Immuno-Oncology Resource Center

Immuno-Oncology Resource Center

July 12, 2018
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Checkpoint inhibitors improve survival for metastatic melanoma with brain metastases

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Treatment with checkpoint blockade immunotherapy more than doubled the rate of 4-year OS among patients with melanoma and metastatic brain metastases, according to study findings.

“The results of our analyses indicate that immune checkpoint inhibitors can achieve a meaningful therapeutic benefit for metastatic melanoma including spread to the central nervous system,” David A. Reardon, MD, clinical director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, said in a press release. “At the same time, not all patients benefit, indicating that much research is still required to optimize the potential of antitumor immune responses for CNS metastatic disease.”

Checkpoint blockade immunotherapy and BRAF V600-targeted therapies have shown promise for the treatment of patients with advanced melanoma; however, the survival benefit for patients with brain metastases had been unknown.

J. Bryan Iorgulescu
J. Bryan Iorgulescu

“Checkpoint blockade immunotherapies have revolutionized how we care for patients with advanced melanoma, leading to long-lasting treatment responses in many patients,” J. Bryan Iorgulescu, MD, postdoctoral fellow in the department of pathology at Brigham and Women’s Hospital/Harvard Medical School and department of medical oncology at the Dana-Farber Cancer Institute, and first author on the study, said in a press release. “However, many of the early clinical trials of checkpoint blockade immunotherapies included few melanoma patients with brain metastases — despite their high incidence — and so the survival benefits of these exciting therapies remained unclear for this substantial subset of patients.”

Researchers used the National Cancer Database to identify 2,753 patients diagnosed with stage IV melanoma and metastatic brain metastases between 2010 and 2015.

Researchers stratified patients based on location of metastatic brain metastases: 39.7% of patients had brain metastases only, and 60.3% of patients had metastatic brain metastases and extracranial metastases.

Patients with metastatic brain metastases with extracranial disease showed involvement in the lung (82.9%), liver (8.1%), bone (6%), and distant subcutaneous skin or lymph nodes (3%).

Independent predictors for brain metastases-only disease included younger age and geographic location.

Patients with metastatic brain metastases who did not undergo treatment (n = 299) had a median OS of 1.8 months (95% CI, 1.5–2.3) and 12.4% (95% CI, 8.9–16.6) achieved 1-year OS.

FDA approved the checkpoint inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb) and BRAF inhibitor vemurafenib (Zelboraf, Genentech) in 2011, after which 81.6% of patients in the study presented with metastatic brain metastases. These approvals “revolutionized” the melanoma treatment landscape, according to the researchers, and were followed by additional targeted and immunotherapy approvals.

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Thus, researchers used 2011 as a time that marked a change in the treatment landscape, and they compared estimated OS for patients diagnosed before and after the start of these FDA approvals.

Median OS among patients with metastatic brain metastases increased from 5.1 months (95% CI, 4.6-5.8) prior to the start of FDA approvals to 6.2 months (95% CI, 5.8-6.7) after the start of FDA approvals.

Rate of 4-year OS improved from 7.4% (95% CI, 5.3-10) to 14.1% (95% CI, 12.2-16.1).

Following the start of FDA approvals, median OS was 4.8 months (95% CI, 4.3-5.4) among patients with metastatic brain metastases and extracranial disease, 9 months (95% CI, 8-10.5) among patients with metastatic brain metastases only, 17.5 months (95% CI, 15.3-20) among patients with stage IV melanoma and lung-only metastatic disease, and 7.1 months (95% CI, 5.6-8.7) among patients with stage IV melanoma and liver-only metastatic disease.

Following the start of FDA approvals, 20.5% of patients received first-line checkpoint blockade immunotherapy; use of frontline checkpoint immunotherapy increased to 34% in 2015 from 10.5% in 2011 (P < .001).

Multivariable logistic analysis showed patients who received a checkpoint blockade immunotherapy in the first line tended to be younger, were more recently diagnosed, had fewer comorbidities, had private insurance or Medicare, were more often diagnosed in New England, had brain-directed radiotherapy or had other metastatic sites.

First-line immunotherapy treatment was associated with a 1.4-fold improvement of median OS — from 5.2 months (95% CI, 4.7–5.9) to 12.4 months (95% CI, 10.4–15.8) — as well as 1.5-fold improved 4-year OS rate, from 11.1% (95% CI, 9.3–13.1) to 28.1% (95% CI, 22.1–34.4).

Multivariable Cox proportional hazards analysis demonstrated improved OS associated with checkpoint blockade immunotherapy among all patients with metastatic brain metastases (HR = 0.12; 95% CI, 0.03-0.49).

Researchers observed a greater OS benefit among patients with brain metastases only, for whom median OS improved from 7.7 months (95% CI, 6.7-8.7) to 56.4 months (95% CI, 25-not reached). The corresponding rate of 4-year OS also improved from 16.9% (95% CI, 13.5-20.6) to 51.5% (95% CI, 38.9-62.8).

Among patients with extracranial involvement, checkpoint blockade immunotherapy also demonstrated improvement in median OS to 9.6 months (95% CI, 7.8-11.1) from 3.9 months (95% CI, 3.5-4.3), and an improved 4-year OS of 17.9% (95% CI, 11.8-24.9) compared with 7% (95% CI, 5.2-9.3).

Among a smaller subset of patients (n = 603) who received targeted therapy, 9.8% also received additional treatment with checkpoint blockade immunotherapy, which conferred a trend toward improved median OS (10.5 months vs. 7.8 months; P = .05).

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“Our findings help bridge the gaps in early clinical trials of checkpoint blockade immunotherapies that largely excluded stage IV melanoma patients with metastatic brain metastases, with checkpoint immunotherapy demonstrating a more than doubling of the median and 4-year OS of metastatic brain metastases,” the researchers wrote. “In support of the National Comprehensive Cancer Network guidelines, we additionally characterized the survival benefits associated with metastatic brain metastases that were amenable to resection and single-fraction SRS.” – by Melinda Stevens

Disclosures : Iorgulescu reports no relevant financial disclosures. Reardon reports honoraria from and consultant/advisory board roles with AbbVie, Agenus, Bristol-Myers Squibb, Celldex, Genentech/Roche, Inovio, Merck KGaA, Merck, Novocure, Oncorus, Oxigene, Regeneron and Stemline. Please see the study for all other authors’ relevant financial disclosures.