Dr Piotrowska on Treatment Sequencing Decisions in HER2-Mutated NSCLC

“In addition to the ongoing trials helping to inform the ultimate optimal placement of T-DXd, we’ve also seen exciting clinical trials with HER2-directed oral TKIs.”

Zosia Piotrowska, MD, MHS, instructor, Harvard Medical School; medical oncologist, Massachusetts General Hospital, discusses patient characteristics and disease factors that guide treatment decision-making and sequencing for patients with HER2-mutated non–small cell lung cancer (NSCLC), as well as ongoing research that may expand this treatment paradigm.

Treatment selection for patients with advanced HER2-mutated NSCLC begins with first-line therapy considerations, Piotrowska says. Currently, the only FDA-approved therapy for patients with HER2-mutated NSCLC is fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), a HER2-directed antibody-drug conjugate that is indicated for patients in the post-chemotherapy setting, she explains. Therefore, platinum-based doublet chemotherapy remains the preferred first-line treatment for newly diagnosed patients, she notes. Immunotherapy is typically avoided for patients with frontline HER2-mutated NSCLC, particularly those with minimal or no smoking history, a common characteristic of this disease, she reports. However, shared decision-making should be employed when selecting between chemotherapy alone or chemoimmunotherapy, she adds.

Upon disease progression following first-line treatment, second-line therapy with T-DXd or enrollment in a clinical trial is typically considered, according to Piotrowska. Findings from the ongoing phase 3 DESTINY-Lung04 trial (NCT05048797), which is investigating T-DXd in the first-line HER2-mutated NSCLC setting, may alter the standard of care in the future, she continues. Additionally, despite the limitations of earlier agents in this class, HER2-directed oral TKIs are showing activity in clinical research. Prior HER2-directed TKIs included pyrotinib and poziotinib, which are associated with high rates of off-target toxicities like severe diarrhea, she says.

Emerging mutant-selective HER2 inhibitors are also demonstrating improved efficacy and safety profiles, Piotrowska continues. Zongertinib (BI 1810631), the most advanced of these agents in development, elicited an overall response rate (ORR) of 66.7%(97.5% CI, 53.8%-77.5%; P <.0001) among patients with HER2-mutated NSCLC treated with 120 mg of the agent (n = 75) in the phase 1b portion of the phase 1 Beamion LUNG-1 trial (NCT04886804). Moreover, early signals of intracranial activity were observed with zongertinib at the 120 mg (n = 27) and 240 mg (n = 25) dose levels. This agent was also associated with manageable grade 3 toxicities, including diarrhea and rash, she explains.

Another HER2-directed TKI, BAY2927088, generated a 72.1% (95% CI, 56.3%-84.7%) ORR among 43 patients with HER2-mutant NSCLC, including those with YVMA exon 20 insertion mutations, in cohort D of the phase 1 SOHO-01 trial (NCT05099172). However, this agent was associated with a relatively high rate of grade 3 or greater diarrhea, which was observed in 25.0% of patients, Piotrowska concludes.