Positive Results Reported for Hernexeos as a First-Line Treatment for NSCLC With HER2 Mutations

Positive results for Hernexeos (zongertinib) as a first-line treatment for non-small cell lung cancer (NSCLC) with HER2 mutations were reported yesterday at the European Society for Medical Oncology (ESMO) Congress meeting in Berlin.

The FDA gave an accelerated approval to Hernexeos in August 2025 for patients who had been previously treated, but the results from this phase 1 study were from patients who had not been treated. Enrollment in a phase 3 randomized controlled trial, called Beamion LUNG-2, has started, according to Sanjay Popat, M.B.B.S., Ph.D., of The Royal Marsden NHS Foundation Trust, who presented the phase 1b results at the ESMO meeting.

A relatively small percentage — between 2% and 4% — of NSCLC tumors have HER2 mutations. But the tumors tend to be highly aggressive and are associated with a high incidence of brain metastases, Popat told the ESMO audience.

The phase 1b trial he described included 74 patients, two of whom were the exception and had been treated. Most (58%) of the study participants were 65 years old or older, and approximately a third (35%) had a history of tobacco exposure. In roughly a third (30%), the cancer had spread to the brain. The primary end point of the trial was the objective response rate (ORR), a commonly used end point in cancer trials that is calculated as the proportion of patients who have had a measurable reduction in the size of their tumors (there are agreed-upon standards on how that reduction is measured). The secondary end points included disease control, duration of response and progression-free survival.

The results reported by Popat showed an ORR of 77% and a disease control rate of 96%. He also said that the response tended to occur early in treatment and shared data that showed a median time to objective response of 1.4 months.

Other data from the trial showed a median follow-up for duration of response of 9.7 months and a six-month duration of response rate of 80% (95% CI, 65%-89%). The median follow-up for progression-free survival was 11.6 months and the six-month progression-free survival rate was 79%.

A large majority (91%) of the study's participants reported treatment-related side effects, but side effects were mainly mild, with 18% reporting a grade 3 side effect on a scale of 1-5; there were no grade 4 or 5 side effects reported, according to Popat. Eleven (15%) of patients had side effects that resulted in a lowering of the dose of Hernexos, and seven (9%) had side effects that led to discontinuation of treatment. There were two cases of interstitial lung disease/pneumonitis.

“Zongertinib given as a first-line therapy demonstrated significant and clinically meaningful benefit in treatment-naïve patients with advanced HER2-mutant NSCLC,” Popat summarized.

Approximately two-thirds of the patients enrolled in the study had the A775_G776insYVMA type of HER2 mutation. In discussing the ORR and disease control data, Popat showed data that patients with that and other types of mutations benefited from Hernexeos treatment.