Treatment for NSCLC Increasingly and Exquisitely Targeted

Newly approved drugs put the brakes on particular “driver mutations,” that when unimpeded, rev up the runaway cell growth and division that characterizes cancer.

Targeted therapies that zero in on cancer with particular genetic anomalies are playing an increasingly important role in the treatment of lung cancers as researchers gain a clearer understanding about the specific “driver mutations” involved in cancer cell growth, down to the level of particular mutations in particular genes.

This kind of mutation-specific targeted therapy has come on especially strong as a strategy for treating for nonsmall cell lung cancer (NSCLC), which accounts for between 80% and 85% of lung cancer. The incidence of lung cancer in the U.S. has been declining, but lung cancer is still the leading cause of cancer death in the country, accounting for about 25% of cancer deaths each year.

Targeted therapies are the cornerstone precision medicine, and they can be either small molecules or monoclonal antibodies, according to the National Cancer Institute. When the FDA approves a targeted therapy, it typically approves a companion diagnostic test that identifies the biomarkers that determine whether the targeted therapy is appropriate.

One of the most recently approved targeted therapies is Rybrevant (amivantamab-vmjw), a bispecific antibody directed against epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) receptors. Developed by Janssen, Rybrevant was approved by the FDA in May 2021. The drug is used to treat adult patients with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 20 insertion mutation who have progressed with chemotherapy. Rybrevant, which is administered intravenously, had previously received the FDA’s priority review and breakthrough therapy designation.

At the same time, the FDA approved Guardant Health’s Guardant360 CDx liquid biopsy as a companion diagnostic. The test will be used for tumor mutation profiling to identify patients with locally advanced or metastatic NSCLC who harbor the EGFR exon 20 insertion.

Rybrevant is the first drug the FDA has approval for patients with NSCLC who have the EGFR Exon 20 mutation. About 2% to 3% of patients with NSCLC will have these mutations; they are the third most common type of EGFR mutation. Patients with this mutation have a worse prognosis because it causes rapid cell growth and spread of cancer. Five other targeted therapies to treat EGFR mutations in NSCLC are available, but they are EGFR genes that have Exon 19 deletion and Exon 21 substitution mutations.

Over the last year, two therapies targeting a different mutation, the MET exon 14 skipping alteration, have been approved, providing the first options for this mutation. The MET gene encodes for a receptor tyrosine kinase that activates signaling pathways involved in cell proliferation, survival and growth. The MET exon 14 skipping alteration (METex14) is seen in about 3% to 4% of cases of NSCLC. Patients with MET-positive lung cancers are most likely to have a smoking history.

In February 2021, the FDA approved EMD Serono’s Tepmetko (tepotinib) for the treatment of adult patients with metastatic NSCLC with MET exon 14 skipping alterations. Tepmetko is a once-daily oral therapy administered as two 225 mg tablets (450 mg). The FDA has not specified a specific diagnostic.

A little over a year ago, in May 2020, the FDA approved Novartis’ Tabrecta (capmatinib) also for patients whose tumors have a mutation that leads to MET exon 14 skipping. Tabrecta is given a twice daily as 400- mg oral medication. Foundation Medicine’s FoundationOne CDx has been approved as a companion diagnostic for Tabrecta.