An open-label, uncontrolled, single arm phase II trial of the PI3K inhibitor buparlisib in patients with melanoma brain metastases.

TPS9595 Background: The approval of effective BRAF +/- MEK inhibitors and immune checkpoint inhibitors has revolutionized the treatment of metastatic melanoma. However, available therapies appear to be less effective on cerebral than extracerebral metastases. Hyperactivation of the PI3K-AKT survival pathway is a prominent feature of melanoma brain metastases (MBM). This trial aims to determine the activity and safety of the PI3K inhibitor buparlisib in patients (pts) with MBM. Methods: The study enrolls adults suffering from MBM not eligible for neurosurgery or/and radiosurgery. Patients must have failed prior treatment with BRAF +/- MEK Inhibitors (BRAF-V600E mutated population) and anti-PD-1 or/and anti-CTLA-4 antibodies (BRAF wild-type population), respectively. Patients are treated with buparlisib 100 mg PO daily until disease progression or unacceptable toxicity. The Simon-Two-Step design for phase 2 studies was used to determine sample size. Assuming a response rate of 12.5% in comparison to historical 10% for chemotherapy 22 (8/14) pts would be required. If there are one or fewer responses in the first 8 pts the study would stop. Prespecified activity goal for the first stage of accrual was met; currently 11/22 pts are enrolled. Clinical trial information: NCT02452294.

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The PI3K inhibitor BKM120 has potent antitumor activity in melanoma brain metastases in vitro and in vivo.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e20050 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e20050-e20050 ◽

Cited By ~ 1

Author(s):

Friedegund Elke Meier ◽

Heike Niessner ◽

Jennifer Schmitz ◽

Andreas Schmid ◽

Carsten Calaminus ◽

...

Keyword(s):

Antitumor Activity ◽

Brain Metastases ◽

Metastatic Melanoma ◽

Conditioned Medium ◽

Melanoma Cells ◽

Pi3k Inhibitor ◽

Survival Pathway ◽

Melanoma Brain Metastases

e20050 Background: In melanoma, the RAF-MEK-ERK and PI3K-AKT signaling pathways play a major role in melanoma progression and drug resistance. On the basis of significant improvement in overall survival, the BRAF inhibitor vemurafenib gained FDA approval for the treatment of patients with metastatic BRAFV600E mutated melanoma. However, vemurafenib appears to be less effective in melanoma brain metastases, and brain metastases are the most common cause of death in patients with metastatic melanoma. In our previous study we reported that the AKT survival pathway is hyperactivated in melanoma brain metastases. Methods: The current study aims to investigate the mechanisms of AKT hyperactivation and the antitumor activity of the PI3K inhibitor BKM120 in melanoma brain metastases in vitro and in vivo. Results: To simulate the tumor environment of brain metastases and extracerebral metastases, brain and matched extracerebral metastatic melanoma cells were stimulated by astrocyte- and fibroblast-conditioned medium, respectively. Both brain and extracerebral metastatic melanoma cells stimulated by astrocyte-conditioned medium showed higher AKT activation and invasiveness in a transwell matrigel invasion assay than cells stimulated by fibroblast-conditioned medium. The PI3K inhibitor BKM120 inhibited the phosphorylation of AKT and the growth of >10 newly isolated cell lines derived from melanoma brain metastases achieving growth inhibition rates of up to 80%. These effects did not depend on BRAF, NRAS or KIT mutation status. Furthermore, BKM120 potently induced apoptosis in brain metastatic melanoma cells and significantly inhibited the tumor growth of human brain metastatic melanoma cells in the brain of nude mice as shown by MRI scans. Conclusions: Brain-derived factors induce hyperactivation of the AKT survival pathway and promote invasiveness and drug resistance of melanoma cells in the brain. The PI3K inhibitor BKM120 inhibits activation of the AKT survival pathway and demonstrates potent antitumor activity in melanoma brain metastases in vitro and in vivo.

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Melanoma Brain Metastases in the Era of Targeted Therapy and Checkpoint Inhibitor Therapy

Cancers ◽

10.3390/cancers13071489 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1489

Author(s):

John M. Rieth ◽

Umang Swami ◽

Sarah L. Mott ◽

Mario Zanaty ◽

Michael D. Henry ◽

...

Keyword(s):

Overall Survival ◽

Brain Metastases ◽

Checkpoint Inhibitor ◽

Checkpoint Inhibitors ◽

Performance Status ◽

Multivariable Analysis ◽

Treatment Strategies ◽

Poor Performance Status ◽

Poor Overall Survival ◽

Melanoma Brain Metastases

Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different treatment strategies in patients with melanoma brain metastases in the era of checkpoint inhibitors. Patients with brain metastases secondary to melanoma were identified at a single institution. Univariate and multivariable analyses were performed to identify baseline and treatment factors, which correlated with progression-free and overall survival. A total of 209 patients with melanoma brain metastases were identified. The median overall survival of the cohort was 5.3 months. On multivariable analysis, the presence of non-cranial metastatic disease, poor performance status (ECOG 2–4), whole-brain radiation therapy, and older age at diagnosis of brain metastasis were associated with poorer overall survival. Craniotomy (HR 0.66, 95% CI 0.45–0.97) and treatment with a CTLA-4 checkpoint inhibitor (HR 0.55, 95% CI 0.32–0.94) were the only interventions associated with improved overall survival. Further studies with novel agents are needed to extend lifespan in patients with brain metastases in melanoma.

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Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9508 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9508-9508

Author(s):

Georgina V. Long ◽

Victoria Atkinson ◽

Serigne Lo ◽

Alexander David Guminski ◽

Shahneen Kaur Sandhu ◽

...

Keyword(s):

Brain Metastases ◽

Braf Inhibitor ◽

Local Therapy ◽

Leptomeningeal Disease ◽

Open Label ◽

Phase 2 Study ◽

Melanoma Brain Metastases ◽

Secondary Endpoints ◽

Local Brain ◽

Clinical Trial Information

9508 Background: Preliminary data from the ABC (76 pts) and CheckMate 204 (94 pts) trials showed that nivo and nivo+ipi have activity in active melanoma brain metastases, with durable responses in a subset of pts. Here, we report updated 5-yr data from all pts enrolled on the ABC trial (NCT02374242). Methods: This open-label ph2 trial enrolled 3 cohorts of pts with active melanoma brain mets naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014-Apr 2017. Pts with asymptomatic brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3Wx4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets i) that failed local therapy, ii) with neuro symptoms and/or iii) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥wk12. Key secondary endpoints were IC PFS, overall PFS, OS, & safety. Results: A total of 76 pts (med f/u 54 mo) were enrolled; median age 59y, 78% male. For cohorts A, B and C: elevated LDH 51%, 58% and 19%; V600BRAF 54%, 56% and 81%; prior BRAFi 23%, 24%, 75%. Efficacy and toxicity are shown in the table. There were no treatment-related deaths. 1/17 deaths in cohort A & 4/16 in cohort B were due to IC progression only. Conclusions: Nivo monotherapy and ipi+nivo are active in melanoma brain mets, with durable responses in the majority of patients who received ipi+nivo upfront. A study of upfront ipi+nivo+/-SRS is underway (NCT03340129). Clinical trial information: NCT02374242. [Table: see text]

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Changing Landscape of Radiotherapy for Melanoma Brain Metastases, in Light of Newer Targeted Agents and Immune Checkpoint Inhibitors

Journal of Oncology Practice ◽

10.1200/jop.2016.012716 ◽

2016 ◽

Vol 12 (6) ◽

pp. 543-544 ◽

Cited By ~ 1

Author(s):

Mohammad K. Khan ◽

Walter J. Curran

Keyword(s):

Brain Metastases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Targeted Agents ◽

Melanoma Brain Metastases

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NIMG-04. PREDICTING THE BRAF MUTATIONAL STATUS IN PATIENTS WITH MELANOMA BRAIN METASTASES USING RADIOMICS - A BICENTRIC STUDY

Neuro-Oncology ◽

10.1093/neuonc/noab196.504 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi127-vi128

Author(s):

Anna-Katharina Meissner ◽

Robin Gutsche ◽

Norbert Galldiks ◽

Martin Kocher ◽

Stephanie T Juenger ◽

...

Keyword(s):

Brain Metastases ◽

Test Data ◽

Targeted Therapies ◽

Braf V600e Mutation ◽

Braf V600e ◽

Support Vector ◽

Mutational Status ◽

Melanoma Brain Metastases ◽

Group 2 ◽

Group 1

Abstract BACKGROUND The BRAF V600E mutation is present in approximately 50% of patients with melanoma and is an important prerequisite for a response to targeted therapies such as BRAF inhibitors. In the majority of patients, the BRAF mutational status is based on the analysis of tissue samples from the extracranial primary tumor only. Since the extracranial and intracranial BRAF mutational status may be discrepant, the additional information on the BRAF mutational status of melanoma brain metastases would be of clinical value, e.g., for the prediction of response to targeted therapies. Here, we evaluated the potential of MRI radiomics for the determination of the intracranial BRAF mutational status in patients with melanoma brain metastases. PATIENTS AND METHODS Fifty-nine patients with melanoma brain metastases from two university hospitals (group 1, 45 patients; group 2, 14 patients) were operated with subsequent genetic analysis of the intracranial BRAF mutational status. All patients underwent structural MRI preoperatively. Areas of contrast enhancement were manually segmented and analyzed. Group 1 was used for model training and validation, group 2 for model testing. After image preprocessing and radiomics feature extraction, a test-retest analysis was performed to identify robust features prior to feature selection. Finally, the best performing radiomics model was applied to the test data. Diagnostic performances were evaluated using receiver operating characteristic (ROC) analyses. RESULTS Twenty-two patients (49%) in group 1, and 6 patients (43%) in group 2 had an intrametastatic BRAF V600E mutation. Using the best performing six parameter radiomics signature, a linear support vector machine classifier yielded an area under the ROC curve (AUC) of 0.92 (sensitivity, 83%; specificity, 88%) in the test data. CONCLUSION The developed radiomics classifier allows a non-invasive prediction of the intracranial BRAF V600E mutational status in patients with melanoma brain metastases and may be of value for treatment decisions.

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BREAKWATER: Randomized phase 3 study of encorafenib (enco) + cetuximab (cetux) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps3619 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS3619-TPS3619

Author(s):

Scott Kopetz ◽

Axel Grothey ◽

Rona Yaeger ◽

Fortunato Ciardiello ◽

Jayesh Desai ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Performance Status ◽

Objective Response ◽

Braf Inhibitor ◽

Braf V600e ◽

Egfr Inhibitor ◽

Braf Mutations ◽

Open Label ◽

Phase 3 ◽

Previously Treated

TPS3619 Background: Approximately 10% of patients (pts) with mCRC have BRAF mutations (mostly V600E). 1L tx options for BRAFV600E mCRC are limited to cytotoxic chemotherapy ± anti-VEGF or anti-EGFR, or immune checkpoint inhibitors in pts with MSI-H tumors. In Europe, Japan, and USA, the combination of BRAF inhibitor enco + EGFR inhibitor cetux is approved for tx of BRAFV600E mCRC after prior therapy. In BEACON CRC, enco + cetux resulted in a median overall survival (OS) of 9.3 months (95% confidence interval [CI]: 8.0–11.3) and an objective response rate (ORR) of 19.5% (95% CI: 14.5%–25.4%) in previously treated pts with BRAFV600E mCRC (median follow-up: 12.8 months); 57.4% of pts had grade 3/4 adverse events (AEs); 9% discontinued due to AEs. Given the poor prognosis of pts with BRAFV600E mCRC and based on the efficacy and tolerability of enco + cetux from BEACON CRC, BREAKWATER will evaluate efficacy and safety of enco + cetux ± chemotherapy in tx-naive pts with BRAFV600E mCRC. Methods: BREAKWATER is an open-label, global, multicenter, randomized, phase 3 study with a safety lead-in (SLI). Approximately 60 and 870 pts will be enrolled in the SLI and phase 3 parts of the study, respectively. Pts must have BRAFV600E mCRC (determined using tumor tissue or blood); ECOG performance status 0/1; and adequate bone marrow, hepatic, and renal function. Pts in the SLI must have evaluable disease (RECIST v1.1) and have received ≤ 1 prior tx regimen; those previously treated with a BRAF or EGFR inhibitor, or both oxaliplatin and irinotecan, will be excluded. Pts in the phase 3 study must have measurable disease and be tx naive for metastatic disease. Study tx and endpoints are shown in the table. Enrollment began on 6 January 2021. Clinical trial information: NCT04607421. [Table: see text]

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Immune checkpoint inhibitors and radiosurgery for newly diagnosed melanoma brain metastases

Journal of Neuro-Oncology ◽

10.1007/s11060-018-2930-5 ◽

2018 ◽

Vol 140 (1) ◽

pp. 55-62 ◽

Cited By ~ 11

Author(s):

Tyler P. Robin ◽

Robert E. Breeze ◽

Derek E. Smith ◽

Chad G. Rusthoven ◽

Karl D. Lewis ◽

...

Keyword(s):

Brain Metastases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Newly Diagnosed ◽

Melanoma Brain Metastases

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CA184-240: A single-arm, open-label phase II study of vemurafenib followed by ipilimumab in patients with BRAF V600-mutated advanced melanoma (AM).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps9103 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS9103-TPS9103

Author(s):

F. Stephen Hodi ◽

Asim Amin ◽

Yvonne M. Saenger ◽

Gregory K. Pennock ◽

Troy H. Guthrie ◽

...

Keyword(s):

Disease Progression ◽

Treatment Guidelines ◽

Cytotoxic T Lymphocyte ◽

Human Monoclonal Antibody ◽

Resistance Mechanisms ◽

Braf V600e ◽

Phase Iii ◽

Open Label ◽

Ecog Ps ◽

Unacceptable Toxicity

TPS9103 Background: Ipilimumab (Ipi), a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 expressed on T cells, and vemurafenib (Vem), a small molecule inhibitor of BRAF V600-mutated kinase, are both approved treatments for AM. Ipi has shown improved overall survival (OS) in two randomized phase III trials of patients with previously treated (3 mg/kg monotherapy) and previously untreated (10 mg/kg plus dacarbazine) AM. Vem has shown improved OS in a randomized phase III trial of patients that harbor the BRAF V600E mutation. The most common drug-related adverse events (AEs) with Ipi monotherapy were immune-related GI tract and skin toxicities, which were generally manageable using treatment guidelines. The most common AEs with Vem were arthralgia, rash, and fatigue. Vem can induce rapid and substantial responses, and resistance mechanisms are a focus of current investigation. This study will evaluate the safety of Vem lead-in followed by Ipi (prior to resistance) in patients with BRAF V600-mutated AM. Methods: An estimated 45 patients will be enrolled. Eligible patients include those ≥18 years old with previously untreated AM, a BRAF V600 mutation, and an ECOG PS of 0 or 1. Major exclusion criteria are primary ocular melanoma, active brain metastases, and autoimmune disease. Patients will initially receive Vem for 6 weeks (960 mg twice daily). After a washout period of 3-10 days (per protocol), patients will be initiated on Ipi at 10 mg/kg (every 3 wk for 4 doses, then once every 12 wk beginning at week 24, until disease progression or unacceptable toxicity). Vem will be restarted at the time of disease progression on Ipi (no minimum time to restart) or unacceptable toxicity on Ipi (restart minimum of 1 mo after the last dose of Ipi). Vem will be restarted at the last dose level tolerated at the end of the lead-in phase. Patients will be followed every 12 weeks for toxicity and/or disease progression, and subsequently will be followed every 12 weeks for survival. The objectives of this study are to estimate the incidence of grade 3-4 drug-related AEs. Exploratory objectives include the evaluation of efficacy (OS). Clinical trial information: NCT01673854.

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