BI and Bayer Challenge Enhertu's Dominance in HER2-Mutant NSCLC with Promising Oral TKIs Zongertinib and BAY 2927088

In the treatment of patients with a rare and critical mutation of the human epidermal growth factor receptor 2 (HER2) in non-small cell lung cancer (NSCLC), the ADC drug Enhertu from AstraZeneca/Daiichi Sankyo currently holds an unshakable position.

But the challengers are ready. At the 2024 World Conference on Lung Cancer, Boehringer Ingelheim (BI) and Bayer announced their newly developed oral drugs—Zongertinib and BAY 2927088—which both demonstrated the potential to challenge the current market leader Enhertu. In their respective Phase 1b and Phase 1/2 trials, they achieved objective response rates of 66.7% and 72.1%, with HER2-mutant lung cancer patients recruited for the trials.

Zongertinib is an orally administered HER2 tyrosine kinase inhibitor (TKI) currently under development. Zongertinib is designed to avoid affecting wild-type EGFR, thereby reducing associated toxicity.

In the recently published Beamion LUNG-1 Phase Ib trial, a total of 132 patients received Zongertinib treatment at doses of either 120mg or 240mg daily (n=75/n=57). According to the central independent blinded review (BICR) assessment, the confirmed objective response rate (ORR) was 66.7%. Tumor shrinkage of varying degrees was observed in 94% of patients across all dose groups. Patients treated with Zongertinib at 120mg daily demonstrated a response rate of 72.4%, while those receiving 240mg daily had a response rate of 78.2%, with disease control rates (DCR) of 95% and 100%, respectively.

According to Boehringer Ingelheim, data also preliminarily demonstrated Zongertinib's activity against brain lesions. Based on independent central blinded review (BICR) and RANO-BM (Response Assessment in Neuro-Oncology - Brain Metastases) criteria, among patients with asymptomatic brain metastases, 33% (120mg; n=27) and 40% (240mg; n=25) achieved confirmed objective responses, with disease control rates (DCR) of 74% and 92%, respectively.

Moreover, 17% of patients receiving the 120 mg dose and 19% of patients receiving the 240 mg dose experienced grade 3 or higher adverse events, with the most common side effects being mild, such as diarrhea and rash.

Boehringer Ingelheim will announce progression-free survival and duration of response data later this year. However, it is worth noting that in the Beamion LUNG-1 trial, 3% of patients had to discontinue Zongertinib treatment due to side effects.

BAY 2927088 is an orally reversible tyrosine kinase inhibitor (TKI) that effectively inhibits mutant human epidermal growth factor receptor 2 (HER2), including HER2 exon 20 insertions and HER2 point mutations, as well as epidermal growth factor receptor (EGFR), with high selectivity for mutant EGFR.

In the Phase 1/2 expansion trial of Bayer's recently announced SOHO-01 trial, one patient treated with BAY 2927088 experienced complete cancer disappearance. The median duration of response in the study was 8.7 months, and the median progression-free survival was 7.5 months.

SOHO-01 is an ongoing open-label, multicenter Phase 1/2 study. The results reported are from patients with advanced NSCLC harboring HER2 activating mutations who had progressed after receiving ≥1 prior lines of systemic therapy for advanced disease and had not received HER2-targeted therapy. In the trial, patients were administered BAY 2927088 orally at 20 mg twice daily. Of the 44 enrolled patients, 43 were evaluable for efficacy, with a confirmed objective response rate (ORR) of 72.1% (n=31; 95% CI 56.3, 84.7), including one complete response (2.3%). The median duration of response (DOR) and progression-free survival (PFS) were 8.7 months (95% CI 4.5, not estimable) and 7.5 months (95% CI 4.4, 12.2), respectively. Among patients with the HER2 YVMA insertion (the most common mutation), the ORR was 90.0%, with a DOR of 9.7 months and PFS of 9.9 months. Three patients (6.8%) discontinued treatment due to treatment-related adverse events (TRAEs).

Zongertinib and BAY 2927088 are both currently in Phase 3 trials and are expected to complete Phase 3 trials by May 2028.

Although Enhertu is an ADC drug, both Zongertinib and BAY 2927088 are small molecules with different mechanisms of action, meaning they may potentially be used in combination with Enhertu.

"Imagine the ADC drug binding to the membrane and then the TKI entering the ATP-binding pocket (of the protein)," said Xiuning Le, M.D., an oncologist at The University of Texas MD Anderson Cancer Center and the lead researcher of Bayer, during a press release. "They have real synergy, targeting, deep inhibition, so the tumor shrinkage and duration can be fantastic." She added that combinations like these still need to be tested in preclinical and clinical settings.

As these two fiercely competitive pharmaceutical companies intensify their preparations, potentially posing a challenge to Enhertu, AstraZeneca and Daiichi Sankyo have been striving to expand the dominance of their drug across different cancer types. Enhertu generated $893 million in revenue in the second quarter of 2024, marking a 1.6% increase from the first quarter.

Recently, Bayer's global Phase 3 SOHO-02 trial has enrolled its first patient, an open-label, randomized, multicenter clinical trial designed to evaluate the efficacy and safety of the investigational drug BAY 2927088 as a first-line therapy for patients with advanced non-small cell lung cancer harboring activating HER2 mutations.

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