Asymptomatic Brain Research Articles

ECOG-ACRIN LUNG-MAP S1900E substudy: A phase II study of sotorasib in participants (Pts) with previously treated stage IV or recurrent KRAS G12C mutant non-squamous (Non-sq) non-small cell lung cancer (NSCLC).

TPS9143 Background: KRAS mutant NSCLC is further defined molecularly by specific mutation subtypes and co-mutations in tumor suppressor genes. Two targeted therapeutics, sotorasib and adagrasib, are currently approved for the treatment of previously treated advanced KRAS G12C mutant NSCLC. Sotorasib has also demonstrated superiority to docetaxel in the randomized phase III CodeBreaK 200 study ( de Langen et al Lancet. 2023 Feb 7 Epub). The impact of co-mutations in tumor suppressors, including TP53 and STK11, on the efficacy of first generation KRAS G12C inhibitors has been inconclusive. The S1900E substudy aims to prospectively understand, using rigorous biomarker testing/definitions, the impact of co-mutations on the clinical activity of sotorasib in pts with KRAS G12C mutant NSCLC. Methods: S1900E is a phase 2 open-label study of sotorasib in biomarker-defined cohorts for pts who have KRAS G12C stage IV/recurrent non-sq NSCLC, received at least one line of systemic treatment, and are naïve to KRAS G12C inhibitors. Pts are assigned to S1900E under the Lung-MAP screening protocol (NCT03851445) using FoundationOne F1CDx next generation sequencing assay on tissue (Foundation Medicine, Cambridge, MA). S1900E cohorts include: #1) Presence of TP53 co-mutation AND Wild Type STK11, KEAP1, NFE2L2, CUL3; #2) Presence of STK11 co-mutation AND Wild Type TP53, KEAP1, NFE2L2, CUL3; 3) All pts not eligible for Cohorts 1 and 2 (e.g. dual co-mutations in STK11 and TP53; co-mutations in KEAP1, NFE2L2, CUL3, or others; or lack of any co-mutations). Pts with treated, clinically controlled, and asymptomatic brain metastases are eligible and with amendment 3 (Mar 20 2022), eligibility expanded to pts with asymptomatic untreated brain metastases. Sotorasib is dosed 960 mg oral daily. The primary objective is to evaluate the RECIST 1.1 response rate (ORR) per cohort. For cohorts 1 and 3, the target sample size is 40 eligible pts based on a design with 92% exact power to rule out a 14% ORR at the 1-sided 5% level, if the true ORR were 34%; ≥10 responses would rule out a 14% ORR. Cohort 2 has a target sample size of 25 eligible pts with 93% exact power to rule out a 14% ORR at the 1-sided 5% level, if the true ORR were 40%; ≥7 responses would rule out a 14% ORR. Secondary endpoints include PFS, OS, duration of response, and toxicity. Circulating tumor DNA is being collected at day 1 of cycle 1, 2, and 3 and at progression. Enrollment started April 2 2021 with conservative accrual targets met, currently with 72% enrolled (84/116) as of Feb 14 2023, including 37, 16, and 31 pts, in cohorts 1, 2, and 3, respectively. Clinical trial information: NCT04625647 .

Phase IIa study of αDC1 vaccines targeting HER2/HER3 combined with pembrolizumab in patients with asymptomatic brain metastasis from triple negative breast cancer or HER2+ breast cancer.

TPS1112 Background: Brain metastases develop in up to 50% patients (pts) with metastatic triple negative breast cancer (TNBC) and HER2+ BC, constituting an increasing source of morbidity and mortality. HER3, overexpressed in triple negative and HER2+ brain metastatic breast cancer (BMBC), is a resistance factor to HER2-targeted therapies and a driver of CNS metastasis. Disease progression is associated with loss of anti-HER2 and anti-HER3 immunity. Previously, we have demonstrated that glioma-specific peptide-loaded αDC1 which produce CXCL9, CXCL10, CXCL11, CCL5, the chemokines which attract CXCR3- and CCR5- expressing cytotoxic T-lymphocytes (CTLs) and T-helper 1 (Th1) cells, induce clinical responses and long-term disease stabilization in pts with aggressive recurrent primary brain tumors (Okada et al. JCO 2011. PMID: 21149657). We hypothesized that anti-HER2/3-loaded αDC1 in combination with PD1 blockade will result in strong Th1/CTL response against HER2/3 epitopes (Basu A et al. Cancer Immunol Res. 2022 PMID: 34785506), being effective against brain lesions and systemic disease. Methods: This is a phase II single-arm, non-randomized multicenter study (NCT04348747). Eligibility includes pts with triple negative and HER2+ BMBC ≥18 years, ECOG PS ≤1, normal marrow and organ function with asymptomatic untreated brain metastases ≥ 5 mm who will receive αDC1 q3 weeks x 3 along with pembrolizumab every 3 weeks. Thereafter, αDC1 booster doses (if available) would be administered every 3 months until disease progression, intolerable side effects or withdrawal from study, up to 24 months. Baseline and 9-week post-αDC1 peripheral biopsies (non-CNS) are required for six pts. 1 of the planned 21 pts have been enrolled and is undergoing treatment. Primary endpoint is CNS response rate (RR) by RANO-BM criteria. If no CNS response is observed after 12 pts, study will be terminated. If ≥ 1 response observed, then 9 more pts will be enrolled, for a total of 21 pts. If ≥ 3 CR are observed, the proposed therapy will be considered as promising for further evaluation. Secondary endpoints include non-CNS RR per RECIST v1.1, median CNS, non-CNS and overall progression-free survival, overall survival and safety. Exploratory endpoints include changes in intratumoral biomarkers (CTLs, PDL1, chemokines) in pre- and post-treatment peripheral tumor biopsies and immune changes in the blood. Clinical trial information: NCT04348747 .

A pilot trial of autologous tumor infiltrating lymphocytes (lifileucel, LN-144) for patients with asymptomatic melanoma brain metastases.

TPS9606 Background: Melanoma brain metastases (MBM) are a leading cause of morbidity and mortality for patients with advanced melanoma. Modern systemic therapies are insufficient at controlling MBM, and median overall survival (OS) for pts with MBM is < 1 year. Adoptive T cell therapy using tumor infiltrating lymphocytes (TIL) has demonstrated efficacy in advanced melanoma. Lifileucel (LN-144), an autologous TIL product, was recently shown to be safe and effective for patient with PD-1 refractory melanoma. Patients with active MBM were excluded from lifileucel trials to date. Methods: This single-center pilot trial (NCT05640193) is enrolling up to 10 pts with asymptomatic MBM from non-uveal melanoma to receive lifileucel. Patients must have ≥1 intracranial lesion measuring 5-30mm visible on MRI to be used as a target lesion for modified (m)RECIST measurement, progression on prior anti-PD-1 therapy (with or without anti-CTLA-4), progression on targeted therapy if BRAF V600E/K-mutated), ECOG PS ≤1, ≥1 resectable lesion(s) (≥1.5 cm), recovered from prior surgery/anticancer treatment-related AEs (grade ≤1). Patients are not eligible if they have symptomatic MBM and/or require corticosteroids of ≥10 mg/day of prednisone or equivalent. Lifileucel is generated from resected tumor in a centralized GMP process. The regimen includes nonmyeloablative lymphodepletion, lifileucel infusion, and a short course of high-dose IL-2. The primary endpoint is feasibility, defined as ≥7/10 patients who undergo tumor harvest receiving lifileucel infusion. Secondary endpoints are safety, feasibility of manufacturing lifileucel in patients with MBM, and brain metastasis response rate (BMRR) per mRECIST 1.1. Exploratory endpoints include overall objective response rate by mRECIST 1.1, best extracranial response rate, intracranial progression-free survival (PFS), overall PFS, OS. Extensive correlative analyses of peripheral blood mononuclear cells, plasma, tumors, and cerebrospinal fluid are planned to better understand MBM growth, treatment resistance, and response of the central nervous system to lifileucel. Clinical trial information: NCT05640193 .

Phase II trial of lazertinib in patients with epidermal growth factor receptor (EGFR) mutation-positive (M+), metastatic non-small cell lung cancer (NSCLC) with asymptomatic or mild symptomatic brain metastases after failure of EGFR tyrosine kinase inhibitor (TKI) (KCSG LU20-15).

9054 Background: Central nervous system (CNS) metastases occur not infrequently, ultimately devastating consequences in advanced EGFR M+ NSCLC. Lazertinib, a 3rd-generation (G) EGFR-TKI, has shown potent antitumor activity in EGFR-mutant NSCLC. We conducted a phase II single-arm study of lazertinib in EGFR M+ NSCLC patients (pts) having CNS metastases to evaluate its CNS activity. Methods: The patients exhibiting CNS progression upon 1st or 2nd-G EGFR-TKIs with least one measurable CNS lesion were enrolled. The primary endpoint was intracranial objective response rate (iORR) in evaluable for response set (ERS). Secondary endpoints included iORR without T790M mutation, overall ORR (oORR), disease control rate (DCR), intracranial progression-free survival (iPFS) in ERS. Overall survival (OS) and safety analyses were performed in pts who received at least one dose of lazertinib. Cerebrospinal fluid (CSF) penetration was measured as exploratory biomarker study. Results: Of 40 pts enrolled, 38 were evaluable for tumor response. Nineteen pts harbored exon 19 deletion and 21 pts for exon 21 L858R and 30% of pts had radiologic evidence of leptomeningeal carcinomatosis (LM) with 2 cytological confirmed cases. Forty-five percent of pts received afatinib as first line treatment, followed by 42.5% of gefitinib and 12.5% of erlotinib. Baseline plasma samples of all the 40 patients obtained for liquid-based next-generation sequencing (Guardant360) and T790M was found in 5 pts prior to lazertinib treatment. iORR was 57.9% (22/38). iORR with T790M-negative, oORR, and DCR were 54.5%, 39.5%, and 97.4%, respectively. With median follow-up of 13.6 months, median iPFS and OS were not reached. Treatment-related adverse events (TRAEs) emerged in 85.0% of pts with most common TRAEs being skin rash (50.0%) and paresthesia (42.5%). Grade 3 or 4 TRAEs were reported in 10.0%. The CSF penetration rates of lazertinib and its metabolite (YH26334) were 46.2% and 33.1%, respectively in paired CSF and plasma samples, suggesting high CNS penetration efficacy. Conclusions: Lazertinib has substantial CNS activity regardless of T790M status against the progression of intracranial metastases ± LM during the treatment of 1st or 2nd-G EGFR-TKIs in metastatic EGFR M+ NSCLC pts. These results suggest that using lazertinib instead of brain local treatment would be a potential strategy in EGFR M+ NSCLC, who progressed on CNS metastases after prior EGFR-TKI. Clinical trial information: NCT05326425 . [Table: see text]

Tislelizumab plus chemotherapy in patients with advanced brain metastases of non-squamous non-small cell lung cancer: A multicenter, prospective, open-label phase 2 study.

9080 Background: Patients (pts) with brain metastases (BM) were usually unrepresented in clinical trials assessing the efficacy of PD-(L) 1 inhibitors. Here, we investigated the efficacy and safety of tislelizumab (TIS) plus chemotherapy in NSCLC pts with asymptomatic untreated BM or with stable BM after local radiotherapy. Methods: This multicenter, prospective, open-label phase 2 study enrolled systemic treatment-naïve pts with stage IV non-squamous (nsq) NSCLC without EGFR or ALK mutations who had BM. Pts received TIS combined with pemetrexed and carboplatin for 4 cycles, followed by maintenance TIS and pemetrexed. RECIST v1.1 and RANO-BM were applied for assessment for systematic and brain disease, respectively. The primary endpoint was the investigator-assessed 1-year PFS rate per RECIST v1.1. Results: 36 pts were enrolled with 77.8% having stage IVB disease, 25.0% liver metastases and 41.7% bone metastases. 29 (80.6%) pts were with untreated, asymptomatic brain metastases, and the other 7 (19.4%) received radiotherapy for BM previously. As of 30 Nov 2022, the median follow-up was 12.3 months. 1-year systematic PFS rate was 36.8% (95% CI, 18.0-55.7), with median PFS of 7.5 months (95% CI, 5.1-NE). Systematic ORR was 50.0% (95% CI, 31.9-68.1%). Median OS was not reached, with 1-year OS rate of 70.5% (95% CI, 51.7-83.1). For intracranial efficacy assessment per RANO-BM, 1-year intracranial PFS (iPFS) rate was 56.6 % (95% CI, 31.7-75.5), with 45.5% (95% CI, 19.4, 68.5) and 100% in pts with untreated and pretreated BM, respectively. Intracranial ORR was 56.7% (95% CI, 37.4-74.5%), with 53.8% (95% CI, 33.4-73.4%) in pts with untreated BM and 75% (95% CI, 19.4-99.4%) in pretreated BM. No grade 5 toxicities were observed. Grade 3-4 TRAEs occurred in 33.3% (12/36) of pts. 13.9% of pts experienced irAEs; grade 3-4 irAEs occurred in 2 (5.6%) pts. Conclusions: TIS plus chemotherapy yielded promising systematic and intracranial PFS, and was generally well tolerated in nsq-NSCLC pts with untreated or pretreated BM. Clinical trial information: NCT04507217 . [Table: see text]

A first-in-human, open-label, dose escalation and expansion study of orally administered NX-019 in patients with advanced EGFR mutant cancer.

TPS9159 Background: CNS involvement, brain metastases and/or leptomeningeal disease, is common in patients with EGFR mutant NSCLC and occurs in 25-50% of patient’s journeys. Despite the activity and increased CNS penetration of later generation EGFR inhibitors, management of CNS disease remains a clinical challenge. NX-019 is a broad-spectrum EGFR inhibitor targeting both common and rare mutations including EGFR ex20ins, G719S, and L861Q. NX-019 exhibits selective activity towards mutant vs. wt. EGFR in preclinical studies. Substantial CNS exposure has been demonstrated in animal models, as well as potent anti-tumor activity toward intracranial xenografts with prolonged inhibition of EGFR signaling. Similar drug levels compared to plasma were measured in the brains of rats and mice. NX-019 was readily detectable in the CSF of cynomolgus monkeys, dogs and rats at concentrations similar to the estimated plasma free fraction. Methods: NT019-101 is a first-in-human, international, open-label study designed to evaluate single-agent NX-019 in patients with EGFR-mutant, locally advanced or metastatic NSCLC that has progressed following prior treatment. Patients with ECOG performance status 0–2 and EGFR mutant cancers including stable, asymptomatic brain metastases are eligible for Dose Escalation. Patients with known EGFR C797S mutations and secondary drivers, e.g., MET amplification and RET fusions, are excluded. Primary endpoints are to determine recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), safety and tolerability (part 1), and to evaluate antitumor activity at the RP2D by RECIST v1.1 and RANO-BM (part 2). Secondary endpoints are to evaluate pharmacokinetics (PK) and antitumor activity by RECIST v1.1 (part 1) and PK, safety, tolerability, and CNS antitumor activity (part 2). Dose escalation will utilize a 3+3 design with up to 6 patients per cohort in part 1. Part 2 will enroll patients in 5 cohorts (n = 10 or 29 each), including patients with NSCLC who have (1) new or progressing CNS metastases including leptomeningeal disease after treatment with osimertinib, (2) active CNS disease and ex20ins mutations, (3) ex20ins mutations without CNS disease and (4) other rare mutations, based on a Simon 2-stage design. First patient was treated in October 2022 and enrollment is ongoing. The study is planned for approximately 35 centers in North America and Asia-Pacific region. Clinical trial information: NCT05514496 .

Integrated efficacy and safety of brigatinib in patients with ALK TKI-naive advanced ALK+ NSCLC in the ALTA-1L and J-ALTA studies.

9078 Background: Brigatinib demonstrated efficacy and manageable safety in patients (pts) with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI)-naive ALK+ non-small cell lung cancer (NSCLC) in phase 3 (ALTA-1L) and phase 2 (J-ALTA) trials. We present results of integrated efficacy and safety analyses of ALTA-1L and J-ALTA. Methods: ALTA-1L (NCT02737501) and J-ALTA (NCT03410108; conducted in Japan) were open-label, multicenter studies in pts with advanced or metastatic ALK+ NSCLC. Pts in ALTA-1L and in part 3 of J-ALTA were ALK TKI-naive. Stable or asymptomatic brain metastases were allowed in both studies. Pts received brigatinib 180 mg qd (7-day lead-in at 90 mg). Primary endpoints were blinded independent review committee (IRC)-assessed progression-free survival (PFS) in ALTA-1L and IRC-assessed 12-month PFS in the J-ALTA ALK TKI-naive cohort (both per RECIST v 1.1). Secondary endpoints included IRC-assessed objective response rate (ORR), duration of response, intracranial ORR, intracranial PFS, overall survival, and safety. Pooled efficacy and safety data from both studies are presented. Results: The pooled analysis population included 169 pts (ALTA-1L, N = 137; J-ALTA ALK TKI-naive cohort, N = 32). Median follow-up overall was 35.8 months (last pt last contact: ALTA-1L, January 2021; J-ALTA, July 2021). Most (66%) pts were aged < 65 years, 24% had baseline brain metastases, 95% had stage IV disease at study entry, and 21% had received prior chemotherapy for locally advanced or metastatic disease. With brigatinib treatment, median PFS by IRC was 29.3 months (95% CI, 23.9‒44.7). The confirmed ORR was 79% (95% CI, 72‒85%), with 36 complete responses and 97 partial responses. Median duration of response was 38.1 months (95% CI, 22.9‒not reached). Median overall survival was not reached; the 3-year survival rate was 74% (95% CI: 66‒80%; 84 pts at risk). Intracranial ORR and intracranial PFS will be presented. Grade 3/4 treatment-emergent adverse events were reported in 74% of pts; the most common were increased blood creatine phosphokinase (31%), hypertension (18%), and increased lipase (16%). Any grade interstitial lung disease/pneumonitis was reported in 12 (7%) of pts. Adverse events led to treatment discontinuation in 11% of pts. Conclusions: Brigatinib treatment demonstrated clinically meaningful systemic and intracranial efficacy in this integrated analysis of pts with ALK TKI-naive advanced or metastatic ALK+ NSCLC in the ALTA-1L or J-ALTA trials. Safety results were consistent with the known profile for brigatinib, with no new safety findings. Clinical trial information: NCT02737501 ; NCT03410108 .

Intracranial activity of first-line immune checkpoint inhibitors combined with chemotherapy in advanced non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) are increasingly used as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) harboring no actionable mutations; however, data on their efficacy among patients presenting with intracranial lesions are limited. This study aimed to explore the efficacy and safety of ICIs combined with chemotherapy in advanced NSCLC patients with measurable brain metastasis at initial diagnosis. Our study retrospectively analyzed clinical data of a total of 211 patients diagnosed with driver gene mutation-negative advanced NSCLC with measurable, asymptomatic brain metastasis at baseline from Hunan Cancer Hospital between January 1, 2019 and September 30, 2021. The patients were stratified into two groups according to the first-line treatment regimen received: ICI combined with chemotherapy ( n = 102) or chemotherapy ( n = 109). Systemic and intracranial objective response rates (ORRs) and progression-free survival (PFS) were analyzed. Adverse events were also compared between the groups. Compared with the chemotherapy-based regimen, the ICI-containing regimen was associated with a significantly higher intracranial (44.1% [45/102] vs . 28.4% [31/109], χ2 = 5.620, P = 0.013) and systemic (49.0% [50/102] vs . 33.9% [37/109], χ2 = 4.942, P = 0.019) ORRs and longer intracranial (11.0 months vs . 7.0 months, P <0.001) and systemic (9.0 months vs . 5.0 months, P <0.001) PFS. Multivariable analysis consistently revealed an independent association between receiving ICI plus platinum-based chemotherapy as a first-line regimen and prolonged intracranial PFS (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.37-0.73, P <0.001) and systemic PFS (HR = 0.48, 95% CI: 0.35-0.66, P <0.001). No unexpected serious adverse effects were observed. Our study provides real-world clinical evidence that ICI combined with chemotherapy is a promising first-line treatment option for driver gene mutation-negative advanced NSCLC patients who present with brain metastasis at initial diagnosis. https://www.clinicaltrials.gov/ , OMESIA, NCT05129202.

Right-to-Left Shunt in Divers with Neurological Decompression Sickness: A Systematic Review and Meta-Analysis.

The aim of this study was to assess the association between the presence of a right-to-left shunt (RLS) and neurological decompression sickness (NDCS) and asymptomatic brain lesions among otherwise healthy divers. Next to drowning, NDCS is the most severe phenotype of diving-related disease and may cause permanent damage to the brain and spinal cord. Several observational reports have described the presence of an RLS as a significant risk factor for neurological complications in divers, ranging from asymptomatic brain lesions to NDCS. We systematically reviewed the MEDLINE, Embase, and CENTRAL databases from inception until November 2021. A random-effects model was used to compute odds ratios. Nine observational studies consisting of 1830 divers (neurological DCS: 954; healthy divers: 876) were included. RLS was significantly more prevalent in divers with NDCS compared to those without (62.6% vs. 27.3%; odds ratio (OR): 3.83; 95% CI: 2.79-5.27). Regarding RLS size, high-grade RLS was more prevalent in the NDCS group than the no NDCS group (57.8% versus 18.4%; OR: 4.98; 95% CI: 2.86-8.67). Further subgroup analysis revealed a stronger association with the inner ear (OR: 12.13; 95% CI: 8.10-18.17) compared to cerebral (OR: 4.96; 95% CI: 2.43-10.12) and spinal cord (OR: 2.47; 95% CI: 2.74-7.42) DCS. RLS was more prevalent in divers with asymptomatic ischemic brain lesions than those without any lesions (46.0% vs. 38.0%); however, this was not statistically significant (OR: 1.53; 95% CI: 0.80-2.91). RLS, particularly high-grade RLS, is associated with greater risk of NDCS. No statistically significant association between RLS and asymptomatic brain lesions was found.

Amount and Distribution of Intracranial Calcification in Symptomatic and Asymptomatic Primary Familial Brain Calcification.

In clinical practice, it can be difficult to differentiate between intracranial calcifications related to primary familial brain calcification (PFBC) or aging. Also, little is known about the consequences of the amount of intracranial calcifications in patients with PFBC. Therefore, we aimed to compare the amount and distribution of intracranial calcifications in persons with PFBC with controls and between asymptomatic and symptomatic PFBC cases. This was a case-control study including patients with PFBC and controls. Controls received a CT of the brain because of a trauma and had at least some basal ganglia calcification. The Nicolas score and volume of calcification were used to quantify intracranial calcifications on the CT scans. Receiver operating characteristic curves were obtained to calculate optimal cutoff points to discriminate between cases and controls. Mann-Whitney U tests and logistic regression, adjusted for age and sex, were used to compare the amount of calcification. Twenty-eight cases (median age 65 years, 50.0% male) and 90 controls (median age 74 years, 46.1% male) were included. Calcification scores were higher in cases (median volume: 4.91 cm3 against 0.03 cm3, p < 0.001, median Nicolas score: 26.5 against 2.0, p < 0.001) than controls. Calcifications were also more diffusely distributed in cases. To differentiate between cases and controls, optimal cutoff points were ≥0.2 cm3 for the calcification volume and ≥6.0 for the Nicolas score. Calcification was higher for symptomatic than asymptomatic cases (calcification volume: 13.62 cm3 against 1.61 cm3, p = 0.01, Nicolas score: 39.0 against 15.5, p = 0.02). After adjustment for age and sex, the Nicolas score remained significantly higher in symptomatic patients, and the calcification volume did not. Patients with PFBC had more severe intracranial calcifications, and these calcifications were more diffusely distributed through the brain compared with controls. Symptomatic patients with PFBC might have more intracranial calcifications than asymptomatic persons.

High tumor burden in patients with non-small-cell lung cancer: a Delphi survey among Spanish oncologists.

Aim: To define high tumor burden (HTB) in non-small-cell lung cancer. Methods: A total of fiveoncologists initiated the project, selecting 66 participants, and elaborated a questionnaire with 26 statements using the Delphi method with a 9-point Likert scale of agreement. Results: Factors with moderate strength of consensus wereidentified, including a sum of the longest diameter of lesions ≥10cm, elevatedLDH, hepatic involvement, lymphangitis carcinomatosis, brain involvement unapproachable with local techniques and pericardial effusion. There was a consensus against increases intumor markers and asymptomatic brain involvement being related to HTB. HTB was considered a relevant factor for treatment selection supporting thechoice of combination regimens versus immunotherapy only. Conclusion: In this Delphi study, experts defined several factors associated with HTB in non-small cell lung cancer.

Ramucirumab Plus Docetaxel for Patients with Non-small cell Lung Cancer with Brain Metastases: A Multicenter, Open-Label Single-Arm Phase II Trial.

Ramucirumab plus docetaxel combination therapy (DOC/RAM) for advanced non-small cell lung cancer (NSCLC) achieves favorable outcomes; however, efficacy and safety for patients with brain metastases are still unclear. Eligible patients included those with advanced NSCLC with measurable asymptomatic brain metastases that progressed after chemotherapy. Patients were intravenously administered ramucirumab (10 mg/kg) and docetaxel (60 mg/m2) every 21-day cycle. Due to difficulties in accumulating the planned 65 participants, enrollment was terminated early when 25 patients were enrolled. Primary endpoint: Median progression-free survival (PFS) was 3.9 months (95% CI, 1.8-5.3). Secondary endpoints: Median intracranial progression-free survival was 4.6 months (95% CI, 2.5-5.9); median overall survival was 20.9 months (95% CI, 6.6-not possible to estimate); objective response rate was 20% (95% CI, 6.8-40.7); disease control rate was 68% (95% CI, 46.5-85.1). The most common grade 3 or higher toxicities were neutropenia in 10 patients (40%). Neither intracranial hemorrhage nor grade 5 adverse events were observed. Patients with higher serum soluble vascular endothelial growth factor receptor 2 concentrations at the start of treatment had slightly longer PFS. No clinical concerns were identified with DOC/RAM for NSCLC with brain metastases in this study. Further investigation with a larger sample size is needed to determine the tolerability and safety of these populations (Trial Identifiers: University Hospital Medical Information Network in Japan [UMIN000024551] and Japan Registry of Clinical Trials [jRCTs071180048]).

Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

Advanced melanoma-A curable disease? Implications of systemic treatment on patients' daily life.

Abstract 5105: TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis

Abstract Brain metastasis is an unmet clinical need, affecting between 10-30% of cancer patients with 200000 to 400000 newly diagnosis per annum in the US. Recently, several clinical trials have reported benefits using immunotherapy to treat brain metastasis. However, variability of the responses is broad and high benefit is found mainly in asymptomatic brain metastasis, while the benefit is dramatically reduced in the clinically relevant stage. Thus, it is currently unknown how to effectively target symptomatic brain metastases with immunotherapy. We previously reported a clinically relevant protumoral program driven by STAT3 activation in a subpopulation of reactive astrocytes in these advanced stages of the disease. Our current study further exploited the heterogeneity within the metastasis-associated microenvironment as a resource to identify novel therapeutic vulnerabilities to improve the benefits of immunotherapies based on immune checkpoint blocking antibodies (ICB) in symptomatic brain metastasis. Our results demonstrate that reactive astrocytes are strong immunomodulatory cells in brain tumors. We have identified the molecular profile of disease-associated glial cells and defined its connection to modulatory activities on specific lymphocyte populations in experimental brain metastasis as well as human-derived samples. scRNASeq and high content multiplex immunofluorescence allowed us to report a novel local immunomodulatory axis dependent on TIMP1 (astrocytes)/CD63 (CD8 T cells), which is present in brain metastasis patients with high immunoscore and would imply an additional immunosuppressive signal for potential ICB responders in brain metastasis. Genetic and pharmacologic approaches targeting this STAT3-dependent local immunomodulatory axis have allowed us to define the rationale to combine immune checkpoint blockade with a STAT3 inhibitor, which we previously used in patients. We proved that such combined immunotherapy boost the systemic activation of T cells while also preventing the local blockade. Additionally, our comprehensive strategy includes the possibility to stratify patients that are best qualified to benefit from this therapy by measuring TIMP1 in liquid biopsies from CSF. Even more, our data using Patient Derived Organotypic Cultures (PDOC) from fresh brain metastasis neurosurgeries confirms that our therapeutic strategy might benefit brain metastases generated from any primary source. In conclusion, we describe an immunosuppressive mechanism in the brain microenvironment that could explain the lack of response to ICB in patients with advanced brain metastasis. Our finding provides the rationale to implement complementary approaches targeting local immunosuppression to increase the benefit of immunotherapy in symptomatic brain metastasis. Citation Format: Neibla Priego, Pedro García-Gómez, Ana de Pablos-Aragoneses, María Perea-García, Laura Álvaro-Espinosa, Carolina Hernández-Oliver, Elena Martínez-Saez, Ángel Pérez-Núñez, Aurelio Hernández-Laín, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J. Crocker, Diego Serrano, Asís Palazón, RENACER Red Nacional de Metástasis Cerebral, Manuel Valiente. TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5105.

Development of a stroke risk score with MRI asymptomatic brain lesions attributes to evaluate prognostic vascular events

BackgroundThe use of a combination of stroke predictors, such as clinical factors and asymptomatic lesions on brain magnetic resonance imaging (MRI), may improve the accuracy of stroke risk prediction. Therefore, we attempted to develop a stroke risk score for healthy individuals. MethodsWe investigated the presence of cerebral stroke in 2365 healthy individuals who underwent brain dock screening at the Health Science Center in Shimane. We examined the factors that contributed to stroke and attempted to determine the risk of stroke by comparing background factors and MRI findings. ResultsThe following items were found to be significant risk factors for stroke: age (≥60 years), hypertension, subclinical cerebral infarction, deep white matter lesion, and microbleeds. Each item was scored with 1 point, and the hazard ratios for the risk of developing stroke based on the group with 0 points were 17.2 (95% confidence interval [CI] 2.31–128) for 3 points, 18.1 (95% CI 2.03–162) for 4 points, and 102 (95% CI 12.6–836) for 5 points. ConclusionsA precise stroke prediction score biomarker can be obtained by combining MRI findings and clinical factors.

Abstract OT3-19-01: Phase II Study of Screening Brain MRIs in Stage IV Breast Cancer

Abstract Background: As systemic therapy improves, there has been an increasing number of breast cancer patients who develop brain metastasis. Screening of asymptomatic stage IV breast cancer patients with brain MRIs is not currently recommended by the National Comprehensive Cancer Network (NCCN) Guidelines. Retrospective reports suggest breast cancer patients are more likely to present with more advanced central nervous system disease at the time of brain metastasis diagnosis compared to melanoma and non-small cell lung cancer (NSCLC) patients. This may be in part due to routine screening recommendations in melanoma and NSCLC. Early detection and treatment of brain metastases may improve outcomes for breast cancer patients. Trial Design: The study is designed as a single arm, nonrandomized phase II study, with the goal of investigating the role of screening brain MRIs in neurologically asymptomatic patients with metastatic breast cancer. Breast cancer patients will be allocated based on receptor subtypes into triple negative (TN), HER2+, and hormone receptor (HR)+/HER2- breast cancer. Following study enrollment, patients will undergo a screening brain MRI. Patients will undergo a second brain MRI at first systemic progression or at 6 months whichever event occurs sooner. Eligibility: Asymptomatic, stage IV breast cancer patients that have progressed past first line therapy in the metastatic setting with an ECOG/= 6 months are eligible. Specific Aims: The primary objective is to determine the incidence of asymptomatic brain metastasis in metastatic breast cancer by subtype. Secondary objectives include determining the incidence of asymptomatic leptomeningeal disease, the number and size of brain metastases at diagnosis, the number of patients requiring whole brain radiation therapy vs. stereotactic radiation following diagnosis and overall survival and brain metastasis specific survival following brain metastasis diagnosis in metastatic breast cancer by subtype. Statistical Methods: A total of 30, 30, and 40 TN, HER2+, and HR+/HER2-, breast cancer patients will be enrolled, respectively. Using an incidence rate of 17%, the 95% CI by subtype will be (0.06,0.351), (0.06,0.351), and (0.07,0.322). Patient Accrual: This study is open with 30 patients enrolled at the time of submission. A total of 100 patients will be enrolled. Contact Information: Kamran A. Ahmed MD, Moffitt Cancer Center, email: kamran.ahmed@moffitt.org, Clinical trial information: NCT05115474. Funding: Florida Breast Cancer Foundation. Citation Format: Kamran A. Ahmed, Youngchul Kim, Avan Armaghani, John Arrington, Ricardo Costa, Brian J. Czerniecki, Roberto Diaz, Peter A. Forsyth, Hung Khong, Kimberley Lee, Loretta Loftus, Marilin Rosa, Hatem H. Soliman, Iman Washington, Aixa Soyano, Hyo S. Han. Phase II Study of Screening Brain MRIs in Stage IV Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-19-01.

Reader Response: Frequency of Asymptomatic Optic Nerve Enhancement in a Large Retrospective Cohort of Patients With Aquaporin-4+ NMOSD.

This study by Shah et al. demonstrated that asymptomatic optic nerve enhancement could occur in optic neuritis (ON) patients.1 For multiple sclerosis, silent lesions on MRI have diagnostic and prognostic values and are used in disease monitoring.2 However, the frequency of new silent lesions (including asymptomatic ON, myelitis, and brain lesions) and their association with future relapse in aquaporin-4 antibody neuromyelitis optica spectrum disorder remain unclear.1,3,4 The authors indicated that optic nerve enhancement at the site of prior attacks with shorter lesion length presumably represented intermittent blood-brain barrier breakdown; however, recurrent ON cannot be completely ruled out, especially when it has been a long time since the last attack. New asymptomatic lesions in 2 scans could be subclinical relapses and often require acute therapeutic intervention.

Risk Factors for the Occurrence of Asymptomatic Brain Lesions in Patients with β-Thalassemia: a Systematic Review and Meta-Analysis.

Several factors, including increased platelet aggregation, decreased platelet survival, decreased antithrombotic factors cause a hypercoagulable state in thalassemia patients. This is the first meta-analysis designed to summarize the association of age, splenectomy, gender, and serum ferritin and hemoglobin levels with the occurrence of asymptomatic brain lesions in thalassemia patients using MRI. This systematic review and meta-analysis was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. We searched four major databases and included eight articles for this review. The quality of the included studies was assessed based on the Newcastle-Ottawa Scale checklist. Meta-analysis was performed using STATA 13. Odds ratio (OR) and standardized mean difference (SMD) were considered as effect sizes for comparing the categorical and continuous variables, respectively. The pooled OR for splenectomy in patients with brain lesions compared to those without lesions was 2.25 (95% CI 1.22 - 4.17, p = 0.01). The pooled analysis for SMD of age between patients with/without brain lesions was statistically significant, 0.4 (95% CI 0.07 - 0.73, p = 0.017). The pooled OR for the occurrence of silent brain lesions was not statistically significant in males compared to females, 1.08 (95% CI 0.62 - 1.87, p = 0.784). The pooled SMD of Hb and serum ferritin in positive brain lesions compared to negatives were 0.01 (95% CI -0.28, 0.35, p = 0.939) and 0.03 (95% CI -0.28, 0.22, p = 0.817), respectively, which were not statistically significant. Older age and splenectomy are risk factors for developing asymptomatic brain lesions in β-thalassemia patients. Physicians should consider a careful assessment of high-risk patients for starting prophylactic treatment.

Evidence of Chronic Complement Activation in Asymptomatic Pediatric Brain Injury Patients: A Pilot Study.

Physical insult from a mild Traumatic Brain Injury (mTBI) leads to changes in blood flow in the brain and measurable changes in white matter, suggesting a physiological basis for chronic symptom presentation. Post-traumatic headache (PTH) is frequently reported by persons after an mTBI that may persist beyond the acute period (&gt;3 months). It remains unclear whether ongoing inflammation may contribute to the clinical trajectory of PTH. We recruited a cohort of pediatric subjects with PTH who had an acute or a persistent clinical trajectory, each around the 3-month post-injury time point, as well as a group of age and sex-matched healthy controls. We collected salivary markers of mRNA expression as well as brain imaging and psychological testing. The persistent PTH group showed the highest levels of psychological burden and pain symptom reporting. Our data suggest that the acute and persistent PTH cohort had elevated levels of complement factors relative to healthy controls. The greatest change in mRNA expression was found in the acute-PTH cohort wherein the complement cascade and markers of vascular health showed a prominent role for C1Q in PTH pathophysiology. These findings (1) underscore a prolonged engagement of what is normally a healthy response and (2) show that a persistent PTH symptom trajectory may parallel a poorly regulated inflammatory response.

Evaluating the impact of early identification of asymptomatic brain metastases in metastatic renal cell carcinoma.

Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have been reported to be present in up to 25% of patients diagnosed with mRCC. There is limited published literature evaluating the role of routine intra-cranial imaging for the screening of asymptomatic BM in mRCC. To evaluate the potential utility of routine intra-cranial imaging, a retrospective cohort study was conducted to characterize the outcomes of mRCC patients who presented with asymptomatic BM, as compared to symptomatic BM. The Canadian Kidney Cancer Information System (CKCis) database was used to identify mRCC patients diagnosed with BM. This cohort was divided into two groups based on the presence or absence of BM symptoms. Details regarding patient demographics, disease characteristics, systemic treatments, BM characteristics and survival outcomes were extracted. Statistical analysis was through chi-square tests, analysis of variance, and Kaplan-Meier method to characterize survival outcomes. A p-value of <0.05 was considered statistically significant for all analyses. A total of 267 mRCC patients with BM were identified of which 106 (40%) presented with asymptomatic disease. The majority of patients presented with multiple (i.e., >1) BM (75%) with no significant differences noted in number of BM or BM-directed therapy received in symptomatic, as compared to asymptomatic BM patients. Median [95% confidence interval (CI)] overall survival (OS) from mRCC diagnosis was 42 months (95% CI: 32-62) for patients with asymptomatic BM, and 39 months (95% CI: 29-48) with symptomatic BM (p=0.10). OS from time of BM diagnosis was 28 months (95% CI: 18-42) for the asymptomatic BM group, as compared to 13 months (95% CI: 10-21) in the symptomatic BM group (p=0.04). Given a substantial proportion of patients may present with asymptomatic BM, limiting intra-cranial imaging to patients with symptomatic BM, may be associated with a missed opportunity for timely diagnosis and treatment. The utility of routine intra-cranial imaging in patients with renal cell carcinoma, warrants further prospective evaluation.