New Hope for Rare but Challenging HER2 Mutations in NSCLC

Novel targeted therapies show promising signs of treating HER2-mutated non–small cell lung cancer (NSCLC), according to new results presented in the second Presidential Symposium at the 2024 World Conference on Lung Cancer (WCLC).

About 1 in 5 patients with breast cancer carry the HER2 mutation,¹ but it’s much rarer in lung cancer, seen about 2% to 4% of patients with NSCLC.² There’s also a great unmet need for these patients, considering the poor prognosis driven by brain metastases and that current treatment options are limited to chemotherapy and antibody-drug conjugates. Abstracts detailing results of novel agents were selected for the WCLC symposium on September 9, 2024, in San Diego, California.

There’s a great unmet need for patients with HER2-mutated non–small cell lung cancer, considering the poor prognosis driven by brain metastases. | Image Credit: © C Davids/peopleimages.com - stock.adobe.com

SOHO-01: BAY 2927088

Xiuning Le, MD, PhD, of MD Anderson Cancer Center, presented findings from the phase 1/2 SOHO-01 study of BAY 2927088, a novel oral tyrosine kinase inhibitor (TKI), in patients with HER2-mutant NSCLC.² These data focused on a cohort of patients who had received chemotherapy but no prior targeted therapy. Of these 44 patients, 63.6% were female and 18.2% had brain metastases at baseline.

Investigator assessment by RECIST 1.1 criteria revealed a 72.1% overall response rate (ORR) and 83.7% disease control rate (DCR), with tumor shrinkage observed regardless of HER2 alteration subtype and presence of brain metastases. Le described good tolerability and manageable adverse events (AEs) observed with BAY 2927088, with no new safety signals seen.

“These data support ongoing investigation of BAY 2927088 in patients with HER2-mutated non–small cell lung cancer,” Le said. In a press briefing following the symposium, she confirmed that the phase 3 SOHO-02 trial is ongoing in hopes of providing further evidence. She also noted that if oral TKIs can move into the frontline setting, their convenience and tolerability vs chemotherapy could improve quality of life for patients and allow them to stay on the treatment for a longer duration.

Beamion LUNG-1: Zongertinib

Data from the phase 1b Beamion LUNG-1 trial of zongertinib were presented by Gerrina Ruiter, MD, PhD, of Netherlands Cancer Institute.³ These results focused on 2 dosages of the novel oral HER2-directed TKI in patients with pretreated NSCLC with a HER2 mutation in the tyrosine kinase domain. Of the 132 patients, 75 received 120 mg and 57 received 240 mg daily; the proportions with brain metastases were high, at 37% and 46%, respectively.

Tumor shrinkage was observed in 94% of patients, ORR was 72.4% in the 120-mg group and 78.2% in the 240-mg group, and DCR was 94.8% and 100.0%, respectively. Data on progression-free survival and duration of response were immature as two-thirds of patients were still receiving treatment as of the data cutoff in May, but in the press briefing Ruiter said that those data should be available by the end of this year. Most treatment-related AEs were manageable, and zongertinib also showed encouraging preliminary intracranial activity.

“Zongertinib demonstrated significant and clinically meaningful activity in patients with pretreated NSCLC with a HER2 tyrosine kinase domain mutation, including in those with brain metastases,” Ruiter said. The agent has been granted a breakthrough therapy designation by the FDA, and investigators are now enrolling for the Beamion LUNG-2 phase 3 trial.

A Patient Perspective on the Findings

At the press briefing, patient advocate Angus Pratt took the podium to share what these findings mean to him. When he was diagnosed with breast cancer in 2018 followed by a diagnosis of lung cancer, he heard a lot of discussion of HER2 as it relates to breast cancer, but not as much about its role in lung cancer, so he is excited that “we’re starting to understand that some of these genetic drivers cross over between the solid tumors.”

There’s still work to do to get these advances into the hands of patients who will benefit, Pratt said. About 43% of patients do not receive biomarker testing before treatment, and considering that all of the work presented here was based on biomarkers, “it is so critical that we advocate and make sure that patients have biomarker testing done before they begin treatment.” He also praised the emerging focus on central nervous system progression in this research, considering that the brain is often the first place that lung cancer will spread to.

“I’m really excited as I sit here and think about the variety of treatments that have been presented here today. The options for lung cancer patients are growing, and we’re seeing so many exciting, new, novel treatments. Yes, these are probably 3, 4, 5 years from market and availability to patients, but those who are coming behind me will need these. It’s just an exciting moment to be involved,” Pratt concluded.

References

1. HER2-positive breast cancer. Cleveland Clinic. Accessed September 9, 2024. https://my.clevelandclinic.org/health/diseases/25213-her2-positive-breast-cancer

2. Le X, Girard N, Jänne 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. Presented at: 2024 World Conference on Lung Cancer; September 9, 2024; San Diego, CA.

3. 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. Presented at: 2024 World Conference on Lung Cancer; September 9, 2024; San Diego, CA.