Uncommon EGFR Mutations Come Into Focus With Novel NSCLC Therapies

The understanding of EGFR signaling in non–small cell lung cancer (NSCLC) continues to evolve, helping to spark the development of novel therapies for new patient populations with uncommon alterations.

In May, the FDA granted an accelerated approval to amivantamab-vmjw (Rybrevant) for patients with locally advanced or metastatic NSCLC harboring EGFR exon 20 insertion mutations with disease progression on or after platinum-based chemotherapy. The bispecific antibody, which targets EGF and MET receptors, is the first therapy approved for this subset of patients with NSCLC.¹

Amivantamab is among a growing number of drugs with activity against EGFR exon 20 insertion–mutant disease undergoing clinical testing.

These include mobocertinib (TAK-788), which the FDA is evaluating under its priority review program for patients with metastatic exon 20 insertion mutation–positive NSCLC who have received platinum-based chemotherapy. The agency is scheduled to decide on a new drug application (NDA) by October 26, 2021, according to Takeda Pharmaceutical Company Limited, the company developing the therapy.²

The development of therapies aimed specifically at exon 20 alterations is the latest step in personalizing EGFR-directed therapies in the NSCLC field. Until recently, EGFR inhibitors were available only for patients with the so-called classical EGFR mutations (exon 19 deletions and the L858R substitution in exon 21) and the secondary resistance mutation T790M.^3-5

Growing use of next-generation sequencing (NGS) has increased recognition of less common EGFR mutations in NSCLC.^3-5 In particular, exon 20 insertion mutations have become increasingly therapeutically relevant, with evidence that they confer poorer patient prognosis and insensitivity to first- and second-generation EGFR inhibitors.^3,4,6

In the EGFR mutational landscape in NSCLC, classical aberrations account for about 88% of the primary EGFR alterations found in adenocarcinomas, whereas rare mutations together make up 12% (Figure 1⁵). Overall, activating EGFR mutations are found in the tumors of 10% to 20% of Caucasian patients and at least 50% of Asian patients with NSCLC,⁵ including exon 20 insertion mutations in approximately 2% to 3% of cases.⁶

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