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).

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]

A randomized phase II study of nivolumab or nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases (mets): The Anti-PD1 Brain Collaboration (ABC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9508-9508 ◽  
Author(s):  
Georgina V. Long ◽  
Victoria Atkinson ◽  
Alexander M. Menzies ◽  
Serigne Lo ◽  
Alexander David Guminski ◽  
...  
Keyword(s):  
Antitumour Activity ◽  
Braf Inhibitor ◽  
Local Therapy ◽  
Progression Free Survival ◽  
Leptomeningeal Disease ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Treatment Naïve ◽  
Secondary Endpoints ◽  
Previously Treated

9508 Background: Nivolumab (nivo) and the combination of nivo + ipilimumab (ipi) improve response rates (RR) and progression-free survival (PFS) compared with ipi alone in clinical trials of metastatic melanoma pts, but pts with untreated brain mets were excluded. Brain mets are a major cause of morbidity and mortality in melanoma and their management is critical. We sought to determine the antitumour activity and safety of nivo and nivo+ipi in pts with active melanoma brain mets (NCT02374242). Methods: This open-label, ph II trial enrolled 3 cohorts of pts naïve to anti-PD1/PDL1/PDL2/CTLA4 from Nov 2014 - Feb 2017. Pts with asymptomatic melanoma brain mets with no prior local brain therapy were randomised to cohort A (nivo 1mg/kg + ipi 3mg/kg, Q3W x4, then nivo 3mg/kg Q2W) or cohort B (nivo 3mg/kg Q2W). Cohort C (nivo 3mg/kg Q2W) had brain mets 1) that failed local therapy (new +/- progressed in previously treated met), 2) were neurologically symptomatic and/or 3) with leptomeningeal disease. Prior BRAF inhibitor (BRAFi) was allowed. The primary endpoint was best intracranial response (ICR) ≥ wk12. Secondary endpoints were best extracranial response (ECR), best overall response (OR), IC PFS, EC PFS, overall PFS, OS, and safety. Results: A total of 66 pts (med f/u 14 mo) were included in this analysis of total 76 planned; median age 60y, 77% male. For cohorts A, B and C: elevated LDH 48%, 58% and 19%; V600BRAF 44%, 56% and 81%; prior BRAFi 24%, 24%, 75%. Table shows RR, PFS and OS. ICR in cohort A treatment naïve vs prior BRAFi was 53% vs 16%. Treatment-related gd 3/4 toxicity in cohorts A, B and C were 68%, 40% and 56%, respectively. There were no treatment-related deaths. Conclusions:Nivo monotherapy and ipi+nivo and are active in melanoma brain mets. Ipi+nivo had reduced activity in pts who progressed on BRAFi. Pts with symptomatic brain mets, leptomeningeal mets or previous local therapy responded poorly to nivo alone. Clinical trial information: NCT02374242. [Table: see text]

NCMP-03. ANATOMIC AND SURGICAL FACTORS PREDICT DEVELOPMENT OF LEPTOMENINGEAL DISEASE IN PATIENTS WITH METASTATIC MELANOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi147-vi147
Author(s):  
Stephen Lowe ◽  
Christopher Wang ◽  
Amanda Brisco ◽  
John Arrington ◽  
Kamran Ahmed ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Primary Melanoma ◽  
Female Gender ◽  
Causative Factor ◽  
Leptomeningeal Disease ◽  
Melanoma Brain Metastases ◽  
Highly Correlated ◽  
Periventricular Lesions ◽  
Dural Metastasis

Abstract Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, portending a poor prognosis with an estimated median survival of 4-6 weeks if left untreated. Several reports have suggested surgical resection as a potential causative factor. Herein, we explore if surgical and anatomical factors are correlated with development of LMD in patients with melanoma brain metastases. METHODS: Patients treated at our institution between 1999-2019 for primary melanoma with brain metastasis were compiled into a database based on ICD9/10 coding. 1,079 patients with melanoma brain metastases and appropriate imaging were identified, and 834 patients with a minimum of 3 months’ follow up were included. Patients were dichotomized by development of LMD or lack thereof, and categorized into an overall cohort, and surgical and non-surgical cohorts. Anatomic factors and ventricular access during surgery were investigated as possible correlative factors for the development of LMD. RESULTS: In the overall cohort, female gender(p=0.033), presence of dural metastasis(p=0.018), presence of periventricular lesions(p< .001), presence of intraventricular lesions(p< .001), and ventricular access during surgery(p< .001) were significantly associated with LMD. Patients undergoing surgery, or those undergoing surgery without ventricular access, were not at higher risk of LMD. On multivariate analysis, female gender(p=.033), presence of periventricular lesions (p< .001), presence of intraventricular lesions(p< .002), and presence of dural metastasis(p=0.032) were significantly associated with development of LMD. In patients who had surgery, iatrogenic ventricular access(p< .001) was significantly correlated with LMD. In the group of patients without surgery, those with periventricular lesions had significantly higher odds of LMD(p< .001). CONCLUSIONS: In a retrospective cohort of patients with melanoma metastatic to the brain, surgical intervention does not increase odds of LMD; however, iatrogenic access to the CSF space during surgery is highly correlated with LMD development. Anatomic contact with the CSF space predicts LMD regardless of surgical status.

scholarly journals Melanoma brain metastases: review of histopathological features and immune-molecular aspects

2020 ◽  
Vol 7 (2) ◽  
pp. MMT44
Author(s):  
Lorenzo Salvati ◽  
Mario Mandalà ◽  
Daniela Massi
Keyword(s):  
Brain Metastases ◽  
Local Therapy ◽  
Advanced Melanoma ◽  
Overall Survival Rate ◽  
Histopathological Features ◽  
Dismal Prognosis ◽  
Asymptomatic Patients ◽  
Melanoma Brain Metastases ◽  
Molecular Aspects

Patients with melanoma brain metastases (MBM) have a dismal prognosis, but the unprecedented advances in systemic therapy alone or in combination with local therapy have now extended the 1-year overall survival rate from 20–25% to nearing 80–85%, mainly in asymptomatic patients. The histopathological and molecular characterization of MBM and the understanding of the microenvironment are critical to more effectively manage patients with advanced melanoma and to design biologically driven clinical trials. This review aims to give an overview of the main histopathological features and the immune-molecular aspects of MBM.

Multidisciplinary Approach to Brain Metastasis from Melanoma: The Emerging Role of Systemic Therapies

2013 ◽  
pp. 393-398 ◽  
Author(s):  
Georgina V. Long ◽  
Kim A. Margolin
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Local Therapy ◽  
Whole Brain Radiotherapy ◽  
Brain Radiotherapy ◽  
First Line Therapy ◽  
Melanoma Brain Metastases

Melanoma brain metastases are common, difficult to treat, and carry a poor prognosis. Until recently, systemic therapy was ineffective. Local therapy (including surgery, stereotactic radiotherapy, and whole brain radiotherapy) was considered the only option for a chance of disease control in the brain, and was highly dependent on the patient's performance status and age, number and size of brain metastases, and the presence of extracranial metastases. Since 2010, three drugs have demonstrated activity in progressing or “active” brain metastases including the anti-CTLA4 antibody ipilimumab (phase II study of 72 patients), and the BRAF inhibitors dabrafenib (phase II study of 172 patients, both previously treated and untreated brain metastases) and vemurafenib (a pilot study of 24 patients with heavily pretreated brain metastases). The challenge and unanswered question for clinicians is how to sequence all the available therapies, both local and systemic, to optimize the patient's quality of life and survival. This is an area of intense clinical research. The treatment of patients with melanoma brain metastases should be discussed by a multidisciplinary team of melanoma experts including a neurosurgeon, medical oncologist, and radiation oncologist. Important clinical features that help determine appropriate first line therapy include single compared with solitary brain metastasis, resectablity, BRAF mutation status of melanoma, rate of progression/performance status, and the presence of extracranial disease.

Outcome with stereotactic radiosurgery (SRS) and ipilimumab (Ipi) for malignant melanoma brain metastases.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3032-3032 ◽  
Author(s):  
Sana Shoukat ◽  
David Mitchell Marcus ◽  
Monica Rizzo ◽  
David H. Lawson ◽  
Yuan Liu ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Brain Metastases ◽  
Local Control ◽  
Performance Status ◽  
Ecog Performance Status ◽  
Entire Cohort ◽  
Kaplan Meier ◽  
Patient Reported ◽  
Melanoma Brain Metastases ◽  
Secondary Endpoints

3032 Background: SRS with Ipi for brain metastases from malignant melanoma has been explored for overall survival (OS) (Knisely JP, Yu JB, Flanigan J, et al. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg. 2012;117:227-33). We present the first retrospective analysis to determine if this combination is safe and improves OS, while accounting for lactate dehydrogenase (LDH). Methods: Patients with melanoma brain metastases who underwent SRS between 1998-2010 (n=124) were compared with those who additionally received Ipi (n=11). The primary endpoint was median OS from time of SRS, calculated using Kaplan-Meier method. Cox proportional hazard model was carried out for univariate and multivariable survival analysis. The secondary endpoints were local control at initial site of SRS, anywhere intra-cranial failure, need for repeat SRS, and toxicity. Results: Median OS for the entire cohort was 6.9 months. Patients in the Ipi group had an improved median OS of 28.3 months vs. 6.8 months in the non-Ipi group (p = 0.013). No difference was noted in local control, anywhere intracranial failures, toxicity (radionecrosis, hemorrhage, patient reported memory deficits), or need for repeated SRS. MVA (Table) showed that Ipi independently predicted for improved OS even when taking into account LDH and ECOG performance status. The only confounding factor within the Ipi group was younger age of the Ipi cohort (43 vs. 55 yrs, p = 0.006). Conclusions: Use of SRS with Ipi appears to be safe and associated with an impressive increase in median OS in patients with brain metastases from malignant melanoma; this combination should be further investigated. [Table: see text]

Results of a phase II trial of docetaxel (DOC), bevacizumab (BEV), and androgen deprivation therapy (ADT) for biochemical relapse (BCR) after definitive local therapy for prostate cancer (PC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 54-54
Author(s):  
Rana R. McKay ◽  
Kathryn P. Gray ◽  
Julia H. Hayes ◽  
Glenn J. Bubley ◽  
Jonathan E. Rosenberg ◽  
...  
Keyword(s):  
Specific Antigen ◽  
Local Therapy ◽  
Primary Treatment ◽  
Entire Cohort ◽  
Psa Response ◽  
Secondary Endpoints ◽  
Psa Progression ◽  
Grade 3 ◽  
Clinical Trial Information

54 Background: Despite primary treatment for localized PC, 20-30% of men experience a BCR, detected by a rise in prostate-specific antigen (PSA). Though 30% of these patients develop metastatic disease, the optimal treatment of men with BCR has yet to be determined. In this trial, we evaluate the efficacy of DOC, BEV, and ADT for men with BCR after local therapy for PC. Methods: 41 men with a BCR and PSA doubling time of ≤10 months (mos) were enrolled. Patients received 4 cycles of DOC (75 mg/m2) every 3 weeks, 8 cycles of BEV (15 mg/kg) every 3 weeks, 18 mos of a luteinizing-hormone releasing hormone (LHRH) agonist, and 15 mos of bicalutamide (50 mg daily) beginning after completion of DOC. The primary endpoint was the proportion of patients free from PSA-progression 1 year after completion of ADT. Secondary endpoints included PSA response, testosterone recovery, and toxicity. Results: Median follow-up was 27.6 mos. Median age at diagnosis was 58 years. Median PSA at diagnosis was 6.7 ng/mL, with the majority of patients (59%) having Gleason 7 disease. Most patients underwent radical prostatectomy +/- radiation therapy (n=36). At baseline, 33 men (81%) had a normal testosterone (> 240 ng/dL). The table describes the PSA responses for the entire cohort. 10 men (28%) had a normal testosterone 6 mos after completing ADT. 17 men (47%) had a normal testosterone 12 mos after completing ADT, of whom 5 (29%) had a PSA <0.2 ng/mL at that time. There were 15% grade 1, 34% grade 2, 39% grade 3, and 12% grade 4 adverse events (AEs). The most frequent grade 3-4 AEs included neutropenia (24%), febrile neutropenia (11%), and hypertension (9%). Conclusions: DOC, BEV, and ADT for BCR resulted in complete responses in 16 men (44%) 1 year after completion of therapy. Longer follow-up is needed to determine the efficacy of this regimen. Clinical trial information: NCT00658697. [Table: see text]

A randomized phase 2 study of nivolumab and nivolumab combined with ipilimumab in patients (pts) with melanoma brain metastases: The Anti-PD1 Brain Collaboration (ABC Study).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. TPS9591-TPS9591 ◽  
Author(s):  
Georgina V. Long ◽  
Victoria Atkinson ◽  
Alexander M. Menzies ◽  
Alexander David Guminski ◽  
Shahneen Kaur Sandhu ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Melanoma Brain Metastases ◽  
Randomized Phase 2

scholarly journals P.109 Increased survival when combining BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases

2016 ◽  
Vol 43 (S2) ◽  
pp. S45-S46
Author(s):  
A Wolf ◽  
A Pavlick ◽  
M Wilson ◽  
J Silverman ◽  
D Kondziolka
Keyword(s):  
Overall Survival ◽  
Brain Metastases ◽  
Stereotactic Radiosurgery ◽  
Systemic Disease ◽  
Braf Inhibitor ◽  
Braf Inhibitors ◽  
Actuarial Survival ◽  
Early Management ◽  
Melanoma Brain Metastases ◽  
The Impact

Background: The purpose of the study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. Methods: We prospectively collected treatment outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Results: The median overall survival from first SRS procedure was 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54% and 41% at 6 and 12 months after radiosurgery, in contrast to 28% and 19% for BRAF-WT. Overall survival was extended for patients on a BRAF inhibitor if initiated at or after the first SRS. The local control rate did not differ based on BRAF status and was over 90%. Patients with higher KPS, fewer treated metastases, controlled systemic disease, RPA class 1 and BRAF-M patients had extended overall survival. Conclusions: Patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival. As patients live longer due to more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.

scholarly journals LMD-19. Anatomic and Surgical Factors Predict Development of Leptomeningeal Disease in Patients with Metastatic Melanoma

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii11-iii11
Author(s):  
Stephen Lowe ◽  
Christopher P Wang ◽  
Amanda Brisco ◽  
Kamran Ahmed ◽  
Michael A Vogelbaum ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Univariate Analysis ◽  
Primary Melanoma ◽  
Female Gender ◽  
Causative Factor ◽  
Leptomeningeal Disease ◽  
Melanoma Brain Metastases ◽  
Highly Correlated ◽  
Periventricular Lesions ◽  
Dural Metastasis

Abstract Background Leptomeningeal disease (LMD) is a devastating complication of systemic malignancy, portending a poor prognosis with an estimated median survival of 4–6 weeks if left untreated. Several reports have suggested surgical resection, particularly piecemeal resection, as a potential causative factor. Herein, we explore if surgical and anatomical factors are correlated with development of LMD in patients with melanoma brain metastases. Methods Patients treated at our institution between 1999–2019 for primary melanoma with brain metastasis were compiled into a database based on ICD9/10 coding. 1,079 patients with melanoma brain metastases and appropriate imaging were identified, and 834 patients with a minimum of 3 months’ follow up were included. Patients were dichotomized by development of LMD or lack thereof. General demographic information, surgical and anatomic data, and ventricular access during surgery were investigated as possible correlative factors for the development of LMD. Results On univariate analysis, female gender (p=0.033), presence of dural metastasis (p=0.018), presence of periventricular lesions (p&lt;.001), presence of intraventricular lesions (p&lt;.001), and ventricular access during surgery (p&lt;.001) were significantly associated with LMD. Patients undergoing surgery, or those undergoing surgery without ventricular access, were not at higher risk of LMD. Administration of immunotherapy, either as first-line or salvage therapy, did not impact rates of LMD. On multivariate analysis, female gender (p=.033), presence of periventricular lesions (p&lt;.001), presence of intraventricular lesions (p&lt;.002), and presence of dural metastasis (p=0.032) were significantly associated with development of LMD. In patients who had surgery, iatrogenic ventricular access (p&lt;.001) was significantly correlated with LMD. Conclusions In a retrospective cohort of patients with melanoma metastatic to the brain, those patients with pre-existing lesions in contact with the CSF space are more likely to develop LMD than those who do not. In addition, iatrogenic access to the CSF space during surgery is highly correlated with LMD development.

Sign in / Sign up

Export Citation Format

Share Document