Sunday, June 2, 2013

Brain mets in Melanoma...the latest from ASCO


 Prospective analysis of predictors of survival in melanoma patients with brain metastases.
Authors:  Zakrzewski, et al.  NY University School of Med, Weill Medical College, Cornell.

Melanoma patients with brain mets have limited survival, and brain mets remain an exclusion criterion in most clinical trials.  Recent retrospective analysis at Sloan Kettering identified 4 clinical variables associated with worse post brain met survival.  This study looked to see if tumor features could improve predictability of post brain met survival and the reproducibility of that study.  89 patients were identified. Median post brain met survival = 5.75 months. Median follow-up = 4.2 months. Ulceration and mitotic index >3 were associated with worse post brain met survival.  Age greater than 65, >3 lesions, presence of neurologic symptoms, and extracranial metastases were also associated with worse survival.  CONCLUSION:  Data suggest that ulceration of the primary melanoma might indicate an adverse biologic behavior that impacts post brain met survival.

Association of high T-cell immune infiltrate and low hemorrhage in melanoma brain metastases with prolonged survival.
Authors:  Krauze, et al. University of Pittsburgh and Beth Israel Medical Center, Boston

Despite the poor prognosis of patients with brain mets, several patients have prolonged survival.  We id'd patients who have undergone craniotomy for melanoma brain mets and examined clinical histories, pathology, and genome expression profiling of archived tissues.  Factors associated with prolonged survival were high immune infiltrate plus low hemorrhage, present melanin, and recursive partitioning analysis class 1.  CONCLUSION: High peritumoral T-cell infiltrates are associated with prolonged survival.  High tumor hemorrhage, an adverse prognostic sign, reflects aggressive melanoma cells that migrate and invade the brain.

Phase II trial of ipi monotherapy in melanoma patients with brain metastases.
Authors: Lawrence, et al.  Mass General, Boston. The Angeles Clinic, Santa Monica. Beth Israel, Boston. Vanderbilt, Nashville. Yale, New Haven. Loyola, Maywood, IL. Indiana University, Indianapolis. Dana-Farber Boston. Bristol-Meyers Squibb, NJ. University of Washington, Seattle.

Ipilimumab, a human monoclonal antibody that blocks CTLA-4 has activity in advanced melanoma.  This phase II trial attempted to assess ipi safety and activity in melanoma patients with brain mets.  Patients had measurable brain mets with at least one lesion >0.5cm and/or 2 lesions greater than 0.3cm, and none greater than 3cm in diameter.  Prior whole brain or stereotactic radiation to non-index lesions were allowed.  Ipi 10mg/kg was given IV every 3 weeks for 4 doses.  Responding or stable patients could receive maintenance ipi at 10mg/kg every 12 weeks.  Total of 72 patients in two arms...arm B still ongoing.  No association between brain edema or cerebral hemorrhage and objective response.  Of 51 patients in Arm A, at week 12: 4/51 had a partial response, 5/51 had stable disease, with additional unconfirmed responses.  Duration of responses ranged from 3 to 12+ months and duration of stable disease ranged from 1-7 months.  CONCLUSION:  Ipi has a similar level of activity in brain and non-CNS lesions.  Analyses are ongoing and final data will be presented.

Outcome with stereotactic radiosurgery (SRS) and ipilimumab (ipi) for malignant melanoma brain metastases.
Authors: Shoukat, et al.  Emory, Atlanta, GA.

Retrospective analysis to determine if this combination is safe and improves overall survival.  Patients with melanoma brain mets who underwent SRS b/w 1998-2010 (n=124) were compared to those who additionally got ipi (n=11).  Median overall survival for the entire cohort was 6.9 months.  Patients in the ipi group had an improved median overall survival of 28.3 months.  CONCLUSION:  Uses of SRS with ipi appears to be safe and associated with an impressive increase in median overall survival.

Survival of melanoma patients with brain metastases treated with ipilimumab combined with stereotactic radiosurgery.
Authors:  Tazi, et al. Medical University of South Carolina, Charleston.

Retrospective record review, we report the outcome of patients with stage IV melanoma with brain mets treated with ipi and SRS.  Twelve of 30 patients treated with ipi had brain mets. Median age = 66 years. Group A = no brain mets.  Group B = brain mets.  33% of both groups died as of last f/u. Median survivals from date of Stage IV for Group A = 29.1 months and for Group B = 32.9 months.  Estimated 2 year survival rates from date of cycle 1 ipi administration for A = 58% and for B = 55%.  CONCLUSION:  Survival of patients with melanoma brain mets treated with ipi combined with SRS may be comparable to patients without brain mets.

Response rate to vemurafenib in BRAF-positive melanoma brain metastases.
Authors: Dzienis, et al.  Princess Alexandra Hospital Brisbane, Australia.

Responses to dabrafenib have already been reported in over 50% of patients.  We aimed at assessing response rate to vemurafenib.  Patients with BRAF positive melanoma and asymptomatic brain mets were included.  Conclusion:  Vemurafenib resulted in 50% CNS response rate.  Prospective comparison to dabrafenib may be warranted.


Survival patterns following brain metastases for patients with melanoma in the targeted therapy era.
Authors:  Wattson, et al.  Mass General Hosp, Dpt of Radiation Oncology and Cancer Center, Harvard.

Survival from metastatic melanoma has been significantly prolonged by molecularly targeted therapy, specifically BRAF inhibitors (BRAFi) for patients with V600E mutation.  This is a retrospective review of 191 patients with metastatic melanoma.  Of 98 patients who developed brain mets, median f/u after first one was 7.7 months (15.5 mo for the 25 living patients) and 33 were treated with BRAFi. Median duration of BRAFi use was 5.9 months, which preceded brain mets in 30%, was concurrent in 18%, and followed first brain met in 52%.  Ipi or anti-PD1/PD-L1 was given to 58% of patients who got BRAFi and 95% of those who did not.  CONCLUSION:  Survival for patients with brain mets from BRAF mutant melanoma can significantly exceed the often anticipated 4-6 months, particularly if a BRAFi is initiated after brain mets arise.

 TABLE:                                         Median survival, months            N                  
BRAF mutant, with BRAFi                           13.2                             33
BRAFi started pre brain                                5.6                              16
BRAFi started post brain met             23.2                          17
BRAF mutant, no BRAFi                               6.7                               7
BRAF wild type                                              8.0                              34
BRAF unknown                                              6.5                              24


To those in need, hope this helps.  All their words, not mine!!!  My take....next.  Peace - c

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