Presence Of Brain Metastases Research Articles

Impact of use of CDK4/6i and neratinib among patients with HER2 +ve MBC: Results from a real world dataset.

e13046 Background: The introduction of anti-HER2 therapy has improved the prognostic outcome of pts with HER2+ve MBC. A phase II trial revealed that among pts with HR+ve/HER2+ve MBC the use of CDK4/6i with anti-HER2 and endocrine therapy was associated with a survival advantage compared to anti-HER2 therapy and chemotherapy. A phase III trial showed that neratinib + capecitabine improved OS compared to lapatinib and capecitabine. With a plethora of new and efficacious anti-HER2 therapy now available the true clinical utility of CDK4/6i and neratinib are undetermined. The objective of this retrospective analysis was to look at the prognostic outcome associated with use of CDK4/6i and neratinib among pts with HER2+ve MBC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 107 million pt lives available through the TriNetX Research Network. We identified pts with 6511pts with HER2+ve MBC diagnosed since 2015 who were treated with ant-HER2 therapy including trastuzumab, pertuzumab, neratinib, lapatinib, TDM-1 and margetuximab. OS was computed using the Kaplan Meier product limit method. HR+ve status was defined by treatment with endocrine therapy after metastasis, and triple negative (TNBC) status was identified if they did not receive anti-HER2 therapy or endocrine therapy. Results: Mean age was 57.0 yrs. 3679(57.2%) and 2832(42.8%) pts had HR+ve and HR-ve disease, respectively. 2-year OS among pts diagnosed prior to 2015 and during or after 2015 was 79.7% and 82.8%, respectively (p=0.0041). 2-year OS among pts with HR+ve and HR-ve MBC was 87.0% and 75.4%, respectively (p<0.0001). Among pts with HR+ve MBC, 592(16.1%) received a CDK4/6i. Median time to use of CDK4/6i was 4.7m. 2-year OS among pts who did and did not receive a CDK4/6i was 85.1% and 87.5%, respectively (p=0.1844). Median OS among pts who received CDK4/6i within the first year of MBC diagnosis compared to those who received it after the first year of diagnosis was 71.0m and 69.4m, respectively (p=0.0679). No difference in OS was observed among pts with HR+ve disease who had brain mets who did and did not receive CDK4/6i(49.5m vs 54.5m p=0.7335). 327(5.0%) pts received neratinib, of whom 63.9% had HR+ve MBC. 2-year OS among pts who did and did not receive neratinib was 85.1% and 82.6%, respectively(p=0.2366). No difference in 2-year OS was observed among pts who did and did not receive neratinib stratified by HR status and presence of brain metastasis. Conclusions: OS among pts with HER2+ve MBC has significantly improved over time. The use of CDK4/6i among pts with HR+ve/HER2+ve MBC and use of neratinib among pts with HER2+ve MBC did not impact OS.

Comparison of bevacizumab plus doublet chemotherapy regimens in patients with metastatic or recurrent ovarian cancer.

e17537 Background: Ovarian cancer is the most common cause of death due to gynecological malignancies. Although the primary treatment is surgery, there are different chemotherapy regimens that can be used in metastatic disease. In this study, it was aimed to compare doublet chemotherapy regimens in combination with bevacizumab in patients with metastatic ovarian cancer. Methods: Our study was designed as a retrospective observational study. The clinical, pathological, radiological, and treatment characteristics of the patients were recorded. Survival analyzes were performed using the Kaplan-Meier method, and multivariate analysis using cox regression analysis. Results: 198 patients were included in the study. Median follow-up period after bevacizumab was 18.7 months. The most common pathological subtype was serous carcinoma (%85.9). Before bevacizumab treatment, 96% of patients received perioperative chemotherapy. The most common sites of metastasis were the peritoneum (94.5%), liver (43.9%), lung (18.7%), bone (4.5%), and brain (3%). In combination with bevacizumab, 92 (46.4%) patients used gemcitabine + carboplatin, 76 (38.4%) patients used paclitaxel + carboplatin, and 30 (15.2%) patients used gemcitabine + cisplatin. In the whole patient group, the rate of complete response was 18.7%, partial response 56.1%, stable disease 6.6%, and progressive disease 18.7%. The patients received a median of 9 cycles of bevacizumab and a median of 7 cycles of doublet chemotherapy. Median progression-free survival was 11.9 (95% CI, 9.2-14.5) months, and median overall survival was 24.7 (95% CI, 19.9-29.4) months. History of surgery before bevacizumab (p=0.006) and type of doublet chemotherapy (p=0.024) were found to be statistically significant factors affecting overall survival. The presence of brain metastases (p=0.062) had borderline significance. Conclusions: Doublet chemotherapy regimens with bevacizumab have been found to be effective and safe in the treatment of metastatic ovarian cancer in terms of survival. The combination of bevacizumab with gemcitabine + carboplatin was superior to other doublet chemotherapy regimens in terms of overall survival.

Randomized phase 3 study of tarlatamab, a DLL3-targeting bispecific T-cell engager (BiTE),compared to standard of care in patients with relapsed small cell lung cancer (DeLLphi-304).

TPS8611 Background: Small cell lung cancer (SCLC) is an aggressive malignancy for which very few patients achieve long term disease control; response to most treatments is transient and second line treatment options are limited. Delta-like ligand 3 (DLL3) is a Notch ligand aberrantly expressed on the surface of up to 85% of SCLC cells and minimally expressed in normal tissues, making it an attractive therapeutic target. Tarlatamab is a bispecific T cell engager (BiTE) molecule designed to bind DLL3 on target cancer cells and CD3 on T cells, thereby driving T cell-dependent killing of tumor cells. Results from the first-in-human study in patients with relapsed/refractory SCLC (DeLLphi-300; NCT03319940) demonstrate tarlatamab efficacy in pretreated patients with confirmed responses in 23% of patients and median duration of response > 12 months.1 Median overall survival (OS) was 13.2 months. Grade ≥ 3 treatment-related AEs (TRAEs) occurred in 31% of patients and TRAEs resulted in discontinuation in 4% of patients. This promising efficacy/safety profile is being evaluated further in a phase 2, open-label study in patients with relapsed/refractory SCLC after ≥2 lines of prior treatment (DeLLphi-301; NCT05060016). Methods: NCT05740566 is a randomized, open-label, phase 3 study of tarlatamab compared with standard of care (SOC) in ~700 patients with relapsed SCLC after platinum-based first-line chemotherapy. Patients will be randomized 1:1 to receive tarlatamab or SOC therapy (lurbinectedin or topotecan in US, Canada, Australia, Singapore, Korea; amrubicin in Japan; topotecan in all countries except Japan), stratified by prior anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) exposure, chemotherapy-free interval, presence of brain metastases, and SOC (topotecan/amrubicin vs lurbinectedin). The primary objective is to compare the efficacy of tarlatamab with SOC on prolonging OS. Key secondary endpoints include comparison of progression free survival (PFS) based on investigator assessment per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and patient-reported outcomes (PRO) including disease-related symptoms, physical function, and global health status of quality of life. Key eligibility criteria include adults with histologically or cytologically confirmed relapsed SCLC who progressed following 1 platinum-based regimen. Patients must have measurable lesions as defined per RECIST 1.1 within the 21-day screening period and must have adequate organ function. Exclusions include untreated or symptomatic central nervous system metastases, history of immune checkpoint inhibitor use resulting in severe immune-mediated adverse event, and previous history of NSCLC. Enrollment is ongoing.

Characteristics and outcomes of patients with small cell lung cancer (SCLC) detected with CT screening at a single health system.

8581 Background: At diagnosis, the majority of SCLC patients have extensive-stage disease, and their median survival is only 13 months, even with the addition of checkpoint inhibitors. Previous CT screening trials did not reveal reduction in mortality for SCLC patients. The aim of our study was to analyze the baseline characteristics and clinical outcomes of SCLC patients diagnosed with low-dose CT scan as a part of lung cancer screening program. Methods: A retrospective chart review-based study of SCLC patients diagnosed clinically or by lung cancer screening between January 2018 and June 2022 at the Henry Ford Health System was conducted. Baseline characteristics, details of SCLC diagnosis and treatment, and outcome were recorded. Statistical analysis was performed using Chi-squared test, T-test and log-rank test. Results: Of the 258 patients who met eligibility criteria, 34 were diagnosed by lung cancer screening. Patients diagnosed with screening tended to be older (mean age- 70.5 years vs. 67.3 years, p=0.010). There were no differences in gender distribution, race and smoking status. Mean smoking history was 43 pack-years in both groups. Among screen-detected patients, 73.5% had limited-stage disease compared to 36.6% among clinically detected patients (p<0.001). No significant difference in the presence of brain metastases at diagnosis was observed. Among screen-detected patients, 97.1% received any therapy compared to 85.3% among the clinically detected patients (p=0.105). Overall survival (OS) was significantly better in screen-detected patients, with a 3-year survival rate of 45.5% vs. 17% (p=0.00027). By multivariable analysis, OS was better in screen-detected patients (HR=0.37, 95% CI 0.20-0.68; p=0.001) (Table). There was no significant difference in progression-free survival between the groups. Conclusions: Our results demonstrate that SCLC patients diagnosed through the lung cancer screening program have better overall survival rates than those diagnosed clinically. These results suggest that developing appropriate screening measures may impact SCLC-related mortality. [Table: see text]

Trends of using immune checkpoint inhibitors near end of life in limited resources setting: Experience of single cancer center in the MENA region.

6566 Background: Immune checkpoint inhibitors (ICIs) are standard of care nowadays in the treatment of many solid tumors as single agent or in combination. Recent literature suggested increased use of ICI near end of life; our aim was to find the characteristics of the patients who received ICI 30 days or less before their death. Methods: Data of patients with advanced solid tumors who have (ICI) therapy and died with disease were retrospectively retrieved. Patients were categorized into those dying within 30 days of the last dose of ICI and those receiving the last dose of ICI more than 30 days before death. Variables of potential interest were compared between the two groups by the Chi-square and independent sample t-tests as appropriate. Results: A total of 411 patients were included in this analysis; 135 (33%) received the last dose of ICI within 30 days of death and 276 (67%) received their last dose more than 30 days before death. Major cancer types included: lung (n=214; 52%), kidney (n=61; 15%), melanoma (n=44; 11%), head and neck (n=41; 10%), and others (n=14; 3%). Patients’ characteristics: median age = 58, majority were males (310; 75%), 105 (26%) had ECOG PS ≥3, and 147 (36%) had brain metastasis. Patients who received the last dose of ICI within 30 days of death had more frequent ICU admissions (50 (37%) vs. 60 (22%), p=0.001, and were less likely to die under the care of the hospice care service (22 patients (16%) vs. 84 (31%), p=0.001. In addition, patients who received the last dose of ICI within 30 days of death were more likely to have a full code status (89 (66%) vs. 147 (53%), p=0.015, and have received a lower number of doses of ICI treatments (mean number of doses: 4.2 vs. 6.5 doses, p=0.001). We did not observe any significant difference between the two groups regarding type of cancer, age, gender, ECOG PS, presence of brain metastasis, number of hospital admissions, dying inside hospital, and number of emergency room visits. Conclusions: Immune checkpoint inhibitors may be overused near end of life which leads to minimal clinical benefits, less likelihood of dying under hospice care, and utilization of ICU resources.

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.

Survival in Metastatic Renal Cell Carcinoma Treated With Immunotherapy and Stereotactic Radiation Therapy or Immunotherapy Alone: A National Cancer Database Analysis

Immunotherapy (IO) has significantly improved outcomes in metastatic renal cell carcinoma (mRCC). Preclinical evidence suggests that responses to IO may be potentiated via immunomodulatory effects of stereotactic radiation therapy (SRT). We hypothesized that clinical outcomes from the National Cancer Database (NCDB) would demonstrate improved overall survival (OS) in patients with mRCC receiving IO+SRT versus IO alone. Patients with mRCC receiving first-line IO ± SRT were identified from the NCDB. Conventional radiation therapy was allowed in the IO alone cohort. The primary endpoint was OS stratified by the receipt of SRT (IO+SRT vs IO alone). Secondary endpoints included OS stratified by the presence of brain metastases (BM) and timing of SRT (before or after IO). Survival was estimated using Kaplan-Meier methodology and compared via the log-rank test. Of 644 eligible patients, 63 (9.8%) received IO+SRT, and 581 (90.2%) received IO alone. Median follow-up time was 17.7 months (range, 2-24 months). Sites treated with SRT included the brain (71.4%), lung/chest (7.9%), bones (7.9%), spine (6.3%), and other (6.3%). OS was 74.4% versus 65.0% at 1 year and 71.0% versus 59.4% at 2 years for the IO+SRT and IO alone groups, respectively, although this difference did not reach statistical significance (log-rank P=.1077). In patients with BM, however, 1-year OS (73.0% vs 54.7%) and 2-year OS (70.8% vs 51.4%) was significantly higher in those receiving IO+SRT versus IO alone, respectively (pairwise P=.0261). Timing of SRT (before or after IO) did not influence OS (log-rank P=.3185). Patients with BM secondary to mRCC had prolonged OS with the addition of SRT to IO. Factors such as International mRCC Database Consortium risk stratification, oligometastatic tumor burden, SRT dose/fractionation, and utilization of doublet therapy should be considered in future analyses to better identify patients who may benefit from combined IO+SRT. Further prospective studies are warranted.

Indirect comparison of mobocertinib and real-world therapies for pre-treated non-small cell lung cancer with EGFR exon 20 insertion mutations

ObjectivesMobocertinib, a novel oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is available for the treatment of non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations after platinum chemotherapy. We performed an indirect comparison of clinical trial data and real-world data (RWD) to determine the relative efficacy of mobocertinib vs. other treatments for these patients. Materials and methodsData on the efficacy of mobocertinib from a phase I/II trial (NCT02716116) were compared to RWD from a retrospective study in 12 German centers using inverse probability of treatment weighting to adjust for age, sex, Eastern Cooperative Oncology Group score, smoking status, presence of brain metastasis, time from advanced diagnosis, and histology. Tumor response assessment was based on RECIST v1.1. ResultsThe analysis included 114 patients in the mobocertinib group and 43 in the RWD group. The confirmed overall response rate (cORR) according to investigator assessment was 0% for standard treatments and 35.1% (95% confidence interval [CI], 26.4–44.6) for mobocertinib (p < 0.0001). Compared to standard regimens in the weighted population, mobocertinib prolonged overall survival (OS, median [95% CI] = 9.8 [4.3–13.7] vs. 20.2 [14.9–25.3] months; hazard ratio [HR] = 0.42 [0.25–0.69], p = 0.0035), progression-free survival (PFS, median [95% CI] = 2.6 [1.5–5.7] vs. 7.3 [5.6–8.8] months; HR = 0.28 [0.18–0.44], p < 0.0001), and time to treatment discontinuation (median [95% CI] = 2.1 [1.2–3.1] vs. 7.4 [6.4–8.5] months; HR = 0.34 [0.18–0.65], p = 0.0004). ConclusionMobocertinib was associated with an improved cORR and prolonged PFS and OS compared to standard treatments for patients with EGFR ex20ins-positive NSCLC previously treated with platinum-based chemotherapy.

Abstract 4017: TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models

Abstract Patients with brain tumors and metastases have poor prognosis and overall survival rates despite the advancements in neurosurgery, radiotherapy, and chemotherapy. Genomic alterations in HER2 are present in brain metastases of breast cancer (BC; ~20%) and non-small cell lung cancer (NSCLC; 13-20%), and EGFR alterations occur frequently in glioblastoma multiforme (GBM; &amp;gt;50%). Despite the advancements in standard of care options, optimal treatment management for these patients remains an unmet medical need. Recent evidence suggests activity of systemic therapy for immune and targeted therapies in the brain, including agents targeting HER2/EGFR. HER2-targeted tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib and the HER2-targeted antibodies trastuzumab and pertuzumab, in combination with chemotherapy, have been shown to improve survival of patients with HER2 overexpressing BC in the presence of brain metastases. The limited penetration of these compounds into the CNS, however, limits their efficacy. TAS2940 is an irreversible pan-ErbB inhibitor with greater brain-penetrability than poziotinib, tucatinib, and neratinib. Here, we demonstrate that TAS2940 induces downregulation of phosphorylated HER2/EGFR, reduces tumor burden, and promotes a significant increase in survival in intracranial xenograft mouse models with HER2-amplification (BC), HER2-Exon20 insertion mutation (NSCLC), and EGFR-amplification (GBM). These promising preclinical data highlight potential novel therapeutic strategies for patients with EGFR-aberrant GBM and brain metastases harboring HER2/EGFR alterations, and may help support the advancement of the ongoing first-in-human clinical trial (NCT04982926) for TAS2940 in solid tumors with EGFR and/or HER2 alterations. Citation Format: Jing Han, Mikhila Mahendra, Poojabahen Gandhi, Joseph R. Daniele, Caroline C. Carrillo, Benjamin J. Bivona, Ningping Feng, John V. Heymach, Funda Meric-Bernstam, Kei Oguchi, Shinji Mizuarai, Timothy P. Heffernan, Christopher P. Vellano, Joseph R. Marszalek. TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models. [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 4017.

Abstract 3517: Multi-modal single-cell and spatial genomics reveals genomic, adaptive and microenvironmental features of human non-small cell lung cancer brain metastasis

Abstract Non-small cell lung cancer (NSCLC) accounts for nearly half of all newly diagnosed patients with brain metastasis (BM), followed by melanoma and breast carcinomas. The presence of BM is associated with reduced response to several modern cancer therapies and a poor prognosis, but the underlying molecular underpinnings remain poorly understood. Here, we performed multi-modal single-nucleus RNA, T cell receptor, single-cell spatial, and whole-genome sequencing (WGS) of 44 primary NSCLC tumors (PTs) and BMs. Through combination of WGS with inferred copy-number alterations (CNAs) and gene expression snRNA-seq, we robustly identify malignant cells despite the presence of healthy cell mosaicism. We find a strong association of chromosomal instability (CIN) and brain-metastatic organotropism. Through integration with clinical information and thousands of publicly available whole-exome sequencing (WES) profiles obtained from patients with NSCLC, we validate this observation and show that CIN progressively increases from PTs to extracranial metastases (ECMs) and is the highest in BMs. Using non-negative matrix factorization, we identify recurrent transcriptional hallmarks cancer metastasis, and additionally find that cancer cells from BMs strongly enrich for a neuronal-like cell state. At single-cell resolution, we indeed identify a rare cancer cell population genomically define by very high CIN, and transcriptionally characterized by a program of epithelial-to-mesenchymal transition (EMT), neuronal-like differentiation, and loss of lineage attribution. We show in our data and external scRNA-seq data that this cell state does not ecist in healthy lungs, progressively enriches from PTs to ECMs, and is most abundant in BMs, suggesting that these cells may indeed give rise to BMs. Furthermore, through integration of snRNA/TCR-seq and spatial transcriptomics, we find distinct tumor-microenvironments across disease sites, including, nearly exclusive expansion of tissue-resident myeloid cells in PTs, while BMs are largely dominated by dense infiltration with monocyte-derived macrophages and granulocytes, impaired T cell infiltration, activation and clonal expansion. Lastly, spatial transcriptomics also recurrent, cell-type specific patterns of geographic variability in key pathways, including antigen presentation, EMT, oxidative phosphorylation, and inflammatory response and associated cellular micro-niches. Together, this work identifies cellular, genomic, and transcriptional features of NSCLC BMs and has important therapeutic implications for novel therapies, in particular immunomodulatory approaches targeting cell types/states unique to disease sites. Citation Format: Somnath Tagore, Lindsay Caprio, Amit Dipak Amin, Irving Barrera, Johannes Melms, Karan Luthria, Yiping Wang, Yohanna Georgis, Abhi Jaiswal, Galina G. Lagos, Zachary Walsh, Parin Shah, Jana Biermann, Neha Sheikh, Priyanka Ramaradj, Niroshana Anandasabapathy, Hanina Hibshoosh, Gary Schwartz, Brian Henick, Alison Taylor, Fei Chen, Benjamin Izar. Multi-modal single-cell and spatial genomics reveals genomic, adaptive and microenvironmental features of human non-small cell lung cancer 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 3517.

Treatment Patterns, Testing Practices, and Outcomes in Patients with EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer in Poland: A Descriptive Analysis of National, Multicenter, Real-World Data from the REFLECT Study.

Non-small-cell lung cancer (NSCLC) represents 85% of new cases of lung cancer. Over the past two decades, treatment of patients with NSCLC has evolved from the empiric use of chemotherapy to more advanced targeted therapy dedicated to patients with an epidermal growth factor receptor (EGFR) mutation. The multinational REFLECT study analyzed treatment patterns, outcomes, and testing practices among patients with EGFR-mutated advanced NSCLC receiving first-line EGFR tyrosine kinase inhibitor (TKI) therapy across Europe and Israel. The aim of this study is to describe the Polish population of patients from the REFLECT study, focusing on treatment patterns and T790M mutation testing practice. A descriptive, retrospective, non-interventional, medical record-based analysis was performed on the Polish population of patients with locally advanced or metastatic NSCLC with EGFR mutations from the REFLECT study (NCT04031898). A medical chart review with data collection was conducted from May to December 2019.The study involved 110 patients. Afatinib was used as the first-line EGFR-TKI therapy in 45 (40.9%) patients, erlotinib in 41 (37.3%), and gefitinib in 24 (21.8%) patients. The first-line EGFR-TKI therapy was discontinued in 90 (81.8%) patients. The median progression-free survival (PFS) on first-line EGFR-TKI therapy was 12.9 months (95% CI 10.3-15.4). A total of 54 patients started second-line therapy, of whom osimertinib was administered to 31 (57.4%). Among 85 patients progressing on first-line EGFR-TKI therapy, 58 (68.2%) were tested for the T790M mutation. Positive results for the T790M mutation were obtained from 31 (53.4%) tested patients, all of whom received osimertinib in the next lines of therapy. The median overall survival (OS) from the start of first-line EGFR-TKI therapy was 26.2 months (95% CI 18.0-29.7). Among patients with brain metastases, the median OS from the first diagnosis of brain metastases was 15.5 months (95% CI 9.9-18.0). The results of the Polish population from the REFLECT study highlight the need for effective treatment of patients with advanced EGFR-mutated NSCLC. Nearly one-third of patients with disease progression after first-line EGFR-TKI therapy were not tested for the T790M mutation and did not have the opportunity to receive effective treatment. The presence of brain metastases was a negative prognostic factor.

Advances in the Management of Central Nervous System Metastases in Non-Small Cell Lung Cancer.

Central nervous system (CNS) metastases are common among patients with non-small cell lung cancer (NSCLC). While the presence of brain metastases has historically portended poor prognosis, recent advances in local and systemic therapies have greatly improved outcomes for NSCLC patients with CNS involvement. Stereotactic radiology surgery (SRS) has emerged as an effective radiotherapy technique with fewer toxicities compared to whole brain radiotherapy (WBRT). Furthermore, multi-generation tyrosine kinase inhibitors (TKIs) with CNS overall response rates (ORR) of up to 70-80% are now an accepted first-line approach for a subset of advanced NSCLC patients with targetable molecular alterations. In addition, while the CNS was once considered an immunologic sanctuary site, growing evidence shows that immune checkpoint inhibitors (ICIs) can induce durable responses in brain metastases as well. Ongoing efforts to optimize CNS metastases management are necessary to refine multimodal treatment approaches and develop new therapeutics with better CNS penetrance.

Durvalumab plus platinum-etoposide chemotherapy for extensive-stage small cell lung cancer: a retrospective real-world study.

Immune checkpoint inhibitor plus platinum-etoposide (PE) improved overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC). While the CASPIAN trial demonstrated the efficacy of durvalumab plus PE, the clinical trial results may not be representative of the general, real-world population because clinical trials often have strict inclusion and exclusion criteria. We herein report the efficacy and safety of durvalumab plus PE in patients with ES-SCLC in real-world, clinical practice. The present, monocentric, retrospective study evaluated patients with ES-SCLC or recurrent, limited-stage SCLC who received durvalumab plus PE between September 2020 and February 2023. The efficacy and incidence of adverse events (AEs) were also evaluated. The study included 40 patients, of whom 17 were elderly (age >70 years), and 15 had performance status (PS) 2 or 3. The median follow-up time was 13.0 months [95% confidence interval (CI): 8.0-22.2 months]. The objective response rate was 80.0% (95% CI: 63.1-91.6%), and the disease control rate was 88.6% (95% CI: 73.3-96.8%). The median progression-free survival (PFS) was 5.9 months (95% CI: 4.9-6.9), and the median OS was 25.4 months (95% CI: 4.6-46.2). Factors such as advanced age, poor PS, and presence of brain metastases were not associated with lower PFS and OS. Twenty-six patients (65.0%) experienced grade 3 or higher AEs, mainly hematological toxicity. AEs leading to treatment discontinuation occurred in three patients (8%). Durvalumab plus PE in patients with ES-SCLC showed good efficacy and safety according to our real-world data, suggesting that this treatment is well tolerated in clinical practice, even in elderly patients and those with poor PS.

Real-world outcomes of anti-EGFR therapy in advanced non-small cell lung cancer EGFR mutated in Peru.

Despite the advances in the management of advanced non-small cell lung cancer (NSCLC), the access to genetic profiling and target therapies remains a challenge in Latin America, even in countries with a higher rate of targetable mutations. The aim of this study is to evaluate the clinical outcomes of anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) treatment in a Peruvian real-world setting. This is a retrospective study of recurrent or advanced NSCLC EGFR mutated patients diagnosed and treated with anti-EGFR TKI at Instituto Nacional de Enfermedades Neoplásicas (INEN) between January 1, 2015 to December 31, 2020. The outcomes were objective response rate (ORR), progression free survival (PFS), and overall survival (OS). We identify 613 stage IV or recurrent NSCLC patients who were tested for EGFR mutations and found a pathogenic mutation in 39.5% of patients. Only 51.2% of them received anti-EGFR TKI as institutional treatment. ORR was 58%, after median follow-up of 32 months, the estimated median PFS was 13.9months (11.1-16.7months), and the estimated median OS was 21.7months (18.5-24.9months). No differences were found in PFS according to line of treatment or brain metastases at diagnosis (p=0.46 and p=0.07, respectively), respect to OS there were no differences line of treatment (p=0.12), significant difference were found in presence of brain metastases (p=0.006). Our study demonstrates that erlotinib for advanced NSCLC harboring EGFR-activating mutations is effective even in patients usually excluded from clinical trial, like those previously exposed to one or more lines of chemotherapy or with brain metastases.

Stereotactic Body Radiation Therapy for Oligoprogressive Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> The role of stereotactic body radiation therapy (SBRT) in oligoprogressive non-small cell lung cancer (NSCLC) is controversial, given the current standard of care in this setting favors changing to the next-line of systemic therapy. To address this important knowledge gap, we hypothesized that SBRT in a subset of patients with oligoprogressive NSCLC offers durable response, omitting the need to change or escalate systemic therapy. We evaluated patients on systemic therapy for NSCLC treated at our institution who subsequently received SBRT in the oligoprogressive setting. <h3>Materials/Methods</h3> A retrospective analysis of NSCLC patients who underwent SBRT for oligoprogressive disease from 2017 to 2021 was performed. Variables included in the analysis were age, gender, presence of brain metastases, and number of metastatic sites treated at the time of progression. Lesions defined as progressing were based on the response evaluation criteria in solid tumors (RECIST v1.1); presence of brain metastases was not considered as a site of progression. Progression-free survival (PFS), our primary endpoint, was calculated using the Kaplan-Meier method and defined as the time from completion of SBRT to next progression or death, whichever occurred first. Subset analyses were performed on epidermal growth factor receptor (EGFR) positive patients receiving a tyrosine kinase inhibitor (TKI) and PD-L1 ≥50% vs <50%. Log-rank and Cox proportional hazards regression were used to evaluate predictors of PFS. <h3>Results</h3> A total of 105 patients were included; median age was 65 and 57% were female. The majority were adenocarcinoma (79%). Twenty-six percent of patients were EGFR positive and received a TKI. PD-L1 expression was <50% in 31%, ≥50% in 16% and unknown in 53% of patients. The number of oligoprogressive sites treated at the time of progression was 1-2 in 77% and 3-6 in 23% of patients. At a median follow up of 12 months (range, 1-60 months), median time to progression after completion of SBRT was 4 months (range, 1-37 months). Median PFS for the entire cohort was 5.5 months (95% confidence interval [CI], 2.9-8.0). Median PFS for patients undergoing SBRT to 1-2 vs 3-6 sites of disease was 5.9 months (95% CI, 3.9-7.9) and 3.4 months (95% CI, 1.9-4.8), respectively. Median PFS for EGFR positive patients on TKI was 8.1 months (95% CI, 4.0-12.2), compared to 5.6 months (2.4-8.9) for EGFR negative patients. Median PFS for PD-L1 <50% was 5.6 months (95% CI, 4.0-7.2) vs 6.6 months (95% CI, 0.71-12.5) for PD-L1 ≥50%. Forty-five (43%) patients underwent additional SBRT. No radiation related grade 3 or higher toxicities were reported. <h3>Conclusion</h3> SBRT is a safe and viable treatment option for oligoprogressive NSCLC. Our findings suggest EGFR positive patients and those with 1-2 sites of progression may benefit more. Future prospective studies are needed to validate these findings.

Breast Cancer Subtypes and Incidence of Brain Metastases in the SEER Database

<h3>Purpose/Objective(s)</h3> Despite the recognition that women with triple-negative (TNBC) and HER2+ breast cancer have a higher risk of developing brain metastases than other subtypes of breast cancer, the recently updated NCCN guidelines for breast cancer do not recommend MR imaging of the brain in women with either primary or metastatic breast cancer (of any type) unless there are neurologic signs/symptoms suspicious for brain metastases. We investigated the relative distribution of synchronous and metachronous brain metastases over the past decade. <h3>Materials/Methods</h3> We evaluated the Surveillance, Epidemiology, and End Results (SEER) SEER-18 database for breast cancer patients diagnosed from 2010-2017. Female patients with complete data regarding presence of brain metastases, stage, breast cancer subtype, and survival were selected. Relative frequencies of subtypes at diagnosis for all patients (localized and metastatic), synchronous brain metastases, and metachronous brain metastases were calculated. Metachronous brain metastases were defined as patients who had both a primary and localized breast cancer diagnosis and subsequent brain metastases diagnosis both recorded in SEER as separate entries from different years with the same patient identifying number. <h3>Results</h3> We found 394,153 patients who fit criteria. The percent incidence of brain metastases at diagnosis did not change significantly over the years examined (range 0.33-0.39%, chi-squared p=0.59) Overall frequency of brain metastases was 0.67%, 0.22%, 1.17%, and 0.71% for luminal B, luminal A, HER2+, TNBC, respectively (chi-squared p<0.001). Relative frequency of breast cancer subtypes among all cases, synchronous brain metastases, and metachronous brain metastases showed increasing proportion of patients with TNBC. Only 26 patients were found that had metachronous brain metastases in the database. Of those patients, 38.5% had TNBC. <h3>Conclusion</h3> This SEER-based analysis shows that although presentation with synchronous brain metastases is relatively balanced across all molecular subtypes, metachronous brain metastases are most commonly seen in TNBC patients, perhaps indicative of the prevalence of occult brain metastases at presentation in patients with TNBC. Unfortunately, metachronous brain metastases are not robustly recorded in SEER. Better data is needed on the prevalence of brain metastases at the time of initial diagnosis and when systemic progression occurs in TNBC patients.

Survival in Metastatic Renal Cell Carcinoma Treated with Immunotherapy and Stereotactic Radiation Therapy or Immunotherapy Alone: A National Cancer Database Analysis

<h3>Purpose/Objective(s)</h3> Immunotherapy (IO) has significantly improved outcomes in metastatic renal cell carcinoma (mRCC). Preclinical evidence suggests that responses to IO may be enhanced through the immunomodulatory effects of stereotactic radiation therapy (SRT). We hypothesized that clinical outcomes from the National Cancer Database (NCDB) would demonstrate improved overall survival (OS) in mRCC patients receiving IO+SRT versus IO alone. <h3>Materials/Methods</h3> Patients with mRCC diagnosed from 2012-2016 and receiving first-line IO±SRT were identified from the NCDB. Complete staging details and radiation treatment characteristics were required for study inclusion. The definition of SRT was ≥10 Gy in 1 fraction, ≥20 Gy in 2 fractions, ≥24 Gy in 3 fractions, or ≥25 Gy in 5 fractions. Conventional radiation therapy was allowed in the IO alone cohort. The primary endpoint was OS (from date of stage IV diagnosis) stratified by the receipt of SRT (IO+SRT versus IO alone). Secondary endpoints included OS stratified by the presence of brain metastases (BM) and timing of SRT (before or after IO). Events beyond 24 months were censored. Survival was estimated using Kaplan-Meier methodology and compared via the log-rank test. Adjustments for multiple comparisons were performed. <h3>Results</h3> Of 644 eligible patients, 63 (9.8%) received IO+SRT and 581 (90.2%) received IO alone. The median follow-up time was 17.7 months (range, 2-24 months). Baseline characteristics were similar between cohorts, although SRT+IO patients were more frequently <60 years old (57.1% vs 40.3%, P=0.010) and had higher rates of BM (71.4% vs 11.2%, P<0.001). There was no difference in metastatic tumor burden (defined as the number of involved organ systems) between cohorts (P=0.48). Sites treated with SRT included the brain (71.4%), lung/chest (6.4%), spine (6.4%), bones (3.2%), and other (12.6%). While there was no significant difference in OS for patients receiving IO+SRT vs IO alone (log-rank P=0.11), OS was consistently higher at 1-year (74.4% vs 65.0%) and 2-years (71.0% vs 58.4%). In patients with BM, 1-year survival rates were 73.0% (95% CI, 57.4-83.7) with IO+SRT and 54.7% (95% CI, 41.8-65.9) with IO alone (P=<0.026). The timing of SRT (before or after IO) did not appear to influence OS (P=0.32). <h3>Conclusion</h3> Patients with BM secondary to mRCC had prolonged OS with the addition of SRT to IO. Prospective clinical trials are warranted to better identify mRCC populations which may benefit from combined modality therapy. Potential synergistic factors, such as oligometastatic tumor burden, IO mechanism of action, and SRT dose should be considered in future analyses of mRCC patients receiving IO+SRT.

Development of Brain Metastases Following Definitive Chemoradiotherapy in Locally Advanced Non-Small Cell Lung Cancer

<h3>Purpose/Objective(s)</h3> To describe the time course and likelihood of symptomatic presentation of brain metastases in the setting of locally advanced non-small cell lung cancer (LA-NSCLC) following definitive therapy. <h3>Materials/Methods</h3> Patients with LA-NSCLC treated with chemoradiation as definitive therapy between 2013-2020 (n = 219) were reviewed. Features including histologic subtype, T, N and clinical prognostic stage, presence of brain metastases and symptoms at time of presentation were recorded. Descriptive statistics were used to characterize the patient population, including incidence of brain metastases by histology, and the method of Kaplan and Meier was used to estimate brain metastasis free survival at 24 months. Fisher's exact tests were used to compare proportions between symptomatic and asymptomatic patients. <h3>Results</h3> A total of 219 patients met inclusion criteria. Histology including squamous cell carcinoma (SCC) (96), adenocarcinoma (88), and NSCLC-Not Otherwise Specified (NOS) (35). Median age was 67 years; 210 (96%) were current/former smokers, T stage was T0 (11.9%), T1 (21.9%), T2 (26.5%), T3 (18.3%), and T4 (21.5%). The majority of patients were N2 or N3 at treatment: N0 (5%), N1 (14.2%), N2 (60.7%), and N3 (20.1%). In total, 39 patients (17.8%) developed brain metastases. Incidence by histology varied with NSCLC-NOS showing the highest incidence (34.3%), followed by adenocarcinoma (23.9%), and SCC (6.2%). Brain metastasis free survival at 24 months was 72.9% (95% CI: 62.5-84.9%) for adenocarcinoma, 92.2% (95% CI: 86.3 – 98.5%) for SCC, and 53.3% (95% CI: 35.4 – 80.1%) for NSCLC-NOS. Median time to development of brain metastasis was 7.7 months (adenocarcinoma), 5.7 months (SCC), and 8.3 months (NSCLC-NOS). Overall, 85% of brain metastases occurred within 1 year. Ninety percent of patients were diagnosed with brain metastases after development of neurologic symptoms. Only 4 total patients had brain metastases discovered without symptoms. For patients presenting with symptomatic brain metastases, 91.4% required steroids versus 0% for those without symptoms (p <0.001). Symptomatic patients were more likely to require hospitalization at presentation, 65.7% vs 0% (p = 0.02). All asymptomatic patients with brain metastases were able to undergo stereotactic radiosurgery (SRS) alone, while only 40% of symptomatic patients received SRS monotherapy (p = 0.04). There was no statistically significant difference brain metastasis incidence based on treatment with adjuvant immunotherapy vs none for any histology (17.1% vs 18.1%, p = 1). <h3>Conclusion</h3> Brain metastases are a common source of morbidity and mortality in the setting of LA-NSCLC; however, there is no standard recommendation for surveillance brain imaging following therapy. Presentation with symptomatic brain metastases was significantly associated with need for more invasive management. This could strengthen an argument for the potential utility of surveillance brain imaging in the post-definitive setting.

P11.29.B Risk factors associated with the presence of brain metastasis at the moment of diagnosis in non-small cell lung cancer patients. Retrospective case series

Abstract Background Lung cancer is the second most frequent neoplasm worldwide and the leading cause of cancer death in both sexes. Furthermore, it is the most common origin of brain metastases. The aim of this study is to identify clinical, histological, and molecular variables associated with a higher risk of presenting brain metastases at the moment of diagnosis in patients with lung cancer. Material and Methods A single-center retrospective case series analysis of patients with a new diagnosis of lung cancer (from January 2015 to December 2018) was performed. A total of 723 total patients with a new diagnosis of non-small cell lung cancer (NSCLC) were identified. Only patients with a brain imaging study at the time of diagnosis were included in the analysis. Non-parametric statistical tests were used to compare patients with or without metastases at the moment of diagnosis. A uni- and multivariate analysis were performed to identify risk factors associated with the presence of brain metastases at NSCLC diagnosis. Statistical significance was considered when p&amp;lt;0.05. Results We included 135 patients with a new diagnosis of lung cancer and with brain imaging study at the time of diagnosis (mean age at diagnosis of 64.69 years [SD= 10.34]; 71.9% men). The most common histology was adenocarcinoma (67.1%) followed by squamous carcinoma (25.2%). Brain metastases were present in 40% of patients at diagnosis. No significant differences in clinical, histological and molecular variables was identified between patients with or without brain metastases. In any case, as expected, the survival analysis showed that brain metastasis at diagnosis was associated with a worse overall survival (Log-Rank test, p&amp;lt;0.01).The univariate analysis showed that presenting neurological symptoms (OR=19.5, p&amp;lt;0.0001 CI [7.895-47.65]), histology of adenocarcinoma (OR= 2.113, p&amp;lt;0.014 CI [1.160-3.849]) and the presence of visceral metastases (OR= 14.444, p&amp;lt;0.0001 CI [6.161-33.86]) were associated to the presence of brain metastases at diagnosis. The presence of metastases limited to the thorax (OR= 0.019, p&amp;lt;0.001 CI [0.003-0.146] was associated to be free of brain metastasis at NSCLC diagnosis. However, only neurological symptoms (OR= 20.290, p&amp;lt;0.0001 CI [4.953-83.118]), presenting visceral metastases (OR= 4.451, p&amp;lt;0.010 CI [1.458-13.777]) and/or metastases limited to the thorax (OR= 0.066, p&amp;lt;0.024 CI [0.006-0.010]) reached statistical significance in the multivariate analysis. Conclusion Neurological symptoms and the presence of visceral metastases are independent predictors or presenting brain metastasis at the moment of diagnosis in lung cancer patients. On the other hand, the presence of lung cancer disease confined in the thoracic cavity is associated with a lower risk to present brain metastasis

992P Updated analyses from the CROWN study of first-line lorlatinib vs crizotinib in Asian patients with ALK-positive non-small cell lung cancer (NSCLC)

Lorlatinib improved progression-free survival (PFS) and demonstrated intracranial (IC) activity in patients with untreated advanced ALK+ non-small cell lung cancer (NSCLC) in the phase III CROWN study (NCT03052608) of lorlatinib vs crizotinib. Here, we report updated results in the Asian subgroup from this study after 36 months of follow-up. Patients were randomized 1:1 to receive lorlatinib 100 mg once daily or crizotinib 250 mg twice daily, stratified by presence of brain metastases (yes/no) and ethnicity (Asian/non-Asian). The primary endpoint was PFS by based on blinded independent central review (BICR). Key secondary endpoints included objective response rate (ORR), intracranial ORR (IC ORR), IC time to progression (IC TTP), and safety. Endpoints were analyzed using unstratified analyses in the Asian subgroup. In the Asian subgroup, 120 patients were randomized to lorlatinib (n=59) or crizotinib (n=61) arm. At data cutoff (Sep 20, 2021), median PFS by BICR was not reached with lorlatinib and 11.1 months with crizotinib (HR 0.40; 95% CI, 0.230-0.710; Table). Both ORR and IC ORR were clinically improved with lorlatinib vs crizotinib. The HR of IC TTP with lorlatinib vs crizotinib was 0.03 (95% CI, 0.004-0.200). All-cause grade 3/4 treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were reported in 79.7% and 8.5% of patients with lorlatinib and 61.7% and 13.3% of patients with crizotinib, respectively. No new safety signals emerged.Table: 992PEfficacy in CROWN Asian subgroupaEndpointLorlatinib (n=59)Crizotinib (n=61)PFS, median (95% CI), monthsNR (33.1-NR)11.1 (9.2-14.8)HR (95% CI)0.40 (0.230-0.710)ORR (95% CI), %78.0 (65.3-87.7)57.4 (44.1-70.0)IC TTP (95% CI), monthsNR (NR-NR)16.6 (11.0-NR)HR (95% CI)0.03 (0.004-0.200)Patients with brain metastases at baselineLorlatinib (n=11)Crizotinib (n=15)IC ORR (95% CI), %72.7 (39.0-94.0)20.0 (4.3-48.1)HR, hazard ratio; IC, intracranial; NR, not reached; ORR, objective response rate; PFS, progression-free survival; TTP, time to progression. aBy blinded independent central review unless stated otherwise. Open table in a new tab HR, hazard ratio; IC, intracranial; NR, not reached; ORR, objective response rate; PFS, progression-free survival; TTP, time to progression. aBy blinded independent central review unless stated otherwise. Efficacy and safety results in the Asian subgroup were consistent with those in the overall population in the CROWN study. Our data support the use of lorlatinib as a first-line treatment option in Asian patients with ALK+ NSCLC.