The recent joint guidelines from the American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) NSCLC Expert Panel provide the rationale for the use of the existing biomarkers for which there were FDA-approved targeted therapies at the time of publication (ie, EGFR, ALK, ROS1 fusions, BRAF V600E mutations, RET fusions, MET exon 14 skipping mutations, and NTRK fusions). Further, there are several emerging targets that have agents that have just received FDA approval.

Two drugs directed against KRAS G12C have been in development, and one of them, sotorasib, was just recently approved by the FDA. The approval was based on a study of 124 patients with locally advanced or metastatic KRAS G12C–mutated NSCLC with disease progression after receiving an immune checkpoint inhibitor and/or platinum-based chemotherapy. The objective response rate was 32% and the median duration of response was 11 months. Adagrasib (MRTX849), also a KRAS G12C inhibitor, has shown promise in early phase clinical trials. Initial data from the phase 1/2 KRYSTAL-1 study were presented during the 2021 European Lung Cancer Virtual Conference 2021. Among 51 patients evaluable for clinical activity, 45% (23 out of 51) had a partial response and 26 patients had stable disease. Investigators are interested in examining co-mutations with KRAS G12C. It is notable that the patients receiving these drugs were all previously treated. Thus, both therapies show relatively good efficacy, and they represent a big step forward. They are 2 of my favorite agents in the category of investigational/recently introduced therapies.

EGFR exon 20 insertions represent another important target. It is a target that has been somewhat understated for a long time because it has been in the shadow of other EGFR abnormalities (eg, sensitizing EGFR exon 19 deletion and EGFR L858R). The exon 20 insertions occur in only approximately 1% of patients with lung cancer, but these individuals have similar characteristics to what we see with a lot of EGFR-mutant lung cancers. They are present more commonly in people who have never smoked.

The available EGFR tyrosine kinase inhibitors have not been particularly effective for these mutations. However, there are newer EGFR tyrosine kinase inhibitors (poziotinib and mobocertinib) and a bispecific antibody (amivantamab) that have shown activity against exon 20 insertions. Amivantamab, which is directed against EGFRs and MET receptors, was just granted accelerated approval for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. I believe that it is likely that there will be additional FDA approvals over the next several months, so identifying patients with these mutations will be important.

Another target that has been around for a while but has not received much attention in NSCLC is the HER2 mutation. When we think about HER2, we normally think of breast cancer and HER2 amplifications; however, in lung cancer, we see insertion mutations that occur in approximately 2% of patients. A trastuzumab drug conjugate (trastuzumab deruxtecan) has been shown to produce an approximate 62% objective response rate in patients with HER2-mutated metastatic NSCLC. More definitive trials are ongoing, and we are looking forward to seeing additional information.

While we have expanded the number of therapeutic targets and available agents, we are still in a transition from testing for a few of the genetic alterations to testing for all of them. Not everyone is doing the level of NGS that is recommended. There are clearly enough data to support the use of NGS and the targeted therapy for actionable alterations in the frontline setting instead of chemotherapy or immunotherapy. 

One of the problems with the transition is that we originally were only testing nonsmokers for these genetic alterations, although that has clearly changed in recent years. The change began with testing smokers for BRAF mutations, and it is also changing for other mutations. Given that KRAS primarily occurs in smokers, the mutation will only be detected if we screen smokers and nonsmokers. I think that the identification of KRAS as a potentially targetable mutation is important not only for those who may have this alteration but also to further advance the concept of broader testing for all patients with NSCLC, independent of smoking status. 

Hopefully, this may spur people to adopt the contemporary guidelines for using NGS first. I think that it is causing the pendulum to swing in favor of broader testing. Having so many targetable mutations makes it difficult to perform only individual tests. The use of broader molecular testing up front is supported by an analysis of newly diagnosed metastatic NSCLC, which found that the use of upfront NGS testing was associated with substantial cost savings and shorter time-to-test results compared with sequential testing.