Treatment of advanced/metastatic NSCLC 

Targeting driver mutations in NSCLC

One of the most significant advances in the treatment of advanced/metastatic NSCLC has been the identification and targeting of driver mutations.^6,7 Several molecular drivers have been identified that represent strong predictive biomarkers and serve as therapeutic targets. Guidelines suggest that all patients with advanced adenocarcinoma should be tested for the presence of oncogenic drivers that can be therapeutically targeted. This includes broad molecular profiling of EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14 skipping, RET, and HER2 genes. Testing for these biomarkers is now considered mandatory in many countries.^6,7 Tyrosine kinase inhibitors (TKIs) that target EGFR mutations or ALK rearrangement are considered the standard of care in the first-line treatment of patients whose tumors bear these mutations, which occur most frequently in non-squamous NSCLC.^6,7

HER2-targeted therapies for NSCLC

Approximately 3% of non-squamous NSCLCs are driven by mutations in the HER2 gene.⁸ While chemotherapy and/or immunotherapy remain the first-line standard of care for patients with HER2-mutated NSCLC, HER2-targeted therapies are being studied in later lines of therapy with variable success.^7,9,10

Trastuzumab deruxtecan is an antibody drug conjugate that binds HER2 and delivers a topoisomerase inhibitor that induces apoptosis in tumor cells.^8,11 In a Phase II study, 91 patients with HER2-mutated NSCLC were treated with trastuzumab deruxtecan and 55% had a confirmed objective response, including 1 complete response and 49 partial responses.¹¹ All 91 patients experienced at least one adverse event, with gastrointestinal and hematologic events, decreased appetite, and alopecia occurring most frequently.¹¹ In August 2022, the US FDA approved trastuzumab deruxtecan for the treatment of HER2-mutated NSCLC in patients who have received prior systemic therapy.⁹

Poziotinib is a HER2-selective tyrosine kinase inhibitor that was studied in HER2-mutated NSCLC.¹² In November 2022, the US FDA issued a complete response letter denying the approval of poziotinib for treatment of patients with previously treated HER2-mutated NSCLC based, in part, on the low objective response rates and poor tolerability.¹⁰

Patients with NSCLC lacking targetable driver mutations

For patients with NSCLC tumors that do not exhibit driver mutations, recent advances in various treatment lines have included agents that inhibit angiogenesis, as well as immunotherapies that target the programmed cell death receptor 1 (PD-1) or programmed cell death ligand 1 (PD-L1).^7,13 Inrecent treatment guidelines, anti-PD-1 and anti-PD-L1 have become the preferred first-line therapy for patients with tumors that are PD-L1 positive ≥50% and have no other targetable driver mutations.^7,13 Combinations of chemotherapy with anti-PD-1 or anti-PD-L1 are recommended for those with tumors that are PD-L1 positive ≥1% to 49%.^7,13

The future of molecular diagnostics and tailored treatment in NSCLC

Alongside treatments targeted to specific mutations, diagnostic techniques that identify these mutations in patients need to be developed. Ideally, a diagnostic test should be sensitive, non-invasive and fast enough to inform a treatment decision. Liquid biopsy is one such technique: plasma samples, rather than tumor samples, can be analyzed for the presence of mutations based on innovative new techniques like next-generation sequencing and digital droplet polymerase chain reaction (ddPCR).¹⁴

Dr Patrick Pauwels, MD, PhD explains how ddPCR can be used as a diagnostic tool to detect known hot-spot EGFR mutations in patients with NSCLC. Filmed in October 2019.

Despite the advances in treatment options and the fact that treatment can be tailored to the individual patient to some extent, there is still much room for improvement. Although EGFR- and ALK-targeted therapies are effective, a proportion of patients with adenocarcinoma and the large majority of patients with squamous disease do not have tumors that bear these driver mutations.^6,7 In addition, while immunotherapy has been widely utilized, not all tumors respond to this class of treatment and almost all patients eventually relapse.¹⁵ Further research is needed to clearly identify which patient subgroups will benefit most from novel treatments such as immunotherapies, and what the optimal treatment options are when these novel treatments fail.