Radiosurgery to 5 or more newly diagnosed brain metastases in the systemic therapy era.

2026 Background: Stereotactic radiosurgery (SRS) is an ablative modality for focal treatment of brain metastases (BM) and is standard of care for limited BM. Suitability for SRS has historically been linked to number of BM, with up to 4 BM considered amenable to SRS. JLGK0901 revealed no difference in overall survival (OS) and similar rates of adverse events for patients with 5-10 vs. 2-4 BM. Evidence supporting for SRS for &gt;10 BM is limited. As systemic treatments have evolved to include agents with improved central nervous system (CNS) efficacy and OS, the role of SRS warrants re-evaluation. Methods: We retrospectively reviewed patients from a single institution with ≥5 BM treated with SRS with no prior history of brain radiation 2015-2022 on an IRB-approved protocol. Clinical history, including sex, histology, Karnofsky performance status (KPS), extracranial disease status and systemic regimen used before and after diagnosis of BM, was reviewed. Systemic regimens were categorized based on potential for CNS efficacy as 1) none: no evidence, 2) weak: single agent immunotherapy or known but limited data on CNS efficacy, or 3) strong: multiple agents with known CNS efficacy, single agents with strong CNS efficacy. Kaplan-Meier method was used to estimate survival with log-rank test used to evaluate differences in survival curves. Cox proportional hazards modeling was used to evaluate differences in CNS progression-free survival (CNS-PFS) and OS. Results: 558 patients (48% female) who received SRS to ≥5 BM (range 5-23) were identified. Primary histologies included: 36% non-small cell lung cancer; 22% melanoma; 14% breast; 7% renal; 5% gastrointestinal; 15% other. Median OS was 11.0 months and did not differ between patients with 5-9 (n=441) vs ≥10 BM (n=117) (median OS 11.1 vs. 10.0 months; p=0.53). Median CNS-PFS was 6.6 months and did not differ between 5-9 vs ≥ 10 BM (median CNS-PFS 6.4 vs. 7.7 p=0.86). On univariate analysis, high KPS (HR 0.96; p&lt;0.001) was associated with improved OS. Histology ( p=0.14), BM number ( p=0.53); average BM volume ( p=0.48), and systemic disease status ( p=0.17) were not associated with OS. Change of systemic therapy at time of SRS was associated with improved OS (HR 0.58; p&lt;0.001) and CNS-PFS (HR 0.63; p&lt;0.001). Amongst patients with systemic therapy change, regimens with increased CNS efficacy compared to prior therapy were associated with improved OS (HR 0.59; p&lt;0.001) and CNS-PFS (HR 0.65; p=0.002). Conclusions: In this large, retrospective analysis of patients with ≥ 5 previously untreated BM treated with SRS, we found no association between BM number and CNS-PFS or OS. Change in systemic therapy, particularly to agents with CNS efficacy, was associated with improved outcomes. While limited by biases inherent to retrospective analyses, these results suggest patients with larger number of BM (≥10) are appropriate for SRS, especially when changing to systemic therapy with CNS penetrance.

Real world outcomes of patients with small cell lung cancer (SCLC) presenting with brain metastasis at diagnosis in a single institution health system.

e20136 Background: Extensive-stage small cell lung cancer (ES-SCLC) is an aggressive lung cancer subtype with high propensity for brain metastases (mets). Despite this, there is no consensus on the treatment of brain mets especially in the setting of frontline chemoimmunotherapy and advanced radiation techniques like Gamma Knife radiosurgery (GKRS). Methods: In this single-institution retrospective study, we queried the Yale Tumor registry for all patients diagnosed with ES-SCLC in 1/2016-4/2023. Patients with brain mets at the time of presentation were identified and underwent manual chart review for abstraction of clinical information specifically pertaining to brain mets and treatment modalities. Survival outcomes including median progression free survival (mPFS), median central nervous system-progression free survival (mcPFS) and median overall survival (mOS) measured in months were also captured. Results: 423 ES-SCLC patients were identified. Of those, 92 (22%) had brain mets at initial presentation and were reviewed. 44 (48%) of patients with brain mets were treated with frontline chemotherapy (platinum doublet) while 42 (46%) were treated with chemoimmunotherapy (platinum doublet with atezolizumab or durvalumab). Patients treated with upfront chemotherapy had mPFS 6.4 (95% CI -1.2, 14.1), mcPFS 7.7 (95% CI -1.2, 17.1), and mOS 9.3 (95% CI -13.7, 36.4), compared to patients treated with chemoimmunotherapy, who had mPFS 4.9 (p=0.23; 95% CI -3.5, 15.4), mcPFS 6.7 (p=0.99; 95% CI 3.3, 20.8), and mOS 7.7 (p=0.89; 95% CI -11.4, 33.9). 63 (68%) of patients underwent upfront brain radiation. 44 (48%) had whole brain radiation (WBRT) while 19 (30%) underwent GKRS. Of the patients undergoing GKRS, 8 (42%) were symptomatic. 7 patients (37%) presented with 1 brain met, and 12 (63%) patients presented with 2-5 brain mets. For patients treated with GKRS, mPFS 6.8 (95% CI 2.3, 10.4), mcPFS 7.2 (95% CI 2.9, 12.6), and mOS 11.1 (95% CI -13.0, 40.9). For patients undergoing WBRT, mPFS 6.5 (p = 1.0; 95% CI -4.5, 20.2), mcPFS 6.5 (p = 0.96; 95% CI -3.9, 21.6), and mOS 8.6 (p = 0.21; 95% CI -17.7, 39.9). Conclusions: GKRS is a viable option for SCLC patients presenting with brain metastases, especially in those with a low number of mets. Further studies are required to determine the optimal ES-SCLC candidates for upfront GKRS. [Table: see text]

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]

Osimertinib plus local treatment for brain metastases versus osimertinib alone in patients with EGFR-Mutant Non-Small Cell Lung Cancer

ObjectivesOsimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib. Materials and MethodsThis multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors. ResultsOf the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan–Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR–NR vs. 31.2, 21.7–33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16–0.87) and 0.36 (95 %CI, 0.15–0.87), respectively. ConclusionsThe OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib.

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.

Clinical characteristics and outcomes of newly diagnosed patients with human immunodeficiency virus-associated Burkitt lymphoma: the Central and Western China AIDS lymphoma league 002 study (CALL-002 study)

BackgroundDespite the introduction of combined antiretroviral therapy, the clinical outcomes of HIV-associated Burkitt lymphoma (BL) remain poor.MethodsTo evaluate the clinical characteristics, prognostic factors, and outcomes of HIV-associated BL, we conducted a retrospective analysis of patients from multiple centers in China.ResultsThe study included 41 patients from 8 medical centers. Among the included population, male patients accounted for 87.8%, with 75.6% in advanced stages. Notably, 46.3% of cases involved bone marrow, while 19.5% involved the central nervous system (CNS). The most commonly used chemotherapy regimen was DA-EPOCH ± R, accounting for 53.6% of cases. The overall response rates for patients receiving DA-EPOCH ± R and R-Hyper-CVAD were 59% and 58.2%, respectively. Interestingly, patients receiving regimens containing rituximab had similar complete remission rates (25% vs. 23.5%) and overall survival time (45.69 ± 11.58 vs. 47.79 ± 11.72 months, P = 0.907) compared to those without rituximab, but differed in progression rates (33.3% vs. 47.1%). For the entire cohort, the 1-year progression-free survival (PFS) and overall survival (OS) rates were 52% and 67%, respectively. CNS involvement was independent risk factors for survival, with 1-year PFS and OS rates of 0% and 38% for patients with CNS involvement, and PFS and OS rates of 66% and 75% for patients without CNS involvement.ConclusionsHIV-associated BL patients in China have poor prognosis and show limited response to current treatment regimens. The absence of CNS involvement significantly improves clinical outcomes. The use of rituximab is not significantly associated with improved outcomes but can reduce disease progression.

The Outcome of Diffuse Large B-Cell Lymphoma Patients with Testicular Involvement - Real World Data

Introduction: Patients (pts) with testicular lymphoma (TL) have an increased risk of central nervous system (CNS) relapse. In rituximab era, the reported incidence vary from 10% (in limited disease) to 25% (advanced disease). More data is needed to guide the managment of TL pts in current era. Optimal strategy for CNS relapse prevention is uncertain. Methods: We studied consecutive pts diagnosed between 2000 and 2022 with testicular diffuse large B-cell lymphoma (DLBCL) prospectively observed in the Czech Lymphoma Study Group Project NiHiL (Clinical Trial gov. NCT03199066). Objectives were to analyze the cumulative incidence of CNS relapse, time to CNS relapse, PFS and OS. The impact of various treatment strategies on CNS relapse was analyzed. Results: We identified 229 pts with testicular involvement: 157 pts with primary testicular lymphoma (PTL) in clinical stage I or II and 72 pts in advanced stage (AD) III or IV. Median age was 70 years (range 33 - 87). Rituximab-based chemotherapy received 192 (83.8%) pts including 127 (81%) cases with PTL. Following localized treatments were used more often in PTL compared to AD: unilateral orchiectomy [148 (94.3%) vs. 47 (65.3%); p &amp;lt; 0.0001], testicular irradiation (RT) [116 (61.7%) vs. 40 (38.7%); p = 0.005]. Most patients (85%) received some form of CNS prophylaxis. There were similar rates in use of prophylactic methotrexate (MTX) between PTL and AD (p = 0.88): intrathecal (i.t.) MTX 64 (40.8%) vs. 29 (40.3%), intravenous (i.v.) MTX with or without cytarabine 20 (12.8%) vs. 7 (9.7%); combined i.t. and i.v. MTX 38 (24.2%) vs. 20 (27.8%). Out of 229 cases 25 (15.9%) PTL and 11 (15.3%) AD pts did not receive any CNS prophylaxis. Median follow-up was 51.8 months.Overall 63 (27.5%) pts relapsed including 14 (6.1%) relapses in CNS. Median time to CNS relapse was 21.9 months and to other systemic relapse was 14.7 months (p = 0.63). The 5-year cumulative incidence of CNS relapse in PTL was 4.55% (95% confidence interval [CI], 0.1 - 28.6) and in AD 12.07% (95% CI 0.8 - 39.6), respectively. In univariate analyses, MTX prophylaxis (i.v. and/or i.t.) and testicular RT had no impact on CNS relapse (p = 0.49 and p = 0.60, respectively). Orchiectomy was the single significant factor associated with lower risk of CNS relapse in PTL (hazard ratio [HR] = 0.11[95% CI 0 - 0.124]; p = 0.001). Rituximab significantly reduced CNS relapse in AD with testicular involvement (HR = 0.1002 [95% CI 0.0 - 0.45]; p = 0.0005). Out of 14 pts with CNS relapse 8 died due to lymphoma progression. Median progression-free survival (PFS) and overall survival (OS) in PTL was significantly better when compared to AD (PFS 92.9 vs. 28.1 months, p &amp;lt; 0.0006; OS 108.7 vs. 56.7 months, p = 0.0002). Median PFS2 and OS2 since CNS relapse was dismal in AD compared to PTL (PFS2 1.6 vs. 37.8 months, p = 0.04 and OS2 2.3 vs. 37.8 months, p = 0.05). Conclusions: The rate of CNS relapses in PTL and advanced disease with testicular involvement is lower than previously reported. This study confirmed a significant favorable impact of rituximab in prevention of CNS relapse. Notably, methotrexate prophylaxis i.v. or i.t. did not alter the CNS relapse risk. Prognosis of CNS relapse is particularly poor in advanced disease. This work was supported by grant AZV NU21-03-00411 from the Ministry of Health of the Czech Republic and by the Cooperatio Program, research area “Oncology and Haematology”

BIOM-01. PROGNOSTIC IMPLICATIONS OF SMALL CELL LUNG CANCER (SCLC) TRANSCRIPTIONAL SUBTYPING FOR CENTRAL NERVOUS SYSTEM (CNS) METASTASES

Abstract BACKGROUND Small cell lung cancer (SCLC) is characterized by a high propensity for brain metastases (BM) and is associated with a poor prognosis. Subtypes characterized by high versus low neuroendocrine states (expressing ASCL1 or NEUROD1) have been identified. This study aims to evaluate the influence of transcription factor-defined SCLC subtypes on the incidence and outcomes of BM. METHODS We identified 164 patients with SCLC based on their ASCL1 and NEUROD1 expression status by immunohistochemistry. Four transcriptional subtypes were defined: ASCL1+/NEUROD1- (A+/N-), ASCL1+/NEUROD1+ (A+/N+), ASCL1-/NEUROD1+ (A-/N+), and ASCL1-/NEUROD1- (A-/N-). Cumulative incidence competing risk analyses examined the incidence of central nervous system (CNS) progression. Cox proportional hazards models were utilized to assess both overall survival (OS) and CNS progression-free survival (CNS-PFS). RESULTS Out of 164 patients, the majority fell into either A+/N- or A+/N+ subtypes (n = 62, n = 63, respectively). BM were detected at the time of diagnosis in 12% (20/164) of patients, while 18% (29/164) developed BM later. In two distinct cohorts of patients (initially free from BM and with de novo BM at diagnosis), the 12-month cumulative incidence of CNS progression was numerically highest for the A+/N- subtype (HR = 11.8, 95%CI: 4.7-22.4, and HR = 44, 95%CI: 10.5-74.7, respectively). OS in both A+/N- and A-/N+ subtypes was worse compared to the A+/N+ subtype (HR = 1.62, 95%CI: 1.03-2.56, and HR = 1.63, 95%CI: 1.06-2.60, respectively). Similarly, CNS-PFS was poorer in same A+/N- and A-/N+ subtypes (HR = 3.10, 95%CI: 1.39-6.93, and HR = 3.38. 95% CI: 1.49-7.67) when compared to A+/N+. CONCLUSIONS This study is the first to explore CNS-specific outcomes based on transcription factor SCLC subtypes. Among patients without BM at SCLC diagnosis, those exclusively expressing ASCL1 or NEUROD1 demonstrated poorer outcomes than those with co-expression. Further investigation is warranted to elucidate the implications of SCLC subtyping, ultimately facilitating tailored disease management.

Craniospinal Irradiation for CNS Leukemia: Rates of Response and Durability of CNS Control.

Craniospinal irradiation (CSI) is used in the management of leukemia patients with central-nervous-system (CNS) involvement, though the data on response and local control are limited. Given the radioresponsiveness of leukemia, we hypothesized that response to CSI would be high, but CNS control would be influenced by control of systemic disease. This retrospective, single-institution analysis included consecutive pediatric and adult patients between 2009-2021 with leukemia that underwent CSI for CNS involvement, defined as presence of blasts (i.e., >0%) on CSF flow cytometry. Endpoints included CNS response rate (RR), CNS local recurrence (LR), progression-free survival (PFS), and overall survival (OS), which were estimated from start of CSI. The probability of CNS LR was summarized using a cumulative incidence estimate, where death without LR was considered a competing risk. The probabilities of OS and PFS were obtained using Kaplan-Meier estimates. Among the 39 eligible patients (43% AML, 49% ALL, 8% blast-phase CML), most were male (59%). All had CSF confirmation of disease. Median age at CSI was 31 years (range 7-67). CSI (protons 54%, photons 46%) was utilized early within the CNS disease course (median 0 CNS relapses prior to CSI). Twenty-five patients (64%) received CSI immediately prior to a stem-cell transplant (SCT), of which 21 (84%) had TBI conditioning to a median dose of 12 Gy (range 2-13.2). Patients treated with CSI alone received a higher CSI dose (median 18 Gy; range 10.8-24) than those treated with SCT consolidation (median 12 Gy; range 10.8-24). Fifteen patients had CSF-positive disease immediately prior to CSI; all 14 of those assessed for response (RR 100%) had confirmed clearance of blasts at a median of 23 days (range 7-197) from CSI start. With a median follow-up of 48 months (range 0.4-123) for survivors, 2-year PFS and OS estimates were 32% and 43%, respectively. Only 5 CNS relapses were noted (2-year CNS LR of 14%). All CNS relapses either occurred after (n = 4) or concurrently (n = 1) with a systemic relapse. In Cox regression univariate models, age, sex, time to CNS disease, positive CSF immediately prior to CSI, and SCT did not show demonstrable evidence of association with CNS LR. However, systemic relapse after CSI (HR 5.9, 95% CI 2.5-13.8, P<0.0001) and systemic disease at the time of CSI (HR 3.9, 95% CI 1.6-9.5, P = 0.003) were associated with higher risk of CNS LR. No grade-3+ acute toxicity was seen during CSI. CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Though CNS local recurrence was modest, there was a high risk of systemic relapse and/or death. Control of systemic disease, both before and after CSI, may be important for CNS local control, and raises consideration that CNS recurrence may reflect reseeding from the systemic space.

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.

Molecular Features of Resected Melanoma Brain Metastases, Clinical Outcomes, and Responses to Immunotherapy

Central nervous system (CNS)-penetrant systemic therapies have significantly advanced care for patients with melanoma brain metastases. However, improved understanding of the molecular landscape and microenvironment of these lesions is needed to both optimize patient selection and advance treatment approaches. To evaluate how bulk and single-cell genomic features of melanoma brain metastases are associated with clinical outcome and treatment response. This cohort study analyzed bulk DNA sequencing and single nuclear RNA-sequencing data from resected melanoma brain metastases and included 94 consecutive patients with a histopathologically confirmed diagnosis of melanoma brain metastasis who underwent surgical resection at a single National Comprehensive Cancer Network cancer center in San Francisco, California, from January 1, 2009, to December 31, 2022. A Clinical Laboratory Improvement Amendments-certified targeted sequencing assay was used to analyze tumor resection specimens, with a focus on BRAF V600E alteration. For frozen pathologic specimens from CNS treatment-naive patients undergoing surgical resection, commercial single nuclear RNA sequencing approaches were used. The primary outcome was overall survival (OS). Secondary outcomes included CNS progression-free survival (PFS), microenvironmental composition with decreased T-cell and macrophage populations, and responses to immunotherapy. To correlate molecular status with clinical outcome, Kaplan-Meier survival analysis of 94 consecutive patients (median age, 64 years [range, 24-82 years]; 70 men [74%]) with targeted BRAF alteration testing showed worse median intracranial PFS (BRAF variant: 3.6 months [IQR, 0.1-30.6 months]; BRAF wildtype: 11.0 months [IQR, 0.8-81.5 months]; P < .001) and OS (BRAF variant: 9.8 months [IQR, 2.5-69.4 months]; BRAF wildtype: 23.2 months [IQR, 1.1-102.5 months]; P = .005; log-rank test) in BRAF V600E variant tumors. Multivariable Cox proportional hazards regression analysis revealed that BRAF V600E status was an independent variable significantly associated with both PFS (hazard ratio [HR], 2.65; 95% CI, 1.54-4.57; P < .001) and OS (HR, 1.96; 95% CI, 1.08-3.55; P = .03). For the 45 patients with resected melanoma brain metastases undergoing targeted DNA sequencing, molecular classification recapitulated The Cancer Genome Atlas groups (NRAS variant, BRAF variant, NF1 variant, and triple wildtype) with no subtype enrichment within the brain metastasis cohort. On a molecular level, BRAF V600E variant lesions were found to have a significantly decreased tumor mutation burden. Moreover, single nuclear RNA sequencing of treatment-naive BRAF V600E variant (n = 3) brain metastases compared with BRAF wildtype (n = 3) brain metastases revealed increased immune cell populations in BRAF wildtype tumors (mean [SD], 11% [4.1%] vs 3% [1.6%] CD45-positive cells; P = .04). Survival analysis of postoperative immunotherapy responses by BRAF status revealed that BRAF wildtype lesions were associated with a response to checkpoint inhibition (median OS: with immunotherapy, undefined; without immunotherapy, 13.0 months [range, 1.1-61.7 months]; P = .001; log-rank test) while BRAF variant lesions (median OS: with immunotherapy, 9.8 months [range, 2.9-39.8 months]; without immunotherapy, 9.5 months [range, 2.5-67.2 months]; P = .81; log-rank test) were not. This molecular analysis of patients with resected melanoma brain metastases found that BRAF V600E alteration is an important translational biomarker associated with worse clinical outcomes, differential microenvironmental composition, and benefit from immunotherapy. Patients with BRAF V600E variant melanoma brain metastases may thus benefit from alternative CNS-penetrant systemic regimens.

Concurrent Lapatinib With Brain Radiation Therapy in Patients With HER2+ Breast Cancer With Brain Metastases: NRG Oncology–KROG/RTOG 1119 Phase 2 Randomized Trial

Lapatinib plus whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) was hypothesized to improve the 12-week intracranial complete response (CR) rate compared with either option of radiation therapy (RT) alone for patients with brain metastases (BM) from human epidermal growth factor receptor 2-positive (HER2+) breast cancer. This study included patients with HER2+ breast cancer with ≥1 measurable, unirradiated BM. Patients were randomized to WBRT (37.5 Gy/3 wk)/SRS (size-based dosing) ± concurrent lapatinib (1000 mg daily for 6 weeks). Secondary endpoints included objective response rate (ORR), lesion-specific response, central nervous system progression-free survival, and overall survival. From July 2012 to September 2019, 143 patients were randomized, with 116 analyzable for the primary endpoint. RT + lapatinib did not improve 12-week CR (0% vs 6% for RT alone, 1-sided P = .97), or ORR at 12 weeks. At 4 weeks, RT + lapatinib showed higher ORR (55% vs 42%). Higher graded prognostic assessment and ≤10 lesions were associated with higher 12-week ORR. Grade 3 and 4 adverse event rates were 8% and 0% for RT and 28% and 6% for RT + lapatinib. The addition of 6 weeks of concomitant lapatinib to WBRT/SRS did not improve the primary endpoint of 12-week CR rate or 12-week ORR. Adding lapatinib to WBRT/SRS showed improvement of 4-week ORR, suggesting a short-term benefit from concomitant therapy.

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.

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 .

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.

Influence of germline variations in drug transporters ABCB1 and ABCG2 on intracerebral osimertinib efficacy in patients with non-small cell lung cancer.

Central nervous system (CNS) metastases are present in approximately 40% of patients with metastatic epidermal growth factor receptor-mutated (EGFRm+) non-small cell lung cancer (NSCLC). The EGFR-tyrosine kinase inhibitor osimertinib is a substrate of transporters ABCB1 and ABCG2 and metabolized by CYP3A4. We investigated relationships between single nucleotide polymorphisms (SNPs) ABCB1 3435C>T, ABCG2 421C>A and 34G>A, and CYP3A4∗22 and CNS treatment efficacy of osimertinib in EGFRm+NSCLC patients. Patients who started treatment with osimertinib for EGFRm+NSCLC between November 2014 and June 2021 were included in this retrospective observational multicentre cohort study. For patients with baseline CNS metastases, the primary endpoint was CNS progression-free survival (CNS-PFS; time from osimertinib start until CNS disease progression or death). For patients with no or unknown baseline CNS metastases, the primary endpoint was CNS disease-free survival (CNS-DFS; time from osimertinib start until occurrence of new CNS metastases). Relationships between SNPs and baseline characteristics with CNS-PFS and CNS-DFS were studied with competing-risks survival analysis. Secondary endpoints were relationships between SNPs and PFS, overall survival, severe toxicity, and osimertinib pharmacokinetics. From 572 included patients, 201 had baseline CNS metastases. No SNP was associated with CNS-PFS. Genotype ABCG2 34GA/AA and/or ABCB1 3435CC --present in 35% of patients-- was significantly associated with decreased CNS-DFS (hazard ratio 0.28; 95% CI 0.11-0.73; p=0.009) in the multivariate analysis. This remained significant after applying a Bonferroni correction and internal validation through bootstrapping. ABCG2 421CA/AA was related to more severe toxicity (27.0% versus 16.5%; p=0.010). ABCG2 34G>A and ABCB1 3435C>T are predictors for developing new CNS metastases during osimertinib treatment, probably because of diminished drug levels in the CNS. ABCG2 421C>A was significantly related with the incidence of severe toxicity. Pre-emptive genotyping for these SNPs could individualize osimertinib therapy. Addition of ABCG2 inhibitors for patients without ABCG2 34G>A should be studied further, to prevent new CNS metastases during osimertinib treatment. No funding was received for this trial.

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.

Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies

BackgroundRezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) which revealed the systematic and central nervous system (CNS) antitumor activities for EGFR T790M-mutated advanced NSCLC in previous clinical studies and is further analyzed here. MethodsEligible patients from the previous phase I and phase IIb studies of rezivertinib were included for pooled analysis. Post-progressive patients who received a prescribed dosage (≥180 mg) of rezivertinib orally once daily were included in full analysis set (FAS), while those with stable, asymptomatic CNS lesions, including measurable and non-measurable ones at baseline were included in CNS full analysis set (cFAS). Patients with measurable CNS lesions were included in CNS evaluable for response set (cEFR). BICR-assessed CNS objective response rate (CNS-ORR), CNS disease control rate (CNS-DCR), CNS duration of response (CNS-DoR), CNS progression-free survival (CNS-PFS), and CNS depth of response (CNS-DepOR) were evaluated. Results355 patients were included in FAS, among whom 150 and 45 patients were included in cFAS and cEFR. This pooled analysis showed the CNS-ORR was 32.0% (48/150; 95% CI: 24.6–40.1%) and the CNS-DCR was 42.0% (63/150; 95% CI: 34.0–50.3%) in cFAS, while that in cEFR were 68.9% (31/45; 95% CI: 53.4–81.8%) and 100% (45/45; 95% CI: 92.1–100.0%). In cEFR, the median CNS-DepOR and the mean of CNS-DepOR were -52.0% (range: -100.0 to 16.1%) and -46.8% (95% CI: –55.5 to -38.1%). In cFAS, the median CNS-DoR and CNS-PFS were 13.8 (95% CI: 9.6-not calculable [NC]) and 16.5 (95% CI: 13.7-NC) months. ConclusionsRezivertinib demonstrated encouraging clinical CNS efficacy among advanced NSCLC patients with EGFR T790M mutation and CNS metastases.