Dr Sabari on the Activity of Zongertinib in Pretreated, Advanced, HER2-Mutated NSCLC

“[This is a] rapidly shifting paradigm, both in the second-line and—hopefully [in the] near future—the front-line [setting]…for our patients with HER2 exon 20 insertion–mutant NSCLC.”

Joshua K. Sabari, MD, an assistant professor in the Department of Medicine at New York University Grossman School of Medicine and director of the High Reliability Organization Initiatives at the Perlmutter Cancer Center, discussed key efficacy findings from the phase 1 Beamion LUNG-1 trial (NCT04886804) investigating the HER2-directed TKI zongertinib (BI 1810631) in patients with previously treated, HER2-mutated advanced non–small cell lung cancer (NSCLC).

Cohort 1 of the trial enrolled patients with HER2 tyrosine kinase domain (TKD) mutations (n = 75) who received zongertinib at 120 mg once per day. This cohort consisted of highly pretreated patients, with 44% in this cohort treated at 120 mg having received 2 or more prior lines of therapy. The predominant subtype of HER2 TKD mutation in this population was A775_G776insYVMA, which was present in 65% of patients.

Among patients in cohort 1 who received the agent at 120 mg, zongertinib produced a robust objective response rate (ORR) of 71% (95% CI, 60%-80%), with a disease control rate (DCR) of 96% (95% CI, 89%-99%). Importantly, responses were observed early in the treatment course, with a median time to response of 1.4 months (range, 1.1-6.9), Sabari emphasized. These responses were also durable, with a median duration of response of 14.1 months (95% CI, 6.9-not evaluable [NE]). The median progression-free survival was notable at 12.4 months (95% CI, 8.2-NE), indicating significant clinical benefit in a population lacking previously approved HER2-targeted therapies, he explained.

Additionally, among evaluable patients with HER2 TKD–mutated NSCLC from cohort 5, which included those previously treated with platinum-based chemotherapy with or without immunotherapy and a subsequent HER2-directed antibody-drug conjugate (n = 31), zongertinib generated an ORR of 48% (95% CI, 32%-65%). Specifically, in patients previously treated with fam-trastuzumab deruxtecan-nxki (n = 22; T-DXd; Enhertu), an ORR of 41% (95% CI, 23%-61%) was observed. These findings raise important considerations regarding the optimal sequencing of HER2-directed agents in NSCLC, Sabari noted.

Currently, T-DXd holds FDA accelerated approval in the second-line NSCLC setting, and the randomized frontline phase 3 DESTINY-Lung04 trial (NCT05048797) comparing T-DXd with chemotherapy plus immunotherapy is ongoing, Sabari reported. Zongertinib at the 120-mg dose is also being compared with standard-of-care therapy in patients with HER2-mutated NSCLC in the phase 3 Beamion LUNG-2 trial (NCT06151574), which may position the investigational agent as a viable first-line therapeutic option in this molecular subset of NSCLC, Sabari concluded.