Competition for first-line HER2-mutant lung cancer

Enhertu improved progression-free survival compared to standard of care in Phase 3 trial

Boehringer ingelheim secures first-line treatment approval…Bayer joins the competition

The competition surrounding targeted therapy for HER2-mutated non-small cell lung cancer (NSCLC), a mutation found in a small subset of lung cancer patients, is rapidly shifting toward first-line treatment.  

​Previously, the conventional treatment paradigm for HER2-mutated lung cancer involved treating patients with immune checkpoint inhibitors and chemotherapy as first-line treatment, followed by HER2-targeted agents upon disease progression.

​Recently, the therapeutic landscape has shifted as both antibody-drug conjugates (ADCs) and oral tyrosine kinase inhibitors (TKIs) continue to deliver positive clinical outcomes earlier in treatment.

ADC drug 'Enhertu'

According to industry sources on the 19th, AstraZeneca recently unveiled high-level results from its pivotal global Phase 3 clinical trial, DESTINY-Lung04, evaluating the efficacy of 'Enhertu (trastuzumab deruxtecan).'  

DESTINY-Lung04 is a head-to-head study directly comparing Enhertu against the standard of care, 'Keytruda (pembrolizumab)' + platinum-based chemotherapy, in patients with unresectable, locally advanced, or metastatic HER2-mutated non-squamous NSCLC.  

​The trial enrolled 454 patients with HER2 exon 19 or 20 mutations. Patients were randomized 1:1 to receive either Enhertu or standard chemotherapy plus immunotherapy. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review (BICR).  

​Trial results demonstrated that Enhertu achieved a statistically significant and clinically meaningful improvement in PFS compared with the standard-of-care regimen. Specific median PFS values and hazard ratios (HR) have not yet been disclosed.  

​This study is clinically significant as the first Phase 3 trial in which a HER2-targeted therapy demonstrated superior PFS over the global standard of care in the first-line treatment of these patients.  

​Overall survival (OS) evaluation remains ongoing. The safety profile was broadly consistent with previously established data for Enhertu, with no new safety signals observed. The company will present detailed study findings at an upcoming medical congress.  

​Later-line treatment 'Enhertu' to first-line…HER2-targeted therapy advances

Enhertu may help move targeted therapy earlier in the disease course for HER2-mutated lung cancer.  

​Currently, first-line treatment of HER2-mutated metastatic NSCLC relies primarily on the combination of immunotherapy and platinum-based chemotherapy. HER2 mutations are identified in approximately 2% to 4% of all NSCLC cases.  

​HER2-mutated lung cancer is recognized as a molecular subtype predominantly observed in younger female patients and non-smokers, with a relatively high reported incidence of brain metastases. This mutation is biologically distinct from HER2 protein overexpression or gene amplification. Both Enhertu and the oral TKIs entering the first-line treatment race specifically target patients harboring activating HER2 mutations.

​Before the entry of Enhertu, therapeutic options utilizing direct HER2-targeted agents in this patient population were severely limited. After Enhertu's successful establishment in later lines of therapy, the emergence of oral targeted agents has fueled intense therapeutic development competition.

​Notably, this competition is shifting from pretreated patients to treatment-naïve first-line treatment cohorts.

​As Enhertu demonstrated superiority over chemoimmunotherapy in a randomized Phase 3 trial, anticipated regulatory approvals are expected to bolster the strategy of deploying targeted therapies immediately upon biomarker confirmation of HER2 mutations.

​However, because mature OS outcomes and detailed PFS data have yet to be disclosed, thorough evaluation of the granular dataset will be necessary to fully gauge the magnitude of clinical benefit over current standard therapies.

Not limited to ADCs...Oral TKIs join the first-line treatment competition

Boehringer Ingelheim's 'Hernexeos (zongertinib)'

Oral TKIs have also entered the first-line treatment area for HER2-mutated lung cancer. The first agent to secure first-line approval is Boehringer Ingelheim's 'Hernexeos (zongertinib).'

​In February, the U.S. Food and Drug Administration (FDA) approved an expanded indication for Hernexeos in adult patients with unresectable or metastatic non-squamous NSCLC harboring HER2 (ERBB2) tyrosine kinase domain (TKD) activating mutations, allowing its use regardless of prior systemic therapy.  

​Hernexeos' indication expanded to first-line treatment just six months after its initial U.S. approval in August of last year for previously treated patients.

​The 'Beamion LUNG-1 trial,' which supported the first-line treatment expansion, included 72 treatment-naïve patients with HER2 TKD mutations.

​In the study, Hernexeos demonstrated an objective response rate (ORR) of 76%. Among responding patients, 64% maintained their response for at least 6 months, and 44% maintained it for 12 months or longer.

Its once-daily oral administration distinguishes Hernexeos, dosed at 120 mg or 180 mg based on patient body weight.

​Bayer's 'Hyrnuo (sevabertinib)' is closely pursuing this space. Hyrnuo received accelerated approval from the U.S. FDA in November of last year for patients with HER2 TKD-mutated locally advanced or metastatic non-squamous NSCLC who had received prior systemic therapy. It is an oral TKI administered twice daily.  

​Bayer has since advanced clinical development to broaden its indication to treatment-naïve patients. In May, the FDA granted priority review designation to Hyrnuo's supplemental application for the first-line setting, supported by findings from the SOHO-01 trial, which enrolled treatment-naïve patients.  

​Concurrently, Bayer is conducting the 'SOHO-02' trial, a Phase 3 trial comparing Hyrnuo against standard-of-care therapy in treatment-naïve patients with HER2-mutated NSCLC, which serves as the confirmatory study to verify the clinical benefit underlying its accelerated approval.

​Consequently, competition among distinct formulations of HER2-targeted agents in the first-line treatment of HER2-mutated lung cancer is set to intensify.

​Enhertu is an antibody-drug conjugate (ADC) designed to bind HER2 on tumor cells and deliver a potent cytotoxic topoisomerase I inhibitor payload. In contrast, ​Hernexeos and Hyrnuo are oral small-molecule TKIs that selectively and directly inhibit oncogenic signaling driven by HER2 mutations.  

In the future, once Enhertu is approved for first-line treatment and Hyrnuo clears regulatory review, establishing optimal treatment sequencing strategies, specifically the order of administering ADCs versus oral TKIs, will emerge as a central clinical challenge.

Notably, therapeutic strategy is expected to be guided by key factors such as duration of response, efficacy against central nervous system (CNS) and brain metastases, safety and tolerability profiles, and real-world clinical outcomes observed with sequential use of ADCs and TKIs.

​Although HER2-mutated lung cancer represents a rare molecular subtype with a relatively small patient population, the sequential emergence of targeted therapies into commercial reality, initiated by Enhertu and followed by oral TKIs, is rapidly establishing an upfront, biomarker-driven treatment paradigm akin to EGFR- and ALK-mutated NSCLC.