TKIs Look to Solidify a Role Alongside T-DXd in the Second-Line HER2-Mutant NSCLC Setting

Treatments are rapidly evolving in the second-line setting and beyond for patients with HER2-mutated non–small cell lung cancer (NSCLC), with several promising TKIs under development looking to join fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in this setting.

Following standard of care (SOC) systemic frontline therapy, T-DXd is the NCCN guideline preferred option alongside the other recommended regimen ado-trastuzumab emtansine (Kadcyla).1 Data from the final analysis of the phase 2 DESTINY-Lung02 trial (NCT04644237) that were presented at the 2024 ASCO Annual Meeting showed that patients with metastatic HER2-mutated NSCLC who received at least 1 prior anticancer therapy achieved a confirmed objective response rate (ORR) of 50.0% (95% CI, 39.9%-60.1%) when treated with 5.4 mg/kg of the antibody-drug conjugate (ADC; n = 102).2 Patients who received 6.4 mg/kg of T-DXd (n = 50) achieved an ORR of 56.0% (95% CI, 41.3%-70.0%). The median overall survival (OS) was 19.0 months (95% CI, 14.7-not estimable [NE]) in the 5.4 mg/kg arm and 17.3 months (95% CI, 13.8-NE) in the 6.4 mg/kg arm.

HER2 alterations are not as common in NSCLC as in other tumor types—occurring in approximately 1% to 4% of patients—but challenges remain regarding treatments for patients with HER2-mutant NSCLC such as the optimal sequencing of therapies.3 Balancing toxicities with efficacy for patients with HER2-mutated NSCLC is also a key consideration. The safety of T-DXd reported in the final analysis of DESTINY-Lung02 showed that the 5.4 mg/kg dose was associated with a more favorable benefit/risk profile than the 6.4 mg/kg dose.2

There were also no significant changes in toxicity seen according to the longer follow-up data. Drug-related treatment-emergent adverse effects (TEAEs) in the 5.4 mg/kg and 6.4 mg/kg arms were grade 3 or higher (39.6%; 60.0%, respectively), serious (13.9%; 28.0%), and associated with treatment discontinuation (14.9%; 26.0%), treatment interruption (30.7%; 54.0%), dose reduction (16.8%; 34.0%), and death (1.0%; 2.0%). Further, any-grade interstitial lung disease (ILD)/pneumonitis occurred in 14.9% of patients treated with 5.4 mg/kg of T-DXd and 32.0% of those given 6.4 mg/kg of the ADC.

Given the efficacy of T-DXd in this setting, the phase 3 DESTINY-Lung04 study (NCT05048797) is currently enrolling patients with NSCLC and HER2 exon 19 or 20 mutations to receive the agent vs SOC platinum-chemotherapy plus pemetrexed and pembrolizumab (Keytruda) in the frontline setting.4

Promising TKIs under examination in the second line of the evolving NSCLC space include zongertinib (BI 1810631), which is an irreversible TKI that selectively inhibits HER2 but spares EGFR, thus avoiding associated toxicities.5 Data from the phase 1 Beamion LUNG-1 study (NCT04886804) presented during the 2024 ESMO Asia Congress showed that patients with HER2-altered advanced solid tumors (n = 75) who received 120 mg of zongertinib achieved a confirmed ORR of 71% (95% CI, 60%-80%; P < .0001). At the August 29, 2024, data cutoff, 55% of responding patients remained on treatment.

Safety data also revealed that no fatal treatment-related AEs (TRAEs) were reported, and most TRAEs associated with zongertinib were of low grade; grade 3 or higher TRAEs included increased alanine aminotransferase levels (8%), increased aspartate aminotransferase levels (5%), diarrhea (1%), and decreased neutrophil count (1%). Additionally, there were no cases of ILD reported and rates of dose reduction and treatment discontinuation due to AEs were low at 5% and 3%, respectively.

Following the encouraging data seen in Beamion LUNG-1, the phase 3 Beamion LUNG-2 trial (NCT06151574) is currently enrolling patients to receive zongertinib vs SOC as first-line therapy for patients with HER2-mutated advanced NSCLC. The FDA also granted fast track designation to the agent in 2023 and breakthrough therapy designation to it in 2024 for patients with advanced, unresectable, or metastatic NSCLC who have received prior systemic therapy and have activating HER2 mutations.6

Furthermore, the oral, small molecule, TKI BAY 2927088 demonstrated efficacy according to data from the phase 1/2 SOHO-01 trial (NCT05099172) that were presented at the 2024 IASLC World Conference on Lung Cancer.7 Patients with advanced NSCLC harboring a HER2 activating mutation (n = 43) experienced an ORR of 72.1% (95% CI, 56.3%-84.7%) with a median duration of response (DOR) of 8.7 months (95% CI, 4.5-NE). The median progression-free survival (PFS) was 7.5 months (95% CI, 4.4-12.2). Additionally, in patients with HER2 YVMA insertions who were treated with BAY 2927088 (n = 30), the ORR was 90.0% (95% CI, 73.5%-97.9%) with a median DOR of 9.7 months (95% CI, 5.5-NE); these patients also achieved a median PFS of 9.9 months (95% CI, 6.9-NE).7,8

Data also revealed that 40.9% of patients treated with BAY 2927088 experienced grade 3 TRAEs.7 The most common TRAEs that occurred were diarrhea (86.4%), rash (43.2%), paronychia (25.0%), and nausea (25.0%).8 Grade 3 or higher TRAEs included diarrhea (25.0%), vomiting (4.5%), decreased appetite (4.5%), nausea (2.3%), stomatitis (2.3%), pruritis (2.3%), and increased aspartate aminotransferase levels (2.3%). No grade 4 TRAEs or ILD/pneumonitis were reported, and 1 patient experienced a grade 5 TRAE of dyspnea. Additionally, 31.8% of patients had dose reductions due to TRAEs and 6.8% had TRAEs that led to treatment discontinuation.

The management of HER2-mutated NSCLC continues to shift with agents that showed efficacy in the second-line setting undergoing examination in the frontline—along with T-DXd, BAY 2927088 is under examination in the first-line setting.4,9 The phase 3 SOHO-02 trial (NCT06452277) is currently enrolling patients with locally advanced or metastatic NSCLC and HER2 activating mutations to receive BAY 2927088 vs SOC therapy.9 Furthermore, several other TKIs are also under evaluation for patients with HER2-mutated NSCLC, including in phase 3 trials. The phase 3 PYRAMID-1 study (NCT04447118) is currently active and examining pyrotinib vs docetaxel in patients with advanced nonsquamous NSCLC who have a HER2 exon 20 mutation and experienced progression on prior platinum-based chemotherapy.10

References

1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2025. Accessed January 20, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
2. Jänne PA, Goto Y, Kubo T, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant metastatic non–small cell lung cancer (mNSCLC): final analysis results of DESTINY-Lung02. J Clin Oncol. 2024;42(suppl 16):8543. doi:10.1200/JCO.2024.42.16_suppl.8543
3. Yu Y, Yang Y, Li H, Fan Y. Targeting HER2 alterations in non-small cell lung cancer: therapeutic breakthrough and challenges. Cancer Treat Rev. 2023;114:102520. doi:10.1016/j.ctrv.2023.102520
4. A study to investigate the efficacy and safety of trastuzumab deruxtecan as the first treatment option for unresectable, locally advanced/​metastatic non-small cell lung cancer with HER2 mutations. ClinicalTrials.gov. Updated January 7, 2025. Accessed January 20, 2025. https://clinicaltrials.gov/study/NCT05048797
5. YamamotoN, Tu H, Ahn MJ, et al. Zongertinib in patients with HER2-mutant NSCLC: updated analysis of beamion LUNG-1.Ann Oncol. 2024;35(suppl 4):S1623-S1624. doi:10.1016/j.annonc.2024.10.642
6. Boehringer Ingelheim to unveil groundbreaking oncology research at WCLC, demonstrating strength of portfolio. News release. Boehringer Ingelheim. August 27, 2024. Accessed January 20, 2025. https://www.boehringer-ingelheim.com/human-health/cancer/lung-cancer/groundbreaking-oncology-research-zongertinib
7. New results from the investigational agent BAY 2927088 in HER2-mutant non-small cell lung cancer (NSCLC) presented at WCLC. News release. Bayer. September 9, 2024. Accessed January 20, 2025. https://www.bayer.com/en/us/news-stories/non-small-cell-lung-cancer
8. 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. J Thorac Oncol. 2024;19(10):S4. doi:10.1016/j.jtho.2024.09.017
9. A study to learn more about how well BAY 2927088 works and how safe it is compared with standard treatment, in participants who have advanced non-small cell lung cancer (NSCLC) with mutations in the genes of human epidermal growth factor receptor 2 (HER2) (SOHO-02). ClinicalTrials.gov. Updated November 15, 2024. Accessed January 20, 2025. https://clinicaltrials.gov/study/NCT06452277
10. Phase 3 study of pyrotinib versus docetaxel in patients with advanced non-squamous NSCLC harboring a HER2 exon 20 mutation who failed platinum based chemotherapy (PYRAMID-1). ClinicalTrials.gov. Updated March 8, 2023. Accessed January 20, 2025. https://clinicaltrials.gov/study/NCT04447118