Lung cancer in the evolving field of precision medicine

According to Dr. David Gandara, University of California Davis, Comprehensive Cancer Center, United States, the requisites for implementing precision medicine are: i) the ability to profile tumors for biomarkers, ii) having drugs against these biomarker targets, and iii) having clinical trial designs that characterize the drug activity.

Currently, precision medicine is not perceived as universally successful. Apart from BRCA gene testing for breast cancer, only a few cancer-related genes have diagnostic or prognostic values.1 However, non-small cell lung cancer (NSCLC) is an exception that is found to have genomicallydefined histologic subsets, including adenocarcinoma and squamous cell carcinoma, through next-generation sequencing (NGS).2 As such, the National Comprehensive Cancer Network (NCCN) NSCLC Guidelines Panel now strongly recommends broader molecular profiling to identify rare NSCLC driver mutations for which effective drugs may already be available, and encourages patients to participate in clinical trials for best disease management.3 Particularly for advanced NSCLC, testing for 8 oncogene drivers is recommended as these drivers can be targeted by the currently available medications.3

In addition to driver mutations, NSCLC biomarker studies have evolved from testing clinical-histologic factors to single genes, then multiplex molecules, and finally high throughput NGS of the entire genomes, exomes or transcriptomes for drug selection.2 Compared with other high throughput tumor profiling methods such as hotspot panels or exclusionary sequential testing, NGS testing is more cost-effective with a faster turnaround time.4 However, NGS of tumor biopsy is not always feasible due to tissue availability and adequacy. In these cases, plasma circulating tumor DNA (ctDNA) genotyping in parallel might be useful for treatment selection.

Apart from tumor genotyping, immune phenotyping through biomarker measurement also helps assess the potential benefit of receiving checkpoint immunotherapy. An example of an effective, predictive biomarker is the programmed death ligand-1 (PD-L1), its high expression (specifically 50% or greater), indicates a survival benefit from receiving immune checkpoint single or combination therapy. Nevertheless, Dr. Gandara pointed out that PD-L1 is an incomplete biomarker, and that patients with no PD-L1 expression may still experience survival benefit from checkpoint immunotherapy.

On the other hand, tumor mutational burden (TMB) is emerging as a promising biomarker for immunotherapy response in cancer patients. TMB can be quantitated by a number of NGS-based sequencing technologies. However, the lack of harmonization in panel-based TMB quantification, adequate methods to convert TMB estimates across different panels and robust predictive cut-offs, currently represents one of the main limitations to adopt TMB as a biomarker in clinical practice.5 Other biomarkers associated with checkpoint immunotherapy efficacy in NSCLC also include gene expression signature and tumor infiltration lymphocytes. However, these biomarkers are quantified continuously, but not discreetly, and the combination of these biomarkers is only useful for adding predictive value.

While successful tumor profiling has to be complemented by robust clinical trial design, which is challenging or infeasible.6 As many mutations are rare, occurring in only 5-15% of patients, a large number of patients have to be screened at multiple centres to accrue sufficient participants, and they have to wait for several weeks with a small chance of participating in the study at the end.6 To address these unmet needs, biomarker-driven master protocols were conceived to investigate multiple therapies matched to biomarkers within a single clinical trial infrastructure aiming to accelerate the drug testing and approval process.6

The S1400 Lung-MAP Master Protocol is one such study that included a screening component for NGS and a clinical trial component with biomarker-driven substudies or non-match substudies for patients who were ineligible.6 Combining data from the substudies, 7% of patients responded to targeted therapy, 16.8% responded to anti-PD-1 or anti- PD-L1 therapy for immunotherapy-naïve disease and 5.4% responded to docetaxel in the second-line therapy setting.6 From the results, the Lung-MAP study demonstrated that a biomarker-driven master protocol is feasible in an aggressive disease setting and can serve as an infrastructure to efficiently evaluate the activity of targeted therapies in rare disease populations.6 Through rapid evaluation, all targets evaluated by Lung-MAP, with the exception of MET, have received regulatory approval for drugs in class.6 While Lung-MAP has yet to identify new treatment biomarkers, it has prevented prolonged evaluation of ineffective drug targets that are already identified in lung cancer.6

In conclusion, cancer patients, especially those with NSCLC, should receive broad molecular profiling to identify oncogene driver mutations and select the best treatment option. When applying precision medicine to NSCLC, Dr. Gandara added, “We now have commercially available NGS-based testing that is both specific and sensitive…that enables community oncologists to [obtain results] in a timely fashion.”

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