Dr Popat on the Efficacy and Safety Profiles of Zongertinib in HER2-Mutated NSCLC

“[Zongertinib] is very active against the [HER2] YVMA mutation…The drug also has some activity in the brain, with a response rate of 33%. It’s a very tolerable drug.”

Sanjay Popat, BSc, MBBS, FRCP, PhD, consultant medical oncologist, The Royal Marsden NHS Foundation Trust; professor, thoracic oncology, the Institute of Cancer Research, discusses data that have been reported with zongertinib (BI 1810631) in patients with HER2-mutated non–small cell lung cancer (NSCLC) and how these findings may affect clinical practice in the future.

Recent data with 2 leading HER2-targeted therapies for patients with HER2-mutated NSCLC highlight promising advancements in this treatment paradigm, Popat begins. One of the drugs, zongertinib, was evaluated in the phase 1 Beamion LUNG-1 trial (NCT04886804), whereas the second drug is earlier in development, he notes.

Zongertinib has been studied extensively across several Beamion LUNG-1 analyses in patients with previously treated metastatic NSCLC, Popat says. In cohort 1 of the trial, patients with pretreated NSCLC harboring a HER2 TKD mutation were randomly assigned to receive zongertinib at 120 mg (n = 75) or 240 mg (n = 57) daily. The drug exhibited robust efficacy, with an overall response rate (ORR) of 71% (95% CI, 60%-80%; P less than .0001) among patients who received the agent at 120 mg, he explains. Notably, zongertinib is active against the YVMA insertion mutation within HER2 exon 20, which is the most common HER2 mutation in this setting, he emphasizes. HER2 mutations are relatively rare in NSCLC, and the YVMA insertion mutation presents a diagnostic challenge due to its variable nomenclature on mutation reports, he cautions. Furthermore, the agent demonstrated central nervous system activity among evaluable patients at the 120-mg dose (n = 27), generating an intracranial ORR of 33% (95% CI, 19%-52%).

The safety profile of zongertinib is favorable, he adds. In Beamion LUNG-1, 5% of patients required dose reductions. Since zongertinib was designed to target HER2, it has minimal off-target effects on EGFR, resulting in low rates of EGFR-associated toxicities like diarrhea and skin toxicity, Popat concludes.