Dr Li on Choosing Between a TKI and ADC in HER2-Mutant NSCLC

“We expect [that] both modalities will come into our armamentarium, so the question is, which one should go first, and would the first [treatment] impact the effect of the second? It seems that the [TKI] may be less effective if [patients] were previously treated with an ADC.”

Molly Li, MBBS, an assistant professor in the Department of Clinical Oncology at the Chinese University of Hong Kong, discussed the emerging decision between HER2-directed tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs) as first-line therapy for HER2-mutant non–small cell lung cancer (NSCLC), weighing efficacy across mutation subtypes, central nervous system activity, toxicity, and treatment sequencing.

Two oral HER2 TKIs, zongertinib (Hernexeos) and sevabertinib (Hyrnuo), are now FDA approved in both the first- and second-line settings for HER2 TKD–mutant NSCLC, with sevabertinib’s frontline approval based on data from the phase 1/2 SOHO-01 trial (NCT05099172), Li noted. In the frontline cohort of SOHO-01, sevabertinib produced an objective response rate (ORR) of 75% (95% CI, 64%-85%; n = 69); in the frontline cohort of the phase 1/2 Beamion LUNG-1 trial (NCT04886804), zongertinib produced an ORR of 76% (95% CI, 65%-84%) and a median progression-free survival (PFS) of 14.4 months (95% CI, 11.1-not evaluable; n = 74). Meanwhile, fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), an ADC approved in the second line based on data from the phase 2 DESTINY-Lung02 trial (NCT04644237), produced a statistically significant PFS improvement over platinum-pemetrexed chemotherapy plus pembrolizumab (Keytruda) as first-line therapy in the phase 3 DESTINY-Lung04 trial (NCT05048797), according to topline results.

According to Li, efficacy is strongest against YVMA-type exon 20 insertions, the predominant HER2 TKD mutation; non-TKD mutations, excluded from DESTINY-Lung04, respond poorly to either class, leaving frontline chemoimmunotherapy an option there. Intracranial response rates with zongertinib and T-DXd are both roughly 40%, Li said, and toxicity differs: the TKIs cause mainly diarrhea, rash, and transaminitis with no reported interstitial lung disease (ILD), while T-DXd carries chemotherapy-related toxicity and a 15% to 20% ILD rate. The unresolved question, Li said, is sequencing: in small cohorts, TKI response rates fell to 40% to 50% after prior ADC exposure, vs 60% to 70% in ADC-naive patients. Li concluded that having both modalities available marks real progress, with DESTINY-Lung04’s full results expected to clarify the optimal frontline choice.