Including Brain Metastases Research Articles

Delayed and Concurrent Stereotactic Radiosurgery in Immunotherapy-Naïve Melanoma Brain Metastases

Melanoma remains a formidable challenge in oncology, causing the majority of skin cancer deaths in the United States, with brain metastases contributing substantially to this mortality. This paper reviews the current therapeutic strategies for melanoma brain metastases, with a focus on delayed and concurrent stereotactic radiosurgery (SRS). While surgery and traditional chemotherapy offer limited efficacy, recent advances in immunotherapy, particularly immune checkpoint inhibitors (ICIs), have played a major role in the advancement and improved efficacy of the treatment of cancers, including brain metastases. Recent studies indicate that monotherapy with ICIs may lead to a higher median overall survival compared to historical benchmarks, potentially allowing patients to delay radiosurgery. Other studies have found that combining SRS with ICIs demonstrates promise, with results indicating improved intracranial control. Ongoing clinical trials explore novel combinations of immunotherapies and radiotherapies, aiming to optimize treatment outcomes while minimizing adverse effects. As treatment options expand, future studies will be necessary to understand the interplay between therapies and their optimal sequencing to improve patient outcomes.

T cells standing at the gates of brain metastasis

Insufficient influx of Tcells into the tumor microenvironment, including brain metastasis, dramatically limits efficacy of conventional immunotherapy. In this issue of Immunity, Messmer etal. interrogate spatiotemporal dependencies of melanoma brain metastasis Tcell infiltration by intravital microscopy. They find that Tcells enter these brain tumors through peritumoral venous vessels and can be stimulated with immunotherapy.

PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cell in lung cancer brain metastasis

BackgroundLung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis.MethodsWe utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells (EpCAM/tdtLL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control.ResultsCompared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect.ConclusionCAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.

507LBA (PB-507) LBA Posters: VRN101099: a novel oral treatment option for patients with advanced solid tumors including brain metastasis driven by HER2 amplification or HER2-activating mutations even with T-DXd resistance

507LBA (PB-507) LBA Posters: VRN101099: a novel oral treatment option for patients with advanced solid tumors including brain metastasis driven by HER2 amplification or HER2-activating mutations even with T-DXd resistance

Heterogeneity of fibroblast activation protein expression in the microenvironment of an intracranial tumor cohort: head-to-head comparison of gallium-68 FAP inhibitor-04 (68Ga-FAPi-04) and fluoride-18 fluoroethyl-L-tyrosine (18F-FET) in positron emission tomography-computed tomography imaging.

Cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) can interact with tumor parenchymal cells to promote tumor growth and migration. Fibroblast activation protein (FAP) expressed by CAFs can be targeted with positron emission tomography (PET) tracers, but studies on FAP expression patterns in intracranial tumors remain scarce. We aimed to evaluate FAP expression patterns in intracranial tumors with gallium-68 FAP inhibitor-04 (68Ga-FAPi-04) and immunohistochemical staining and to observe the interactions between CAFs and tumor cells with a head-to-head comparison of 68Ga-FAPi-04 and fluoride-18 fluoroethyl-L-tyrosine (18F-FET) for PET quantification analysis. We prospectively enrolled 22 adult patients with intracranial mass lesions. 68Ga-FAPi-04 and 18F-FET PET-computed tomography (PET/CT) brain imaging were applied before surgery. Maximal tumor-to-brain ratio (TBRmax), metabolic tumor volume (MTV), and total lesion tracer uptake (TLU) was obtained, and different thresholds were used for 68Ga-FAPi-04-positive lesion delineation owing to the lack of relevant guidelines. The MTV and TLU ratios of both tracers were calculated. Linear regression was applied to observe the differential efficacy of semiquantitative PET parameters. A total of 22 patients with a mean age of 50±13 years (range, 27-69 years) were enrolled. Heterogeneous patterns of 68Ga-FAPi-04 uptake [median of maximal standardized uptake value (SUVmax) =3.8; range, 0.1-19.1] were found. More malignant tumors, including brain metastasis, glioblastoma, and medulloblastoma, generally exhibited more significant 68Ga-FAPi-04 uptake than did the less malignant tumors, while the SUVmax and TBRmax exhibited nonsignificant differences across three intracranial lesion groups of primary brain tumor, brain metastasis, and noncancerous disease (SUVmax: P=0.092; TBRmax: P=0.189). Immunohistochemistry staining showed different stromal FAP expression status in various intracranial lesions. In 15 patients with positive 68Ga-FAPi-04 intracranial tumor uptake, the MTVFAPi:MTVFET ratio had differential efficacy in various types of intracranial tumors [95% confidence interval (CI): 0.572-7.712; P=0.027], and further quantification analyses confirmed the differential ability of the MTVFAPi:MTVFET ratio (95% CI: -0.045 to 11.013, P=0.052; 95% CI: 0.044-17.903, P=0.049; 95% CI: -1.131 to 30.596, P=0.065) with different isocontour volumetric thresholds. This head-to-head study demonstrated heterogeneous FAP expression in intracranial tumors. The FAP expression volume percentage in tumor parenchyma may therefore offer benefit with respect to differentiating between intracranial tumor types.

Histopathological correlation of brain tumor recurrence vs. radiation effect post-radiosurgery as detected by MRI contrast clearance analysis: a validation study.

The differentiation between adverse radiation effects (ARE) and tumor recurrence or progression (TRP) is a major decision-making point in the follow-up of patients with brain tumors. The advent of immunotherapy, targeted therapy and radiosurgery has made this distinction difficult to achieve in several clinical situations. Contrast clearance analysis (CCA) is a useful technique that can inform clinical decisions but has so far only been histologically validated in the context of high-grade gliomas. This is a series of 7 patients, treated between 2018 and 2023, for various brain pathologies including brain metastasis, atypical meningioma, and high-grade glioma. MRI with contrast clearance analysis was used to inform clinical decisions and patients underwent surgical resection as indicated. The histopathology findings were compared with the CCA findings in all cases. All seven patients had been treated with gamma knife radiosurgery and were followed up with periodic MR imaging. All patients underwent CCA when the necessity to distinguish tumor recurrence from radiation necrosis arose, and subsequently underwent surgery as indicated. Concordance of CCA findings with histological findings was found in all cases (100%). Based on prior studies on GBM and the surgical findings in our series, delayed contrast extravasation MRI findings correlate well with histopathology across a wide spectrum of brain tumor pathologies. CCA can provide a quick diagnosis and have a direct impact on patients' treatment and outcomes.

Intracranial Outcomes of De Novo Brain Metastases Treated With Osimertinib Alone in Patients With Newly Diagnosed EGFR-Mutant NSCLC

IntroductionPatients with EGFR-mutant NSCLC have a high incidence of brain metastases. The EGFR-directed tyrosine kinase inhibitor osimertinib has intracranial activity, making the role of local central nervous system (CNS)-directed therapies, such as radiation and surgery, less clear. MethodsPatients with EGFR-mutant NSCLC and brain metastases who received osimertinib as initial therapy after brain metastasis diagnosis were included. Individual lesion responses were assessed using adapted RANO-BM criteria. CNS progression and local progression of brain metastasis from osimertinib start were analyzed using cumulative incidence treating death as a competing risk. Overall survival was estimated using Kaplan-Meier methodology. ResultsThere were 36 patients who had a median interval from brain metastasis diagnosis to first-line osimertinib initiation of 25 days. In total, 136 previously untreated brain metastases were tracked from baseline. Overall, 105 lesions (77.2%) had complete response and 31 had partial response reflecting best objective response of 100%. Best response occurred at a median of 96 days (range: 28–1113 d) from baseline magnetic resonance imaging. This reflects a best objective response rate of 100%. Two-year overall survival was 80%. CNS progression rates at 1-, 2-, and 3-years post-osimertinib were 21%, 32%, and 41%, respectively. Lesion-level local failure was estimated to be 0.7% and 4.7% at 1- and 2-years post-osimertinib, respectively. No clinicodemographic factors including brain metastasis number were associated with post-osimertinib progression. ConclusionsIntracranial response to osimertinib is excellent for patients with EGFR-mutant NSCLC with de novo, previously untreated brain metastases. Very low local failure rates support a strategy of upfront osimertinib alone in selected patients.

Immune dysfunction revealed by digital spatial profiling of immuno-oncology markers in progressive stages of renal cell carcinoma and in brain metastases

BackgroundThe tumor microenvironment (TME) contributes to cancer progression and treatment response to therapy, including in renal cell carcinoma (RCC). Prior profiling studies, including single-cell transcriptomics, often involve limited sample sizes...

Depression in brain tumor patients—early detection and screening

BackgroundDepression is reported in up to 90% of cancer patients but to this date, a standardized screening tool for depression specifically modified for patients diagnosed with brain tumors is lacking. Thus, this study aims to develop an adapted screening tool and identify a suitable time slot for screening.MethodsSixty-one patients with brain lesions were interviewed prior to neurosurgical resection. For screening purposes, established depression scores were used. A study-specific questionnaire (SSQ) was developed based on patient interviews prior to the trial. Two subgroups were analyzed: patients with benign and patients with malignant tumors (including brain metastases). As a subgroup within malignant lesions, patients with glioblastoma (GBM) were also analyzed separately.ResultsOf patients, 87.5% with GBM presented with results > 16 points on the Center for Epidemiologic Studies Depression Scale (CES-D) after surgery. A decline in patients with benign brain tumors (p = 0.0058) and an increase in patients with malignant tumors (p = 0.0491) could be shown over time for CES-D scores. In this study, we established a new prototype screening tool for depression. In patients diagnosed with GBM, the number of patients needed to screen for identification of symptoms of depression was 1.59. Best time for screening was 35 days after surgery.ConclusionsConsidering the high prevalence and low number needed to screen of depression in patients diagnosed with GBM, we strongly encourage their routine screening during follow-up appointments (35 days after surgery). We encourage a plan to further establish the questionnaire developed in this pilot study.

Entrectinib (Rozlytrek)

CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses Entrectinib (Rozlytrek) capsules, 100 mg and 200 mg, oral. Indication: For the treatment of adult patients who have unresectable, locally advanced or metastatic extracranial solid tumours (including brain metastases), that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation and no satisfactory treatment options.

Abstract B038: Remodeling the extracellular matrix environment and establishing distinct immune cell profiles enables the formation of brain metastasis in non-small cell lung cancer adenocarcinoma

Abstract Dissemination of tumor cells from the primary site of the lung to distant sites in non-small cell lung cancer (NSCLC) is poorly understood. With distinct mutation signatures in patients, altering pathways is critical to preventing tumor cell dissemination to distant sites. Towards this, we characterized 21 "trios" patient-matched brain metastases (BrM), primary tumors (LT), and normal samples (LN), revealing a pattern of extracellular matrix remodeling which suppressed immune cell infiltration. Our objectives were to (i) determine if clinically sampled primary lung tumors encode gene expression patterns distinct from normal tissue, suggestive of increased tumor invasiveness including brain metastasis, and (ii) determine the biologic underpinning of immune-suppressive information carryover from primary lung tumor to brain metastasis. Transformation of the normal lung cells to primary tumor cells suggested a breakdown in ECM axes primarily governed by upregulation of collagen (COL1A1, COL1A2, COL3A1, COL10A1), fibronectin (FN1), and matrix metalloproteinases (MMP7, MMP9, MMP11, MMP12, MMP13, MMP14) genes. Collectively, the primary tumor cells used MMPs to break down the main components of lung ECM and reorganized collagen and fibronectin in the tumor microenvironment to facilitate migration and invasion. Migration and subsequent cell adhesion in the brain microenvironment revealed upregulation of neural cell adhesion molecule (NCAM1) and phosphoprotein 1 (SPP1). These changes in ECM profiles between LT and BrM signify primary tumor cells' adaptation in the brain microenvironment. Further computational deconvolution revealed reduced HLA class II gene expression (HLA-DMA, HLA-DOB, HLA-DPA1, HLA-DPB1, HLA-DQA2, HLA-DQB2, HLA-DRA) correlated with lower CIBERSORTx enrichment scores of immune cell populations in BrM. Overall, using the matched sequencing information, we will present the underlying signaling gradients that dictate dissemination of primary lung tumor cells to the brain environment in the background of altered ECM environment using cellular models harboring EGFR, KRAS, and ALK driver mutations. Citation Format: Albert R. Wang, Jared Brown, Andrew Baschnagel, Darya Buehler, Christina Kendziorski, Gopal Iyer. Remodeling the extracellular matrix environment and establishing distinct immune cell profiles enables the formation of brain metastasis in non-small cell lung cancer adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B038.

Entrectinib (Rozlytrek)


 CADTH recommends that Rozlytrek be reimbursed by public drug plans for the treatment of adults with unresectable locally advanced or metastatic extracranial solid tumours, including brain metastases, that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation if certain conditions are met.
 Rozlytrek should only be reimbursed to treat patients who have previously failed on all standard treatments for their current tumour site and who will be able to tolerate the treatment.
 Rozlytrek should only be reimbursed as a single-agent therapy and should not be initiated in patients who have primary CNS tumours or those who have received prior treatment with an NTRK inhibitor.

DDDR-05. ERK INHIBITION INCREASES SENSITIVITY TO ANTI-PD-1 THERAPY IN A MOUSE MODEL OF BRAF MUTANT MELANOMA BRAIN METASTASIS

Abstract BACKGROUND Immune checkpoint inhibitors (ICI) have revolutionized the landscape of cancer treatment, including brain metastases. However, only a subset of patients with brain metastases respond to ICI. Activating mutations in the mitogen-activated protein kinase (MAPK) signaling pathway, a key regulator of cell processes, are frequently found in brain metastases. LY3214996 (LY321) is a selective ERK 1/2 inhibitor that inhibits MAPK signaling and leads to regression of extracranial disease in preclinical models. Our objective was to evaluate whether with ERK inhibition (ERKi) can improve the efficacy of ICI in preclinical models of brain metastases. METHODS We tested sensitivity to LY321 in a BRAFV600E mutant, ICI resistant murine melanoma cell line (D4M) both in vitro and in vivo. To model brain metastases in vivo, we implanted D4M cells subcutaneously with subsequent intracranial implantation three days later. The treatment arms included LY321 and anti-PD-1 combination therapy, single agent therapies, and respective controls. We tested the efficacies of 2-week versus 4-week LY321 treatments, as well as 3-week treatment in an independent experiment. RESULTS D4M demonstrates in vitro sensitivity to LY321 (IC50 value of 4.75 µM). Our model demonstrated that LY321 in combination with anti-PD-1 improves both intracranial and extracranial disease control. Increased survival with combination therapy was observed with 3-week and 4-week LY321 administration. While individually, LY321 and anti-PD-1 produced better survival outcomes than control groups, combination therapy significantly outperformed both monotherapies. CONCLUSION Previous studies demonstrated that LY321 has minimal intracranial activity. However, we found that ERKi reduces intracranial tumor burden, with improved efficacy in combination with ICI in immunocompetent mice. Together, these data suggest that ERKi increases sensitivity to ICI therapy in pre-clinical brain metastasis models. Further investigation is needed to elucidate the mechanisms of this therapeutic approach, and to ultimately determine whether this combination will improve patient outcomes.

Factors Associated With Developing Neurocognitive Adverse Events in Patients Receiving Lorlatinib After Progression on Other Targeted Therapies

IntroductionThe safety profile of lorlatinib includes neurocognitive adverse events (NAEs). Baseline factors associated with developing NAEs remain poorly characterized. MethodsRecords from patients who received lorlatinib through prospective studies at Massachusetts General Hospital (MGH, n = 124) or the phase 1/2 B7461001 (NCT01970865; n = 248) study were reviewed to identify potential associations between comorbidities, baseline medications, and NAEs. ResultsMost patients experienced a NAE (MGH: 60%, B7461001: 49%). Cognitive effects occurred in 40% and 29% of patients in the MGH and B7461001 cohorts, respectively. Brain metastases (p = 0.008), brain radiation (p = 0.033), psychiatric illness (p = 0.008), psychiatric medications (p < 0.001), antiepileptics (p < 0.001), and stimulants (p = 0.026) were associated with developing cognitive effects in B7461001. Mood effects occurred in 36% and 23% of patients in the MGH and B7461001 cohorts, respectively. In the MGH cohort, psychiatric illness (p = 0.02) and stimulants (p = 0.01) were associated with developing mood effects whereas brain surgery (p = 0.020), psychiatric medications (p < 0.001), benzodiazepines (p = 0.002), and sedatives (p = 0.034) were associated with developing mood effects in B7461001. Psychotic effects were infrequent (MGH: 3%, B7461001: 9%) and were associated with brain surgery in the MGH cohort (p = 0.001) and age in B7461001 (p = 0.014). Speech effects were observed in 23% and 11% of patients in the MGH and B7461001 cohorts, respectively. Brain radiation (p = 0.012) and antiepileptics (p < 0.001) were associated with speech effects in B7461001. Dose reductions were implemented for 52% and 18% of patients with NAEs in MGH and B7461001 cohorts, respectively, with mitigating effect. ConclusionsNeurocognitive effects from lorlatinib are common. Lorlatinib-related NAEs may be influenced by multiple factors, including brain metastases, brain radiation, psychiatric illness, and use of neurotropic medications.

The Significance of MicroRNAs in the Molecular Pathology of Brain Metastases.

Simple SummaryBrain metastases are increasingly common in cancer patients and hurt survival and quality of life. Therefore, efforts are increasingly devoted to research into brain metastases and discovering new diagnostic approaches and therapeutic targets. MicroRNAs, which are involved in regulating most cellular processes, including metastasis, appear to be promising molecules in this regard. The number of studies on microRNAs is constantly increasing. This review aims to summarize the current knowledge on the importance of microRNAs in the pathobiology of brain metastases and to suggest possibilities for their use in diagnostic and therapeutic practice.Brain metastases are the most frequent intracranial tumors in adults and the cause of death in almost one-fourth of cases. The incidence of brain metastases is steadily increasing. The main reason for this increase could be the introduction of new and more efficient therapeutic strategies that lead to longer survival but, at the same time, cause a higher risk of brain parenchyma infiltration. In addition, the advances in imaging methodology, which provide earlier identification of brain metastases, may also be a reason for the higher recorded number of patients with these tumors. Metastasis is a complex biological process that is still largely unexplored, influenced by many factors and involving many molecules. A deeper understanding of the process will allow the discovery of more effective diagnostic and therapeutic approaches that could improve the quality and length of patient survival. Recent studies have shown that microRNAs (miRNAs) are essential molecules that are involved in specific steps of the metastatic cascade. MiRNAs are endogenously expressed small non-coding RNAs that act as post-transcriptional regulators of gene expression and thus regulate most cellular processes. The dysregulation of these molecules has been implicated in many cancers, including brain metastases. Therefore, miRNAs represent promising diagnostic molecules and therapeutic targets in brain metastases. This review summarizes the current knowledge on the importance of miRNAs in brain metastasis, focusing on their involvement in the metastatic cascade and their potential clinical implications.

Abstract 3859: Remodeling the extracellular matrix environment enables the dissemination of primary tumor cells through a chemokine gradient to establish brain metastasis in non-small cell lung cancer adenocarcinoma

Abstract Dissemination of tumor cells from the primary site of the lung to distant sites in non-small cell lung cancer (NSCLC) is poorly understood. With distinct mutation signatures in patients, altering pathways is critical to preventing tumor cell dissemination to distant sites. Towards this, we characterized 21 "trios" patient-matched brain metastases (BT), primary tumors (LT), and normal samples (LN), revealing a pattern of extracellular matrix remodeling which suppressed immune cell infiltration. Our objectives were to (i) determine if clinically sampled primary lung tumors encode gene expression patterns distinct from normal tissue, suggestive of increased tumor invasiveness including brain metastasis (ii) determine the biologic underpinning of immune-suppressive information carryover from primary lung tumor to brain metastasis and (iii) determine if synchronous and metachronous (time to disease) clinically sample brain metastases tumors converge on a common signaling mechanism. Transformation of the normal lung cells to primary tumor cells suggested a breakdown in ECM axes primarily governed by upregulation of collagen (COL1A1, COL1A2, COL3A1, COL10A1), fibronectin (FN1), and matrix metalloproteinases (MMP7, MMP9, MMP11, MMP12, MMP13, MMP14) genes. Collectively, the primary tumor cells used MMPs to break down the main components of lung ECM and reorganized collagen and fibronectin in the tumor microenvironment to facilitate migration and invasion. With a disorganized ECM present in LT, a chemokine gradient from LT to BT was discernable with sustained FN1 expression that allowed dissemination into the brain microenvironment. Migration and subsequent cell adhesion in the brain microenvironment revealed upregulation of neural cell adhesion molecule (NCAM1) and phosphoprotein 1 (SPP1). These changes in ECM profiles between LT and BT signify primary tumor cells' adaptation in the brain microenvironment. Further computational deconvolution revealed reduced HLA class II gene expression (HLA-DMA, HLA-DOB, HLA-DPA1, HLADPB1, HLA-DQA2, HLA-DQB2, HLA-DRA) correlated with a lower immune enrichment score of CD4+ T cells in synchronous tumors while metachronous tumors had distinct HLA expression profile. Overall, using the matched sequencing information, we will present the underlying signaling gradients that dictate dissemination of primary lung tumor cells to the brain environment in the background of altered ECM environment using cellular models harboring EGFR, KRAS, and ALK driver mutations cocultured with other cell types such as liver and breast. Citation Format: Albert R. Wang, Saniya Khullar, Jared Brown, Andrew Baschnagel, Darya Buehler, Christina Kendziorski, Gopal Iyer. Remodeling the extracellular matrix environment enables the dissemination of primary tumor cells through a chemokine gradient to establish brain metastasis in non-small cell lung cancer adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3859.

Real-world evaluation of the association between baseline metastatic patterns and clinical outcomes among patients with BRAF-positive metastatic melanoma.

9532 Background: While immunotherapy (IO) and BRAF-targeted therapy (TT) have benefit in BRAFV600 mutant (BRAF+) metastatic melanoma (MM), there is a paucity of real-world data on the impact of systemic therapy choice on outcomes based on key characteristics such as site and number of baseline metastases. Patients with &gt;1 baseline site and certain sites of metastases are also underrepresented or excluded in clinical trials. The aim of this study was to evaluate the association between these characteristics and survival among BRAF+ MM patients. Methods: This was a retrospective cohort study using the Novartis BRAF+ meLanoma patients ObsErvational (NOBLE) dataset – harmonized customized data from Flatiron and ConcertAI. It included patients ≥18 years, who received treatment with a first-line (1L) IO (anti-PD-1 mono or combination therapy ipilimumab + nivolumab) or TT (any BRAF/MEK-inhibitors) after 1/1/2014. Progression free survival (PFS) and overall survival (OS) for IO and TT were analyzed according to number (1, 2, 3+ sites) and location (brain, lung, liver, bone) of baseline metastasis. Treatment sequence from 1L to 2L (i.e. IO/TT vs TT/IO) were also compared for PFS and OS outcomes. Results: A total of 1,961 patients were included, with 620 patients (32%) on IO monotherapy, 501 patients (26%) on IO combo therapy, and 840 patients (43%) on TT in the 1L. When adjusted for sex, age, ECOG, and Charlson Comorbidity Index, there was no difference in PFS or OS between 1L IO mono, IO combo and TT therapies in patients who had 1, 2, or 3+ baseline metastases. For patients who had either baseline brain, liver, lung, or bone metastasis, there was no difference in PFS and OS between IO mono, IO combo, and TT combo therapies. Of the 521 patients included in the sequencing analysis (only patients who received 2L therapy), 239 patients (46%) had 1L IO/2L TT. There was no difference in PFS or OS between treatment sequences for patients with any number or location of baseline metastasis. Conclusions: In this real-world retrospective cohort study, there is no difference in survival between 1L TT and IO for BRAF+ MM patients. Outcomes are comparable regardless of number and location of metastases, including brain metastasis. Whether switching from 1L TT to IO before progression may account for differences compared to trial data will be explored further.[Table: see text]

A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors

IntroductionThis integrated analysis of a phase 1/2 study (NCT03046992) evaluated the efficacy and safety of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), in patients with advanced EGFR T790M-positive NSCLC after previous EGFR TKI therapy. MethodsAdults with EGFR mutation-positive NSCLC that progressed after prior EGFR-directed TKIs received once daily oral lazertinib 240 mg continuously until disease progression. Prior TKIs to treat T790M-positive NSCLC were prohibited. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included progression-free survival, overall survival, and intracranial ORR. ResultsA total of 78 patients received lazertinib 240 mg at 17 centers in South Korea. Among patients with T790M-positive tumors at baseline (N = 76), one (1.3%) had a complete response and 41 (53.9%) had partial responses, giving an ORR of 55.3% (95% confidence interval [CI]: 44.1–66.4). Median progression-free survival was 11.1 months (95% CI: 5.5–16.4). Median overall survival was not reached (median follow-up = 22.0 mo). In patients with measurable intracranial lesions (n = 7), one (14.3%) had a complete intracranial response and five (71.4%) had partial responses, giving an intracranial ORR of 85.7% (95% CI: 59.8%–100.0%). The most common treatment-emergent adverse events were rash (37.2%), pruritus (34.6%), and paresthesia (33.3%); most were mild to moderate in severity. Serious drug-related adverse events occurred in three patients (gastritis, pneumonia, pneumonitis). The major mechanism of resistance was EGFR T790M loss. ConclusionsLazertinib 240 mg/d has a manageable safety profile with durable antitumor efficacy, including brain metastases, in patients with advanced T790M-positive NSCLC after previous EGFR TKI therapy.

TRLS-05. A multicenter observational study of Cs-131 seeds embedded in a collagen carrier tile for newly diagnosed and recurrent operable intracranial neoplasms –Trial in progress

Abstract Background For patients with operable intracranial neoplasms, there are opportunities to augment local control beyond traditional methods, such as external beam radiation therapy (EBRT),. Brachytherapy, the implantation of radioactive sources into the resection cavity, can be useful in this setting by providing immediate initiation of radiation and limiting the exposure of surrounding normal tissue to radiation. Traditional intracranial brachytherapy methods have been limited by uneven dose distributions, complicated workflows, extended procedural times, the cost of dedicated equipment, and frequent adverse events. To address these issues, a permanently implanted device with Cs-131 radiation seeds embedded in a bioresorbable collagen carrier tile (GammaTile, GT Medical Technologies, Tempe, AZ USA) was developed. Described as surgically targeted radiation therapy (STaRT), it is FDA-cleared for use in newly-diagnosed malignant intracranial neoplasms and recurrent intracranial tumors, including brain metastases, and has demonstrated excellent safety and local control in early commercial use. The primary objectives of this multicenter, prospective, observational (phase IV) registry study [NCT04427384] are to evaluate “real-world” clinical outcomes and patient-reported outcomes that measure the safety and efficacy of STaRT using the device. Methods Subjects (N=600) at up to 50 enrolling sites undergoing resection of brain tumors of any pathology with intra-operative GammaTile placement are eligible for enrollment. We project 40% of enrollees to have brain metastasis. Tumor pathology, overall survival, radiation- and surgery-related adverse events, quality of life, serial MRIs, and timing of surgical bed recurrence and/or distant recurrence will be collected. The powered primary endpoint for recurrent brain metastases, surgical bed-progression free survival, will compare STaRT to standard-of-care benchmarks. This study will be the first observational study of resection plus GammaTile. Results will be used to benchmark clinical outcomes in the real-world setting, allow for comparisons to existing treatments, and facilitate the design of future clinical trials.

Prognostic significance of molecular subtype, metastatic site and primary tumor surgery for survival in primary metastatic breast cancer: A SEER-based study.

The incidence of primary metastatic breast cancer (PMBC) has not decreased despite the increasing popularity of mammography screening and data on the survival among these patients are limited. Therefore, we conducted an extensive population-based study to investigate the factors influencing the survival of patients with PMBC.We identified 14,306 patients with de novo stage-IV breast cancer using the Surveillance, Epidemiology, and End Results data from 2010 to 2015. The overall survival (OS) time and breast cancer-specific survival (BCSS) time were compared by the Kaplan-Meier method. Univariate and multivariate analyses were performed to determine the effect of different prognostic factors.Patients with hormone receptor positive/human epidermal growth factor receptor 2 positive showed the longest median survival time in OS (39 months) and BCSS (43 months), and those with triple negative exhibited the shortest in OS (11 months) and BCSS (12 months). We concluded that patients who had undergone primary tumor surgery had better survival than those who did not. The incidence of distant visceral metastasis in the whole cohort was as follows: bone, lung, liver, and brain. This study also substantiated that patients with only brain metastasis had poorer survival than patients with metastasis at multiple sites metastasis, not including brain metastasis (P < .0001).This study confirmed that molecular subtypes, metastatic site and primary tumor surgery were associated with the survival of PMBC patients.