Multimodality Care Is Improving Survival for Patients with Melanoma Brain Metastasis

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The timing and order of treatment modalities to address brain metastases is complex. MSK’s multidisciplinary brain metastasis experts create a customized treatment plan for each patient, ensuring multimodality treatments are delivered in the best order, as quickly as possible, for the greatest benefits.

The timing and order of treatment modalities to address brain metastases is complex. MSK’s multidisciplinary brain metastasis experts create a customized treatment plan for each patient, ensuring multimodality treatments are delivered in the best order, as quickly as possible, for the greatest benefits.

Overall survival (OS) for patients with melanoma brain metastasis treated at Memorial Sloan Kettering Cancer Center has increased significantly over the past five years, up to 13 months, according to our research published recently in Cancer.1 This increased OS duration, much higher than the historical survival of four to six months,2–6 can be traced to advances in targeted therapies and immunotherapies, as well as increased use of surgery and stereotactic radiosurgery (SRS), where needed.1

Numerous advances in targeted therapies for melanoma, including BRAF and MEK inhibitors and the checkpoint inhibitors ipilimumab, nivolumab, and pembrolizumab, have led to significant OS improvements in patients with metastatic melanoma.7–15 Further, studies have found that patients with melanoma brain metastasis respond to many of these therapies.16–21 For example, 58% of patients with BRAF V600E-positive melanoma brain metastases responded to combination treatment with dabrafenib and trametinib in the COMBI-MB trial (NCT02039947),20 and 46% to 57% of patients with untreated active brain metastases showed intracranial benefit to the combination of nivolumab and ipilimumab in the ABC (NCT02374242) and CheckMate 204 (NCT02320058) trials, respectively.19, 21

MSK researchers pioneered BRAF and MEK inhibitors, the use of immunotherapy in melanoma patients, and brain SRS, which is associated with significantly improved local control rates, fewer cognitive side effects, and improved quality of life for patients with brain metastasis than whole brain irradiation.22, 23 Today, more clinical trials are beginning to include patients with melanoma brain metastasis. Yet little data exists on how current treatments have affected survival or revealed prognostic factors associated with better or worse survival.

Our Study—and the Implications of Our Findings

We conducted a retrospective study of 425 patients with 2,488 melanoma brain metastases diagnosed and managed with multimodality treatment at MSK between 2010 and 2019. Median OS was 8.9 months. However, patients diagnosed between 2015 and 2019 experienced a significantly longer OS of 13 months, compared with only 7 months for those diagnosed between 2010 and 2014 (P = 0.0003). The one-year survival rate was 52.4 percent for patients diagnosed in the latter five years, compared with 35.1% for those diagnosed in the earlier five years (P = 0.0003), with a median follow-up of 1.7 years for survivors in the latter group.1

Our empirically derived cutoff for the most significant increase in survival between 2014 and 2015 coincided with the US Food and Drug Administration’s approval of PD-1 blockade with nivolumab and pembrolizumab, and the subsequent approvals of the combinations ipilimumab plus nivolumab, dabrafenib plus trametinib, and vemurafenib plus cobimetinib.1

Worse prognosis was significantly associated with the number of metastases at diagnosis, previous receipt of immunotherapy, leptomeningeal dissemination, elevated serum levels of lactate dehydrogenase, and the presence of extracranial disease. Patients who underwent craniotomy had an improved survival (P = 0.01), likely reflecting appropriate patient selection for invasive procedures. The use of various central nervous system–directed and systemic therapies was associated with presenting symptoms, year of diagnosis, number and size of brain metastases, and the presence of extracranial disease.1

Nelson Moss, MD, neurosurgeon, coheads the Multidisciplinary Brain Metastasis Clinic at MSK

Nelson Moss, MD, neurosurgeon, coheads the Multidisciplinary Brain Metastasis Clinic at MSK

“Our study confirms the prognosis for MSK patients with melanoma brain metastasis has improved in the era of targeted therapies and immunotherapies, especially in the last five years,” said Nelson Moss, MD, a neurosurgeon who coheads MSK’s Multidisciplinary Brain Metastasis Clinic and performs about 150 brain metastasis resection surgeries annually, in addition to removal of other brain tumor types. “These improvements in survival also reflect MSK’s multimodal approach to treatment, including the use of craniotomy and SRS to augment cancer-directed systemic therapies, where needed.”

 

Advancing Brain Metastasis Care with ‘Window of Opportunity’ Studies

MSK is currently planning “window of opportunity” studies in collaboration with pharmaceutical companies to look for new ways to improve outcomes further. Patients scheduled for brain surgery will have the opportunity to volunteer to receive a targeted drug beforehand. Researchers will then analyze resected tumors to see whether a drug or combination therapy crossed the blood-brain barrier and elicited a response. “This innovative approach may allow us to see if a systemic blood level corresponds to a response in brain metastases in a small number of patients, much faster than if we enrolled 50 patients and waited years until the end of their life expectancy,” Dr. Moss said. “If so, there will be significant benefits in terms of greatly advancing research timelines and providing earlier guidance on which drugs or combination therapies should be developed further and studied in clinical trials.”

Learn More about MSK’s Multidisciplinary Brain Metastasis Clinic

At MSK, dedicated radiation oncologists, neurosurgeons, neuroradiologists, medical oncologists, and physiatrists provide care exclusively in our Multidisciplinary Brain Metastasis Clinic. They collaborate to create a customized and centralized treatment plan for each patient, ensuring multimodality treatments are delivered in the best order, as quickly as possible, for the greatest benefits.

MSK treats a large volume of patients with brain metastases annually on expedited timelines and is one of few centers with the most advanced diagnostic and treatment options for these patients. We offer expedited day-1 treatment for patients needing immediate attention, including same-day radiation oncology counseling, CT simulation with mask fitting, radiation treatment planning, and SRS delivery.

Watch this video to learn more about MSK’s dedicated approach to treating patients with brain metastases. Read more about MSK’s Multidisciplinary Brain Metastasis Clinic.

To refer a patient, call 212-619-5837, and we can help set up an appointment within 48 hours.

  1. Bander ED, Yuan M, Carnevale JA, et al. Melanoma brain metastasis presentation, treatment, and outcomes in the age of targeted and immunotherapies. Cancer. 2021;127(12):2062-2073.
  2. Sampson JH, Carter JH, Friedman AH, Seigler HF. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg. 1998;88:11-20.
  3. Raizer JJ, Hwu WJ, Panageas KS, et al. Brain and leptomeningeal metastases from cutaneous melanoma: survival outcomes based on clinical features. Neuro Oncol. 2008;10:199-207.
  4. Davies MA, Liu P, McIntyre S, et al. Prognostic factors for survival in melanoma patients with brain metastases. Cancer. 2011;117:1687- 1696.
  5. Fife KM, Colman MH, Stevens GN, et al. Determinants of outcome in melanoma patients with cerebral metastases. J Clin Oncol. 2004;22:1293-1300.
  6. Frinton E, Tong D, Tan J, et al. Metastatic melanoma: prognostic factors and survival in patients with brain metastases. J Neurooncol. 2017;135:507-512.
  7. Pasquali S, Hadjinicolaou AV, Chiarion Sileni V, Rossi CR, Mocellin S. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev. 2018;2:CD011123.
  8. Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol. 2015;33:1889-1894.
  9. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535-1546.
  10. Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial. Lancet Oncol. 2018;19:1480-1492.
  11. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345-1356.
  12.  12. Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381:626-636.
  13. 13. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372:30-39.
  14. 14. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155-164.
  15. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.
  16. Chapman PB. Changing the standard of care for treating melanoma brain metastases. Lancet Oncol. 2018;19:589-591.
  17. Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol. 2012;13:459-465.
  18. Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2016;17:976-983.
  19. Long GV, Atkinson V, Lo S, et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 2018;19:672-681.
  20. Davies MA, Saiag P, Robert C, et al. Dabrafenib plus trametinib in patients with BRAFV600-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial. Lancet Oncol. 2017;18:863-873.
  21. Tawbi HA, Forsyth PA, Algazi A, et al. Combined nivolumab and ipilimumab in melanoma metastatic to the brain. N Engl J Med. 2018;379:722-730.
  22. Brown PD, Jaeckle K, Ballman KV, et al. Effect of radiosurgery alone vs. radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial. JAMA. 2016;316(4):401–409.
  23. Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037–1044.