CDK4/6 Inhibition Sensitizes Intracranial Tumors to PD-1 Blockade in Preclinical Models of Brain Metastasis.

PURPOSE: Brain metastases are associated with high morbidity and are often resistant to immune checkpoint inhibitors. We evaluated whether CDK4/6 inhibitor (CDKi) abemaciclib can sensitize intracranial tumors to programmed cell death protein 1 (PD-1) inhibition in mouse models of melanoma and breast cancer brain metastasis. EXPERIMENTAL DESIGN: Treatment response was evaluated in vivo using immunocompetent mouse models of brain metastasis bearing concurrent intracranial and extracranial tumors. Treatment effect on intracranial and extracranial tumor-immune microenvironments (TIME) was evaluated using immunofluorescence, multiplex immunoassays, high-parameter flow cytometry, and T-cell receptor profiling. Mice with humanized immune systems were evaluated using flow cytometry to study the effect of CDKi on human T-cell development. RESULTS: We found that combining abemaciclib with PD-1 inhibition reduced tumor burden and improved overall survival in mice. The TIME, which differed on the basis of anatomic location of tumors, was altered with CDKi and PD-1 inhibition in an organ-specific manner. Combination abemaciclib and anti-PD-1 treatment increased recruitment and expansion of CD8+ effector T-cell subsets, depleted CD4+ regulatory T (Treg) cells, and reduced levels of immunosuppressive cytokines in intracranial tumors. In immunodeficient mice engrafted with human immune systems, abemaciclib treatment supported development and maintenance of CD8+ T cells and depleted Treg cells. CONCLUSIONS: Our results highlight the distinct properties of intracranial and extracranial tumors and support clinical investigation of combination CDK4/6 and PD-1 inhibition in patients with brain metastases. See related commentary by Margolin, p. 257.

The ERK inhibitor LY3214996 augments anti-PD-1 immunotherapy in preclinical mouse models of BRAFV600E melanoma brain metastasis.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; however, only a subset of patients with brain metastasis (BM) respond to ICI. Activating mutations in the mitogen-activated protein kinase signaling pathway are frequent in BM. The objective of this study was to evaluate whether therapeutic inhibition of extracellular signal-regulated kinase (ERK) can improve the efficacy of ICI for BM. METHODS: We used immunotypical mouse models of BM bearing dual extracranial/intracranial tumors to evaluate the efficacy of single-agent and dual-agent treatment with selective ERK inhibitor LY3214996 (LY321) and anti-programmed death receptor 1 (PD-1) antibody. We verified target inhibition and drug delivery, then investigated treatment effects on T-cell response and tumor-immune microenvironment using high-parameter flow cytometry, multiplex immunoassays, and T-cell receptor profiling. RESULTS: We found that dual treatment with LY321 and anti-PD-1 significantly improved overall survival in 2 BRAFV600E-mutant murine melanoma models but not in KRAS-mutant murine lung adenocarcinoma. We demonstrate that although LY321 has limited blood-brain barrier (BBB) permeability, combined LY321 and anti-PD-1 therapy increases tumor-infiltrating CD8+ effector T cells, broadens the T-cell receptor repertoire in the extracranial tumor, enriches T-cell clones shared by the periphery and brain, and reduces immunosuppressive cytokines and cell populations in tumors. CONCLUSIONS: Despite the limited BBB permeability of LY321, combined LY321 and anti-PD-1 treatment can improve intracranial disease control by amplifying extracranial immune responses, highlighting the role of extracranial tumors in driving intracranial response to treatment. Combined ERK and PD-1 inhibition is a promising therapeutic approach, worthy of further investigation for patients with melanoma BM.

Association of MTHFR Polymorphisms With Leukoencephalopathy Risk in Patients With Primary CNS Lymphoma Treated With Methotrexate-Based Regimens.

OBJECTIVES: The folate antagonist high-dose methotrexate (HD-MTX) is integral to induction chemotherapy for primary CNS lymphoma (PCNSL); however, it can be associated with leukoencephalopathy. Methylenetetrahydrofolate reductase (MTHFR) is involved in intracellular folate depletion. We assessed whether MTHFR polymorphisms affect the risk of leukoencephalopathy. METHODS: We retrospectively searched our database at the Massachusetts General Hospital for newly diagnosed PCNSL treated with HD-MTX (without radiotherapy nor intrathecal chemotherapy). RESULTS: Among 68 patients with PCNSL, MTHFR polymorphisms were found in 60 individuals (88.2%) including a 677C→T genotype, a 1298A→C genotype, or a combined 677C→T/1298A→C genotype. Neither MTX clearance nor response to induction therapy was affected by specific genotypes, and complete response was achieved in 72.1% of patients by HD-MTX-based induction. However, the 1298A→C genotype was associated with increased frequency and severity of leukoencephalopathy over time (odds ratio 4.0, CI 1.5-11.4). Such genotype predicted treatment-induced leukoencephalopathy with a sensitivity of 71.0% and a specificity of 62.2% (area under the curve 0.67, CI 0.5-0.8; p = 0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was lower for the 1298A→C genotype. DISCUSSION: The MTHFR 1298A→C genotype may serve to identify patients with PCNSL at elevated risk of HD-MTX-induced leukoencephalopathy. This seems to translate into reduced survival, potentially due to decreased functional status.

Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.

PURPOSE: Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized. EXPERIMENTAL DESIGN: A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated. RESULTS: Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. CONCLUSIONS: These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179.

Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas.

High-grade meningiomas are associated with neuro-cognitive morbidity and have limited treatments. High-grade meningiomas harbor an immunosuppressive tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression may contribute to their aggressive phenotype. Here, we present the results of a single-arm, open-label phase 2 trial (NCT03279692) evaluating the efficacy of pembrolizumab, a PD-1 inhibitor, in a cohort of 25 evaluable patients with recurrent and progressive grade 2 and 3 meningiomas. The primary endpoint is the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints include progression-free and overall survival, best intracranial response, and toxicity. Our study has met its primary endpoint and achieved a PFS-6 rate of 0.48 (90% exact CI: 0.31-0.66) and a median PFS of 7.6 months (90% CI: 3.4-12.9 months). Twenty percent of patients have experienced one (or more) grade-3 or higher treatment-related adverse events. These results suggest that pembrolizumab exerts promising efficacy on a subset of these tumors. Further studies are needed to identify the biological facets within the meningioma TME that may drive response to immune-based therapies.

Genomic and transcriptomic correlates of immunotherapy response within the tumor microenvironment of leptomeningeal metastases.

Leptomeningeal disease (LMD) is a devastating complication of solid tumor malignancies, with dire prognosis and no effective systemic treatment options. Over the past decade, the incidence of LMD has steadily increased due to therapeutics that have extended the survival of cancer patients, highlighting the need for new interventions. To examine the efficacy of immune checkpoint inhibitors (ICI) in patients with LMD, we completed two phase II clinical trials. Here, we investigate the cellular and molecular features underpinning observed patient trajectories in these trials by applying single-cell RNA and cell-free DNA profiling to longitudinal cerebrospinal fluid (CSF) draws from enrolled patients. We recover immune and malignant cell types in the CSF, characterize cell behavior changes following ICI, and identify genomic features associated with relevant clinical phenomena. Overall, our study describes the liquid LMD tumor microenvironment prior to and following ICI treatment and demonstrates clinical utility of cell-free and single-cell genomic measurements for LMD research.

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis.

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.

Detection of Leptomeningeal Disease Using Cell-Free DNA From Cerebrospinal Fluid.

Importance: Leptomeningeal disease (LMD) is a devastating complication of cancer that is frequently underdiagnosed owing to the low sensitivity of cerebrospinal fluid (CSF) cytologic assessment, the current benchmark diagnostic method. Improving diagnostic sensitivity may lead to improved treatment decisions. Objective: To assess whether cell-free DNA (cfDNA) analysis of CSF may be used to diagnose LMD more accurately than cytologic analysis. Design, Setting, and Participants: This diagnostic study conducted in a neuro-oncology clinic at 2 large, tertiary medical centers assessed the use of genomic sequencing of CSF samples obtained from 30 patients with suspected or confirmed LMD from 2015 through 2018 to identify tumor-derived cfDNA. From the same CSF samples, cytologic analyses were conducted, and the results of the 2 tests were compared. This study consisted of 2 patient populations: 22 patients with cytologically confirmed LMD without parenchymal tumors abutting their CSF and 8 patients with parenchymal brain metastases with no evidence of LMD. Patients were considered positive for the presence of LMD if previous CSF cytologic analysis was positive for malignant cells. The analysis was conducted from 2015 to 2018. Main Outcomes and Measures: The primary outcome was the diagnostic accuracy of cfDNA analysis, defined as the number of tests that resulted in correct diagnoses out of the total number of tests assayed. Hypotheses were formed before data collection. Results: In total, 30 patients (23 women [77%]; median age, 51 years [range, 28-81 years]), primarily presenting with metastatic solid malignant neoplasms, participated in this study. For 48 follow-up samples from patients previously diagnosed via cytologic analysis as having LMD with no parenchymal tumor abutting CSF, cfDNA findings were accurate in the assessment of LMD in 45 samples (94%; 95% CI, 83%-99%), whereas cytologic analysis was accurate in 36 samples (75%; 95% CI, 60%-86%), a significant difference (P = .02). Of 43 LMD-positive samples, CSF cfDNA analysis was sensitive to LMD in 40 samples (93%; 95% CI, 81%-99%), and cytologic analysis was sensitive to LMD in 31 samples (72%; 95% CI, 56%-85%), a significant difference (P = .02). For 3 patients with parenchymal brain metastases abutting the CSF and no suspicion of LMD, cytologic findings were negative for LMD in all 3 patients, whereas cfDNA findings were positive in all 3 patients. Conclusions and Relevance: This diagnostic study found improved sensitivity and accuracy of cfDNA CSF testing vs cytologic assessment for diagnosing LMD with the exception of parenchymal tumors abutting CSF, suggesting improved ability to diagnosis LMD. Consideration of incorporating CSF cfDNA analysis into clinical care is warranted.

Craniopharyngiomas, including Recurrent Cases, Lack TERT Promoter Hotspot Mutations.

Adamantinomatous craniopharyngiomas (ACP) are characterized by alterations in the CTNNB1 gene while almost all papillary craniopharyngiomas (PCP) harbor a canonical V600E mutation in the BRAF gene. Although other recurrent driver genes have not been described to date in craniopharyngiomas, the heterogeneous clinical course of these tumors might be associated with the acquisition of further genomic alterations. It is well known that telomerase reverse transcriptase (TERT) promoter (TERTp) alterations, including mutations or methylation, upregulate the expression of TERT and increase telomerase activity, promoting tumorigenesis. We investigated whether TERTp mutations or methylation are associated with tumor relapse in a subset of craniopharyngiomas. Samples from 42 patients with histologically confirmed craniopharyngioma were retrieved. We determined TERTp, BRAF, and CTNNB1 hotspot mutations in all samples using targeted sequencing and the TERTp methylation status by methylation-specific polymerase chain reaction (PCR) in 30 samples. While BRAF V600E mutations and CTNNB1 mutations were detected in 12 (28.6%) and 21 patients (50%) in the initial tumors and subsequent recurrences, respectively, none of the patients in our cohort, including those with multiple relapses, harbored a TERTp mutation. Furthermore, TERTp methylation was detected in 14 out of 24 cases (58.3%) with available primary samples; however, no correlation between TERTp methylation with the pathological subtype, genotype, or tumor aggressiveness was detected. These data suggest that elevated telomerase activity via acquisition of TERTp mutations is an infrequent pathway in the tumorigenesis of craniopharyngiomas, regardless of their clinical course.

A rapid genotyping panel for detection of primary central nervous system lymphoma.

Diagnosing primary central nervous system lymphoma (PCNSL) frequently requires neurosurgical biopsy due to nonspecific radiologic features and the low yield of cerebrospinal fluid (CSF) studies. We characterized the clinical evaluation of suspected PCNSL (N = 1007 patients) and designed a rapid multiplexed genotyping assay for MYD88, TERT promoter, IDH1/2, H3F3A, and BRAF mutations to facilitate the diagnosis of PCNSL from CSF and detect other neoplasms in the differential diagnosis. Among 159 patients with confirmed PCNSL, the median time to secure a diagnosis of PCNSL was 10 days, with a range of 0 to 617 days. Permanent histopathology confirmed PCNSL in 142 of 152 biopsies (93.4%), whereas CSF analyses were diagnostic in only 15/113 samplings (13.3%). Among 86 archived clinical specimens, our targeted genotyping assay accurately detected hematologic malignancies with 57.6% sensitivity and 100% specificity (95% confidence interval [CI]: 44.1% to 70.4% and 87.2% to 100%, respectively). MYD88 and TERT promoter mutations were prospectively identified in DNA extracts of CSF obtained from patients with PCNSL and glioblastoma, respectively, within 80 minutes. Across 132 specimens, hallmark mutations indicating the presence of malignancy were detected with 65.8% sensitivity and 100% specificity (95% CI: 56.2%-74.5% and 83.9%-100%, respectively). This targeted genotyping approach offers a rapid, scalable adjunct to reduce diagnostic and treatment delays in PCNSL.

Emerging Immunotherapies in the Treatment of Brain Metastases.

Brain metastases account for considerable morbidity and mortality in patients with cancer. Despite increasing prevalence, limited therapeutic options exist. Recent advances in our understanding of the molecular and cellular underpinnings of the tumor immune microenvironment and the immune evasive mechanisms employed by tumor cells have shed light on how immunotherapies may provide therapeutic benefit to patients. The development and evolution of immunotherapy continue to show promise for the treatment of brain metastases. Positive outcomes have been observed in several studies evaluating the efficacy and safety of these treatments. However, many challenges persist in the application of immunotherapies to brain metastases. This review discusses the potential benefits and challenges in the development and use of checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and oncolytic viruses for the treatment of brain metastases. Future studies are necessary to further evaluate and assess the potential use of each of these therapies in this setting. As we gain more knowledge regarding the role immunotherapies may play in the treatment of brain metastases, it is important to consider how these treatments may guide clinical decision making for clinicians and the impact they may have on patients. IMPLICATIONS FOR PRACTICE: Immunotherapies have produced clinically significant outcomes in early clinical trials evaluating patients with brain metastases or demonstrated promising results in preclinical models. Checkpoint inhibitors have been the most common immunotherapy studied to date in the setting of brain metastases, but novel approaches that can harness the immune system to contain and eliminate cancer cells are currently under investigation and may soon become more common in the clinical setting. An understanding of these evolving therapies may be useful in determining how the future management and treatment of brain metastases among patients with cancer will continue to advance.

Publisher Correction: Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis.

An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1-3. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. The primary endpoint was rate of overall survival at 3 months (OS3). Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Twenty patients-17 with breast cancer, two with lung cancer and one with ovarian cancer-were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39-0.78) patients were alive at 3 months after enrollment. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab.

Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent AKT1 E17K Mutations in Foramen Magnum Meningiomas.

Objective Posterior fossa meningiomas are surgically challenging tumors that are associated with high morbidity and mortality. We sought to investigate the anatomical distribution of clinically actionable mutations in posterior fossa meningioma to facilitate identifying patients amenable for systemic targeted therapy trials. Methods Targeted sequencing of clinically targetable AKT1 , SMO , and PIK3CA mutations was performed in 61 posterior fossa meningioma using Illumina NextSeq 500 to a target depth of >500 × . Samples were further interrogated for 53 cancer-relevant RNA fusions by the Archer FusionPlex panel to detect gene rearrangements. Results AKT 1 ( E17K ) mutations were detected in five cases (8.2%), four in the foramen magnum and one in the cerebellopontine angle. In contrast, none of the posterior fossa tumors harbored an SMO ( L412F ) or a PIK3CA ( E545K ) mutation. Notably, the majority of foramen magnum meningiomas (4/7, 57%) harbored an AKT1 mutation. In addition, common clinically targetable gene fusions were not detected in any of the cases. Conclusion A large subset of foramen magnum meningiomas harbor AKT1 E17K mutations and are therefore potentially amenable to targeted medical therapy. Genotyping of foramen magnum meningiomas may enable more therapeutic alternatives and guide their treatment decision process.

Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors.

The interplay between the immune system and tumor progression is well recognized. However, current human breast cancer immunophenotyping studies are mostly focused on primary tumors with metastatic breast cancer lesions remaining largely understudied. To address this gap, we examined exome-capture RNA sequencing data from 50 primary breast tumors (PBTs) and their patient-matched metastatic tumors (METs) in brain, ovary, bone and gastrointestinal tract. We used gene expression signatures as surrogates for tumor infiltrating lymphocytes (TILs) and compared TIL patterns in PBTs and METs. Enrichment analysis and deconvolution methods both revealed that METs had a significantly lower abundance of total immune cells, including CD8+ T cells, regulatory T cells and dendritic cells. An exception was M2-like macrophages, which were significantly higher in METs across the organ sites examined. Multiplex immunohistochemistry results were consistent with data from the in-silico analysis and showed increased macrophages in METs. We confirmed the finding of a significant reduction in immune cells in brain METs (BRMs) by pathologic assessment of TILs in a set of 49 patient-matched pairs of PBT/BRMs. These findings indicate that METs have an overall lower infiltration of immune cells relative to their matched PBTs, possibly due to immune escape. RNAseq analysis suggests that the relative levels of M2-like macrophages are increased in METs, and their potential role in promoting breast cancer metastasis warrants further study.

Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases.

BACKGROUND: Activating mutations in the pathway of phosphatidylinositol-3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) occur in 43-70% of breast cancer brain metastasis patients. To date, the treatment of these patients presents an ongoing challenge, mainly because of the lack of targeted agents that are able to sufficiently penetrate the blood-brain barrier. GDC-0068 is a pan-Akt inhibitor that has shown to be effective in various preclinical tumor models as well as in clinical trials. The purpose of this study was to analyze the efficacy of GDC-0068 in a breast cancer brain metastases model. METHODS: In in vitro studies, antitumor activity of GDC-0068 was assessed in breast cancer cells of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutant and PIK3CA-wildtype breast cancer cell lines using cell viability and apoptosis assays, cell cycle analysis, and western blots. In vivo, the efficacy of GDC-0068 was analyzed in a PIK3CA-mutant breast cancer brain metastasis orthotopic xenograft mouse model and evaluated by repeated bioluminescent imaging and immunohistochemistry. RESULTS: GDC-0068 decreased cell viability, induced apoptosis, and inhibited phosphorylation of proline rich Akt substrate 40 kDa and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines compared with PIK3CA-wildtype cell lines. In vivo, treatment with GDC-0068 notably inhibited the growth of PIK3CA-mutant tumors and resulted in a significant survival benefit compared with sham, whereas no effect was detected in a PIK3CA-wildtype model. CONCLUSIONS: This study suggests that the Akt inhibitor GDC-0068 may be an encouraging targeted treatment strategy for breast cancer brain metastasis patients with activating mutations in the PI3K pathway. These data provide a rationale to further evaluate the efficacy of GDC-0068 in patients with brain metastases.

Upfront Surgical Resection of Melanoma Brain Metastases Provides a Bridge Toward Immunotherapy-Mediated Systemic Control.

BACKGROUND: Immune checkpoint blockade has systemic efficacy in patients with metastatic melanoma, including those with brain metastases (MBMs). However, immunotherapy-induced intracranial tumoral inflammation can lead to neurologic compromise, requiring steroids, which abrogate the systemic efficacy of this approach. We investigated whether upfront neurosurgical resection of MBM is associated with a therapeutic advantage when performed prior to initiation of immunotherapy. MATERIAL AND METHODS: An institutional review board-approved, retrospective study identified 142 patients with MBM treated with immune checkpoint blockade between 2010 and 2016 at Massachusetts General Hospital, of whom 79 received surgery. Patients were classified based on the temporal relationship between immunotherapy, surgery, and development of central nervous system metastases. Overall survival (OS) was calculated from the date of diagnosis of MBM until death from any cause. Multivariate model building included a prognostic Cox model of OS, the effect of immunotherapy and surgical sequencing on OS, and the effect of immunotherapy and radiation sequencing on OS. RESULTS: The 2-year overall survival for patients treated with cytotoxic T-lymphocyte antigen 4, programmed death 1, or combinatorial blockade was 19%, 54%, and 57%, respectively. Among immunotherapy-naïve melanoma brain metastases, surgery followed by immunotherapy had a median survival of 22.7 months (95% confidence interval [CI], 12.6-39.2) compared with 10.8 months for patients treated with immunotherapy alone (95% CI, 7.8-16.3) and 9.4 months for patients treated with immunotherapy followed by surgery (95% CI, 4.1 to ∞; p = .12). On multivariate analysis, immunotherapy-naïve brain metastases treated with immunotherapy alone were associated with increased risk of death (hazard ratio, 1.72; 95% CI, 1.00-2.99) compared with immunotherapy-naïve brain metastases treated with surgery followed by immunotherapy. CONCLUSION: In treatment-naïve patients, early surgical resection for local control should be considered prior to commencing immunotherapy. A prospective, randomized trial comparing the sequence of surgery and immunotherapy for treatment-naïve melanoma brain metastases is warranted. IMPLICATIONS FOR PRACTICE: In this retrospective study of 142 patients with melanoma brain metastases treated with immune checkpoint blockade, the development of melanoma brain metastases following immunotherapy was associated with decreased survival compared with diagnosis of immunotherapy-naïve brain metastases. The benefit of surgical intervention was seen in immunotherapy-naïve brain metastases in contrast to brain metastases that developed on immunotherapy. These results suggest that upfront local control with surgery for immunotherapy-naïve melanoma brain metastasis may provide a bridge toward immunotherapy-mediated systemic control.