Immune checkpoint inhibitors targeting PD-1 and PD-L1 have become standard first-line therapy for patients with advanced non-small cell lung cancer (NSCLC), but only for patients without activating mutations in EGFR or ALK, as tumors harboring these alterations do not respond well to immunotherapy. In recent years, BRAF-mutated NSCLC has emerged as a recognized molecular subtype of disease, but the sensitivity of patients with these mutations to immune checkpoint inhibitors is not known. A retrospective chart review attempted to evaluate 39 patients with BRAF-mutated NSCLC for presence of known immunotherapy biomarkers and sensitivity to immune checkpoint inhibitor (PD-1 or PD-L1) therapy.
Patients were stratified into two groups on the basis of BRAF V600E mutation (group A) or non-V600E mutation (group B). Of 29 tumors tested for PD-L1 expression, 42% in group A and 50% in group B had high PD-L1 expression (P = .05). Among 11 tumors tested for tumor mutation burden (TMB), only 2 patients in group A (25%) and none in group B had high TMB (>20 muts/Mb). The median TMB was 5 muts/Mb in group A and 11 muts/Mb in group B. Both groups were microsatellite stable (MSS).
A total of 22 patients (56%) received treatment with an immune checkpoint inhibitor. Patients receiving checkpoint inhibitor therapy were more likely to have high PD-L1 expression (P = .056), and both patients with high TMB received checkpoint inhibitor therapy. Presence of BRAF mutation did not negatively influence response to checkpoint inhibitor therapy, regardless of which mutation variant was expressed. The objective response rate (ORR) was 25% in group A and 33% in group B (P = 1.0). The median progression-free survival (PFS) was 3.7 months in group A and 4.1 months in group B (P = .37). Median overall survival (OS) in patients who received immune checkpoint inhibitors was not reached.
The investigators concluded that BRAF-mutant NSCLC is associated with high levels of PD-L1 expression, low/intermediate TMB, and MSS status, and that patients with BRAF mutations V600E and non-V600E appear to benefit from monotherapy with PD-1/PD-L1 inhibitors. In an accompanying editorial, the authors commented that ‘’it is refreshing to know that BRAF-mutant NSCLC does not typically behave like NSCLC with EGFR and/or ALK gene alterations and that the rates of response to PD-1/PD-L1 therapies are similar to those in wild-type populations.” However, in order to answer important questions regarding the sequencing of BRAF/MEK inhibitors and immune checkpoint inhibitors, prospective trials are needed.