An elevated tumor mutational burden (TMB) in the blood has now demonstrated its potential as a reliable clinical biomarker for predicting the clinical efficacy of the checkpoint inhibitor Tecentriq (atezolizumab, Roche Holding AG) in treating patients with advanced non-small-cell lung cancer (NSCLC), a Sino-U.S. study has shown.
"This is the first time a validated blood TMB (bTMB) assay has been shown that it may predict the clinical efficacy of a checkpoint inhibitor," said David Shames, principal scientist in the department of Oncology Biomarker Development at Roche subsidiary Genentech Inc. in South San Francisco.
Shames co-led the study with David Gandara, professor and director of the Thoracic Oncology Program at University of California Davis Comprehensive Cancer Center, Sacramento, and Tony Mok, a professor in the Department of Clinical Oncology at The Chinese University of Hong Kong.
In patients with previously treated, advanced second-line and higher NSCLC, an overall survival (OS) benefit has been observed in patients treated with the checkpoint inhibitors Tecentriq or Opdivo (nivolumab, Bristol-Myers Squibb Co.).
"Checkpoint inhibitors are antibodies targeting programmed death-ligand 1 (PD-L1) or programmed death 1 (PD-1). These proteins regulate an immune checkpoint, which typically guards against autoimmunity by inducing apoptosis of antigen-specific T cells in lymph nodes and inhibiting it in regulatory T cells," explained Shames.
"In cancer, tumor cells express or induce expression of PD-L1 on neighboring T cells, thereby preventing the immune system from recognizing the tumor, which is an example of immune evasion by tumor cells."
Checkpoint inhibition "with anti-PD-L1/PD-1 antibodies reverses this immunosuppressive regulatory process," Shames told BioWorld.
"Checkpoint inhibitors appear to be more effective than doublet chemotherapy in patients who are positive for PD-L1 by immunohistochemistry and/or TMB, while in combination with chemotherapy, they seem to be more effective than chemotherapy alone in most NSCLC patients," he said.
While PD-L1 testing is required prior to checkpoint inhibitor monotherapy as front-line NSCLC treatment, obtaining adequate tumor tissue for molecular testing in patients with advanced disease can be challenging, with around 30 percent of NSCLC patients having inadequate tissue for testing at diagnosis.
"Initially, physicians are interested in obtaining a pathological diagnosis to rule in/out lung cancer, but because many patients present with co-morbidities and tend to be frail, physicians select less invasive procedures such as bronchoscopy. Such procedures are useful for diagnosing lung cancer, but often yield insufficient material for molecular testing," noted Shames.
Furthermore, "historically, it wasn't necessary to obtain substantial tissue, as there weren't any medicines available requiring a molecular diagnosis. This has changed in recent years in the U.S., but in many countries it remains the standard of care to use minimally invasive procedures, which also frequently produce insufficient material."
An unmet medical need therefore exists for diagnostic approaches that do not require tissue biopsies, in order to identify those patients who may benefit from novel immunotherapies like checkpoint inhibitors.
In their new study reported Aug. 2, 2018, in Nature Medicine, the authors described a novel, technically robust, blood-based assay to measure bTMB that obviates tissue-based approaches.
"The investigational bTMB assay uses next-generation gene sequencing to evaluate the number of mutations detectable in a patient's blood plasma. It is quite simple to use at the point of care, as it only requires a simple blood draw – the equivalent of two standard vials of blood," said Shames.
"The plasma is then shipped to [U.S. genomic testing company] Foundation Medicine in Cambridge, Massachusetts, where circulating tumor DNA is extracted, sequenced and subjected to bioinformatic analysis.
"We have made numerous adaptations to standard protocols in upstream processing to improve the assay's sensitivity, specificity and reproducibility," said Shames.
Using a retrospective analysis of the large randomized OAK and POPLAR trials as test and validation studies, respectively, the researchers showed the bTMB assay reproducibly identified patients with second-line and higher NSCLCs who would derive significant improvements in progression-free survival (PFS) from atezolizumab.
Measuring bTMB was shown collectively to be feasible, with a cut-point of >/= 16 reproducibly identifying patients who would obtain an increased PFS benefit in those receiving atezolizumab compared to patients receiving single-agent docetaxel chemotherapy.
"The cut-point of >/=16 was derived by evaluating the specificity and sensitivity of the assay at a range of cut-offs and then evaluating the best technical cut-offs in the POPLAR trial," Shames said.
"In POPLAR, there was a 35 percent reduction in the risk of disease progression for bTMB-positives compared to the intent-to-treat (ITT) population, whereas in OAK, the reduction in risk of disease progression for bTMB-positives was 30 percent versus the ITT group."
Although additional work is needed to better understand the dynamics and biology of bTMB and its relevance to indications beyond NSCLC, the study findings suggest the future potential application of that assay to the molecular diagnostic and therapeutic algorithms for patients who have progressed on first-line therapy for advanced NSCLC.
"We are currently evaluating the performance of the bTMB assay in two prospective studies, which will hopefully validate the platform," Shames said.
"We are also evaluating approaches to improve the assay's efficiency from a cost and turnaround time perspective and are interested in identifying other areas where such an assay might be useful in improving patient outcomes."