HER2-Targeted Treatments for NSCLC: Introducing Zongertinib

Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all diagnosed lung cancers, and harbors oncogenic driver mutations in genes such as EGFR, ALK, KRAS, ERBB2, BRAF, ROS1, NTRK1/2/3, RET, and MET. ERBB2 encodes for HER2, a receptor tyrosine kinase found on the surface of normal epithelial cells that is often overexpressed or mutated in a variety of human malignancies.¹ HER2 alterations consist of 3 forms in NSCLC: gene mutations, gene amplification, and protein overexpression. These are considered distinct tumor subtypes, resulting in different clinical characteristics, prognostics, predictive outcomes and infrequent overlap.^2-5 Approximately 3% of advanced non-squamous NSCLC have a mutation in ERBB2 (HER2) and are associated with female sex, Asian ethnicity, never smoking history, adenocarcinoma histology, a poor prognosis, and a higher incidence of brain metastases.^1,6-8

Currently, standard first-line chemotherapy with or without immunotherapy for patients with NSCLC with HER2 mutations has limited efficacy.^1,9-11 Although HER2-targeted agents are commonly used in the treatment of breast cancer, these agents are lagging in the treatment of NSCLC with only recent approvals in the second-line setting. Over the past few years, additional studies using HER2 tyrosine kinase inhibitors (TKIs), antibody drug conjugates (ADCs), and HER2-targeted monoclonal antibodies have emerged in abundance, with more promising results. Early attempts to target HER2 mutations in pretreated patients with NSCLC were made with pan-ERBB TKIs, such as afatinib (Gilotrif; Boehringer Ingelheim), neratinib (Nerlynx; Puma Biotechnology), and dacomitinib (Vizimpro; Pfizer). However, all prospective small sample studies for these drugs have shown poor outcomes, with an objective response rate (ORR) of 0% to 19.0% and a median progression-free survival (mPFS) of 2.8 to 5.5 months.^12-16 Pan-ERBB inhibitors block all ERBB family members, share common on-target and potentially dose-limiting adverse effects (AEs), including skin rashes and diarrhea, due to inhibiting wild-type (WT) EGFR and thus are hampered in developing their full potential clinical activity in exon 20 dependent tumors.^17,18

A rendering of antibody drug conjugates delivering chemotherapy agents to cancer cells. Image Credit: © Nasnunt

Following the success of ADCs in breast and gastric cancers, these agents have also been evaluated in patients with HER2-positive NSCLC. Ado-trastuzumab emtansine (Kadcyla; Lonza), also known as T-DM1, a humanized ADC consisting of trastuzumab (Herceptin;Roche) and microtubule inhibitor emtansine, produced mixed response rates in patients with metastatic or recurrent NSCLC and HER2 mutations. A small phase 2 trial reported limited efficacy of T-DM1 monotherapy in 15 relapsed HER2-altered patients with NSCLC, 7 with HER2 mutations, but was terminated early due to a poor ORR of 6.7% and median progression free survival (PFS) and overall survival (OS) of 2 months and 10.9 months, respectively.¹⁹ Li et al evaluated the role of T-DM1 in 18 patients with HER2-mutant NSCLC in another small phase 2 basket trial, where the ORR was 44% with a median PFS of 5 months. The updated analyses that included 28 patients showed an ORR of 50%.^20-22

Trastuzumab deruxtecan (Enhertu; Daiichi Sankyo), a newer ADC, consisting of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload through a tetrapeptide-based cleavable linker, was evaluated in patients with metastatic nonsqaumous NSCLC and ERBB2 mutations in the DESTINY-Lung01 trial (NCT03505710). Cohort 2 included 91 HER2-mutant pretreated patients. The ORR was 55%, mPFS of 8.2 months, mDOR of 9.3 months, and mOS of 17.8 months. Efficacy was also observed in 33 patients with brain metastases where the mPFS and mOS were 7.1 months and 13.8 months, respectively.²³ Due to high rates of interstitial lung disease (ILD), which occurred in 26% of patients, leading to 2 deaths, a second trial compared a lower dose of 5.4 mg/kg every 3 weeks vs 6.4 mg/kg every 3 weeks. This was found to show a significant reduction in ILD, 5.9% vs 14%, while maintaining efficacy.²⁴ Based on these data, T-DXd was approved by the FDA for patients with advanced and metastatic HER2-mutant NSCLC who had received prior systemic therapy and is considered the preferred treatment option currently following first-line treatment with chemotherapy with or without immunotherapy. Trastuzumab emtansine is categorized as an “other recommendation” and currently does not hold an FDA-approved indication in the NSCLC setting.¹

Despite efficacy of T-DM1 and T-DXd for advanced NSCLC with HER2 mutations, sample sizes of these trials have been small, with majority of trials excluding those with CNS disease. These treatments have also been associated with treatment-related AEs (TRAEs) including ILD or pneumonitis and require outpatient administration every 3 weeks. Therefore, there exists a critical unmet medical need for selective, orally available, and well-tolerated HER2 TKIs that effectively target HER2 mutants while limiting toxicity.

Zongertinib (BI 1810631; Boehringer Ingelheim), a novel HER2-specific TKI, binds selectively and covalently to the HER2 tyrosine kinase domain while sparing EGFRWT. Beamion LUNG-1 (NCT04886804), a phase 1a/1b, first-in-human, open-label trial, is evaluating the safety and efficacy of zongertinib in patients with HER2 aberration-positive solid tumors (phase 1a) and HER2 mutation-positive (m+) NSCLC (phase 1b). Part 1a was a dose escalation to investigate the safety, tolerability, and pharmacokinetics (PK) of escalating doses of zongertinib as monotherapy (administered orally twice daily or once daily) in patients with advanced and/or metastatic solid tumors of any histology and to determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose.²⁵ At data cut-off (September 15, 2023), 61 patients in phase 1a received zongertinib at 15/30/60/100/150 mg twice daily (n = 3/3/4/4/3) and 60/120/ 180/240/300/360 mg once daily (n = 5/4/9/12/10/4). In 53 evaluable patients, the ORR and disease control rate (DCR) was 49% and 91%, respectively. In patients with HER2 mutations (n=29) the ORR and DCR was 62% and 97%, respectively. In 36 evaluable patients with NSCLC the ORR and DCR were 58% and 97%, respectively. The overall mDoR was 12.7 months. In all treated patients, median PFS was 8.7 months (95% CI: 5.5 months–not evaluable [NE]). In the 36 patients with NSCLC, median PFS was NE (95% CI: 7.6 months─NE). TRAEs occurred in 72% of the patients, with 2% of patients experiencing serious TRAEs (grade 3 increase in liver function tests). Two dose limiting toxicities were observed at data cutoff, grade 3 thrombocytopenia (360 mg once daily) and grade 3 diarrhea (240 mg once daily). In a prespecified interim analysis of phase 1b (July 31, 2023), 42 patients were treated in cohort 1 (pretreated HER2 m+ NSCLC randomized to 120/240 mg QD). TRAEs of all grades occurred in 67% of patients, with 5% of patients having grade 3 and grade 4 TRAEs and 0% with grade 5. The most common TRAE was diarrhea, with 24% of patients having grade 1, and 5% of patients having grade 2, none with grade 3 or higher. Serious TRAEs occurred in 5% of patients (n = 2; grade 4 decreased neutrophils, grade 4 immune thrombocytopenia). No AEs led to treatment discontinuation. The ORR and DCR in phase 1b (n = 23) were 73.9% and 91.3%, respectively.²⁶

Zongertinib was well-tolerated with low rates of EGFR-mediated AEs, and low grade 3 or higher AEs. Based on encouraging efficacy and tolerability data, a phase 3 confirmatory study is underway.²⁷ Similarly to current approved treatment T-DXd for second-line HER2 NSCLC, ORR were approximately 50% with mPFS not reached. Toxicities were tolerable, with no ILD or pneumonitis reported. Most toxicities were limited to grade 1 and 2, potentially indicating a better future tolerated treatment option.

Oncology pharmacists are viewed as cancer medication experts who focus their time providing direct patient care, patient education, and actively participating in clinical decision making. As an oncology pharmacist, it is pivotal to be aware of new treatments in the pipeline and be familiar with current drugs approved. Understanding these newer treatments allows us to work collaboratively with other health care professionals, develop institutional guidelines, and make evidence-based decisions to improve patient care.

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