In 2016, a large-scale analysis of circulating tumor (ct)DNA in more than 17,000 liquid biopsies has identified patterns of genetic changes that closely mirror those identified in traditional tumor biopsy.1,2 However, the data presented at the European Society for Medical Oncology (ESMO) 2017 Congress is the first to show that liquid biopsy for tumor mutational burden (TMB) can also be used to predict response to immunotherapy.3,4
The ability to probe the molecular landscape of solid tumors via a blood draw, known as liquid biopsy (Figure 1), has attracted remarkable interest in the recent years.5 Unlike traditional tumor biopsy, periodic liquid biopsy only requires a simple blood draw, while also allowing physicians to closely monitor disease progression, response to therapy, and development of treatment resistance.1,5
The new data presented at the ESMO Congress 2017 is the retrospective analysis of patients treated with the PD-L1 inhibitor atezolizumab in the phase II POPLAR and phase III OAK studies.3,4,6 The biomarker evaluable population included 211 plasma samples from POPLAR (test set) and assay to measure TMB (bTMB).4,6
The bTMB assay assessed single nucleotide variants (SNV) in the target genes and reports a score based on the number of high-confidence SNVs identified.3,4 The results are then grouped by cut points based on the minimum number of SNVs present.3,4 By validating this blood-based approach, it might allow bTMB testing to more patients, particularly to those who are ineligible or too weak to undergo traditional tumor biopsy.6
In this analysis, a significant progression-free survival (PFS) benefit of atezolizumab was observed across the bTMB range of 4 to ≥26, with increasing magnitude with higher bTMB score (HR ranging from 0.73 to 0.51).3,4,7 Interestingly, bTMB was not found to be correlated with PD-L1 expression, indicating that bTMB may provide an independent predictive information.3,4,7
“This is the first demonstration that tumor mutational burden can be measured in blood and that the blood tumor mutational burden is associated with progression-free survival from immune checkpoint inhibitor therapy,” said lead author Dr. David R. Gandara, director of thoracic oncology at the University of California Davis Comprehensive Cancer Center in Sacramento.
Based on these findings, two studies (B-F1RST and BFAST) are underway to clinically evaluate and prospectively validate novel blood-based diagnostic assays in NSCLC patients. The B-F1RST study is a single-arm study evaluating the safety and efficacy of atezolizumab and the association between bTMB and efficacy in biomarker-unselected patients.6,8 On the other hand, the BFAST study is a phase II/III screening and interventional umbrella trial for patients with unresectable, advanced, or metastatic NSCLC.6,8 In BFAST, treatment selection of atezolizumab or alectinib is based on the presence of positive bTMB score or oncogenic somatic mutations, respectively.6,8
“Our data at ESMO provide the first evidence that response to immunotherapy can be predicted using only a blood sample and we’re pleased that we recently received FDA clinical trial approval for the phase III study to validate bTMB as a biomarker in first-line immunotherapy.” said Dr. Vincent Miller, chief medical officer at Foundation Medicine, which co-developed the blood-based assay with Roche/Genentech.