Critical appraisal:Ahmed KA, Abuodeh YA, Echevarria MI, Arrington JA, Stallworth DG, Hogue C, et al 2016

Critical Appraisal

Article being appraised

Ahmed KA, Abuodeh YA, Echevarria MI, Arrington JA, Stallworth DG, Hogue C, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy. Ann Oncol 2016 Dec;27(12):2288-2294 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27637745.

Applicable clinical question

When is radiotherapy indicated for patients with distant metastasis?

Key Facts

Study Design

cohort study

Study aims:

To compare the intracranial control rate in patients treated with stereotactic radiosurgery for intact melanoma brain mets within 3 mo of the receipt of anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitors or conventional chemotherapy.

Number of Patients:

96

anti-PD-1: n=21

anti-CTLA-4: n=25
BRAF/MEKi: n=12
BRAFi: n=18

Chemotherapy: n=20

Reported outcome(s):

distant melanoma brain metastases
local melanoma brain metastases
systemic progression-free survival
overall survival from SRS and cranial mets diagnosis

Results of outcome(s):

>distant melanoma brain metastases:
- Significant differences were noted among the groups in distant melanoma brain mets control rates following SRS, p=0.008.

6mo distant melanoma brain mets:
anti-PD-1: 61%
anti-CTLA-4: 26%
BRAF/MEK inibitor: 53%
BRAF inhibitor: 30%
conventional chemotherapy: 15%

12mo distant melanoma brain mets:
anti-PD-1: 38%
anti-CTLA-4: 21%
BRAF/MEK inibitor: 20%
BRAF inhibitor: 8%
conventional chemotherapy: 5%

- Treatment with BRAF/MEK inhibitors or anti-PD-1 was found to be significant for distant melanoma brain mets (univariate)
- Treatment remained significant (multivariate)

 - chemotherapy v anti-PD-1 HR 3.1 (95%CI 1.5-6.6), p=0.001

 - chemotherapy v BRAF/MEK inhibitor HR 2.1 (95%CI 1.1-4.4), P=0.03

- No differences chemotherapy v BRAF inhibitor, p=0.27 OR chemotherapy v anti-CTLA-4, p=0.26 (multivariate)

improvement in distant melanoma brain mets in chemotherapy v immunotherapy (anti-PD-1 and anti-CTLA-4), HR 2.1 (95%CI 1.1-3.6), p=0.02 (multivariate)
no improvement in distant melanoma brain mets in chemotherapy v targeted (BRAF inhibitors and BRAF/MEK inhibitors, HR 1.2 (95%CI 0.71-2), p=0.51

>local melanoma brain metastases:
- No significant differences among the groups in local melanoma brain mets control rates, p=0.25

>systemic progression-free survival, p=0.04:

6mo systemic progression-free survival:
anti-PD-1: 41%
anti-CTLA-4: 36%
BRAF/MEK inibitor: 58%
BRAF inhibitor: 29%
conventional chemotherapy: 20%

12mo systemic progression-free survival:
anti-PD-1: 41%
anti-CTLA-4: 27%
BRAF/MEK inibitor: 39%
BRAF inhibitor: 12%
conventional chemotherapy: 5%

- Significantly improved OS on both univariate and multivariate:
(multivariate analysis)
anti-PD-1 v chemotherapy: 2.7 (95%CI 1.4-5.7), p=0.005
anti-CTLA-4 v chemotherapy: 2.5 (95%CI 1.3-5.0), p=0.007
BRAF/MEK inhibitors v chemotherapy: 2.5 (95%CI 1.2-5.5), p=0.02

>overall survival from SRS, p=0.01:
6mo OS from SRS:
anti-PD-1: 76%
anti-CTLA-4: 68%
BRAF/MEK inibitor: 83%
BRAF inhibitor: 52%
conventional chemotherapy: 60%

12mo OS from SRS:
anti-PD-1: 48%
anti-CTLA-4: 41%
BRAF/MEK inibitor: 65%
BRAF inhibitor: 24%
conventional chemotherapy: 10%

>overall survival from cranial mets diagnosis, p=0.004:
6mo OS from cranial mets:
anti-PD-1: 81%
anti-CTLA-4: 84%
BRAF/MEK inibitor: 83%
BRAF inhibitor: 71%
conventional chemotherapy: 70%

12mo OS from cranial mets:
anti-PD-1: 66%
anti-CTLA-4: 50%
BRAF/MEK inibitor: 75%
BRAF inhibitor: 29%
conventional chemotherapy: 15%

> Percentage, p=0.10:
Percentage demonstrating progression in the brain alone:
anti-PD-1: 16%
anti-CTLA-4: 19%
BRAF/MEK inibitor: 70%
BRAF inhibitor: 47%
conventional chemotherapy: 25%

Percentage demonstrating progression in systemic alone:
anti-PD-1: 33%
anti-CTLA-4: 19%
BRAF/MEK inibitor: 0%
BRAF inhibitor: 20%
conventional chemotherapy: 15%

Percentage demonstrating progression in both brain and systemic progression:
anti-PD-1: 50%
anti-CTLA-4: 63%
BRAF/MEK inibitor: 30%
BRAF inhibitor: 33%
conventional chemotherapy: 60%