Two novel oral HER2 tyrosine kinase inhibitors have demonstrated promising efficacy in patients with HER2-mutant non–small cell lung cancer (NSCLC), potentially transforming the treatment landscape for this rare but challenging subset of lung cancer cases. According to data presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer, the oral reversible HER2 inhibitor BAY 2927088 achieved a 72.1% overall response rate in patients with HER2-mutant NSCLC, with even greater efficacy (90% overall response rate) seen in those with HER2 YVMA insertions.¹

Xiuning Le, MD, PhD

“BAY 2927088 treatment led to rapid and durable responses in patients with previously treated HER2-mutant NSCLC,” lead study author Xiuning Le, MD, PhD, Associate Professor, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, said during the presentation.

In a separate study presented during the Presidential Symposium, the selective and covalent HER2 tyrosine kinase inhibitor zongertinib demonstrated significant activity, with a 66.7% confirmed overall response rate, including promising intracranial efficacy.²

Gerrina Ruiter, MD, PhD

“Zongertinib demonstrated significant and clinically meaningful activity in patients with pretreated HER2-mutant NSCLC, including those with brain metastases,” said lead study author Gerrina Ruiter, MD, PhD, a pulmonologist specialized in thoracic oncology at the Netherlands Cancer Institute. “The drug was very well tolerated, with a low incidence of dose reductions and treatment discontinuations.”

SOHO-01 Trial

As the researchers reported, HER2 mutations occur in approximately 3% of NSCLC cases and are associated with a poor prognosis and a higher incidence of brain metastases. Until recently, treatment options have been limited.

Dr. Le presented results from the expansion cohort of the phase I/II SOHO-01 study evaluating BAY 2927088. Overall, 44 patients were included in the efficacy analysis of cohort D, which included patients with HER2-activating mutations, HER2 exon 20 insertions, and those who were naive to other targeted treatments. The recommended dose of BAY 2927088 was 20 mg.

The study demonstrated an overall response rate of 72.1%, with a disease control rate of 83.7%. The median duration of response was 8.7 months, and the median progression-free survival was 7.5 months.

Even more striking results were observed in the subgroup of patients with HER2 YVMA insertions, which comprised 70% of the cohort. In this group, the overall response rate reached 90%, with a disease control rate of 97% and a median progression-free survival of 9.9 months. In addition, said Dr. Le, patients with brain metastases, and those who received prior immunotherapy, derived a similar magnitude of benefit compared with the total cohort.

According to Dr. Le, the safety profile was also manageable, with diarrhea being the most common treatment-related adverse event, primarily grade 1 or 2.

“BAY 2927088 again demonstrated good tolerability, and no new safety signals were observed,” Dr. Le added. “These data support ongoing investigation of BAY 2927088 in this patient population.”

Assessment of BAY 2927088 is ongoing as part of the phase III SOHO-02 trial (ClinicalTrials.gov identifier NCT06452277).

Beamion LUNG-1 Trial

Similarly positive results were presented by Dr. Ruiter from the primary phase Ib analysis of the Beamion LUNG-1 trial investigating zongertinib. The trial consists of two parts: a dose-escalation phase Ia and a dose-expansion phase Ib. In phase Ib, five different cohorts of patients with NSCLC were included, with the presented data focusing on cohort 1.

Cohort 1 included only patients with pretreated NSCLC and HER2 mutations within the tyrosine kinase domain. As part of the U.S. Food and Drug Administration’s (FDA’s) Project Optimus, patients were randomly assigned between the 120-mg and 240-mg doses. After an interim futility analysis, the 120-mg dose was selected for further exploration. At the 120-mg dose, the primary endpoint was met for all patients treated with zongertinib, which achieved a confirmed overall response rate of 66.7% by blinded independent central review. Tumor shrinkage was observed in 94% of patients, and the disease control rate exceeded 94%.

Of note, zongertinib also showed encouraging intracranial activity, with a preliminary intracranial overall response rate of 33% and a high intracranial disease control rate. According to Dr. Ruiter, this finding is particularly significant given the propensity for brain metastases in patients with HER2-mutant NSCLC.

The safety profile of zongertinib was also favorable, said Dr. Ruiter, with most treatment-related adverse events being “mild and easily manageable.” Diarrhea and rash were the most common adverse events but were predominantly grade 1 or 2. No grade 3 rashes were reported. Of 132 patients, only 4 discontinued treatment because of adverse events, Dr. Ruiter added, underscoring the drug’s tolerability. Two-thirds of patients remained on treatment at the data cutoff.

The FDA has granted zongertinib Breakthrough Therapy designation, and the phase III Beamion LUNG-1 trial continues to enroll participants. The randomized study will compare zongertinib with the standard of care as a first-line treatment in this patient population.

EXPERT POINT OF VIEW

Chee Khoon Lee, MBBS, PhD, FRACP

Abstract discussant Chee Khoon Lee, MBBS, PhD, FRACP, Clinical Lead, Thoracic Oncology Program, Professor of Oncology, NHMRC Clinical Trials Centre, The University of Sydney, Australia, contextualized the significance of these findings for this rare patient population.

“The emergence of BAY 2927088 and zongertinib represents a significant step forward in the treatment of HER2-mutant non–small cell lung cancer [NSCLC],” said Dr. Lee. “Both agents demonstrate impressive efficacy, including in patients with brain metastases, and appear to have manageable safety profiles.”

Dr. Lee noted that the results compare favorably with the current standard of care, fam-trastuzumab deruxtecan-nxki (T-DXd), which showed an overall response rate of 55% in the DESTINY-Lung01 trial. An ongoing concern with T-DXd has been grade 3 or higher interstitial lung disease, which occurred in approximately 25% of the patient population, he said. However, a subsequently conducted dose optimization study demonstrated reduced toxicity with preserved efficacy.

Dr. Lee highlighted several important considerations for the field moving forward. He emphasized the importance of dose optimization to balance efficacy and tolerability, which is “crucial for improving patient compliance and outcomes.” He also stressed the need to consider not just safety profiles but also the impact of lower-grade adverse events on patients’ quality of life and treatment adherence.

“Tolerability is subjective and depends on whose perspective you are referring to,” Dr. Lee observed. “Optimization of the dose is obviously important, not only to improve compliance, but the ability to cope with the treatment as well.” Finally, Dr. Lee underscored the importance of proper benchmarking to accurately assess the true benefit of these new therapies compared with existing treatments.

Both BAY 2927088 and zongertinib have received Breakthrough Therapy designation from the U.S. Food and Drug Administration, reflecting their potential to address a significant unmet medical need. Ongoing trials include continued the investigation of BAY 2927088 in HER2-mutant NSCLC and a phase III randomized study (Beamion LUNG-1) comparing zongertinib with the standard of care as first-line treatment.

“As research continues, these oral targeted therapies may offer new hope for patients with this challenging type of lung cancer,” said Dr. Lee. “However, the road map toward routine clinical use requires more consideration of optimized dosing to improve tolerability,” he cautioned. “Ongoing translational work is needed to understand mechanisms of resistance and rationally design future combination therapies,” Dr. Lee concluded.

DISCLOSURE: Dr. Le reported financial relationships with AbbVie, Abion, Amgen, AstraZeneca, Blueprint Medicines, BeiGene, BMS, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lilly, EMD Serono, GENINUS, Gritstone, Hanmi, IMBdx, Incyte Scientific, Janssen Research & Development, Johnson & Johnson, Loxo, Merck KGaA, MSD, Ono Pharmaceutical, Puma Biotechnology, Roche, and Takeda. Dr. Ruiter reported financial relationships with AstraZeneca, AbbVie, Daiichi Sankyo, Cullinan Oncology, Boehringer Ingelheim, Merus, Bayer, Navire, BridgeBio, Bristol Myers Squibb, Ikena Oncology, Scorpion Therapeutics, Taiho Oncology, Revolution Medicine, Pierre Fabre, and Novartis. Dr. Lee reported financial relationships with Amgen, AstraZeneca, Merck KGA, Merck, Roche, GSK, Novartis, Takeda, Pfizer, Janssen, and Gilead Sciences.

REFERENCES

1. Le X, Girard N, Janne PA, et al: Safety and efficacy of BAY 2927088 in patients with HER2-mutant NSCLC: Expansion cohort from the phase I/II SOHO-01 study. 2024 World Conference on Lung Cancer. Abstract PL04.03. Presented September 9, 2024.

2. Ruiter G, Tu HY, Ahn MJ, et al: Primary phase Ib analysis of Beamion LUNG-1: Zongertinib (BI 1810631) in patients with HER2 mutation-positive NSCLC. 2024 World Conference on Lung Cancer. Abstract PL04.04. Presented September 9, 2024.