Dr Ashraf on the Utility of T-DXd in HER2-Mutated NSCLC

Noman Ashraf, MD, hematologist-oncologist, Tampa General Hospital; associate professor, medicine, Division of Hematology/Oncology, the University of South Florida Health Morsani College of Medicine, discusses notable data seen 

-directed antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd)

-mutated and -overexpressing non–small cell lung cancer (NSCLC).

The phase 2 DESTINY-Lung01 study (NCT03505710) evaluated 2 patient cohorts: one with HER2 overexpression and another with 

 mutations, Ashraf begins. Both cohorts benefited from T-DXd, but patients with 

 mutations who received the agent at 6.4 mg/kg appeared to derive greater benefit, with a confirmed objective response rate (ORR) of 55% (95% CI, 44%-65%), a median progression-free survival of 8.2 months (95% CI, 6.0-11.9), and a median overall survival of 17.8 months (95% CI, 13.8-22.1), he reports. The phase 2 DESTINY-Lung02 trial (NCT04644237) further examined T-DXd dosing, revealing that a lower dose of 5.4 mg/kg resulted in efficacy outcomes comparable with those achieved with a higher dose, as well as reduced toxicity; subsequently, in 2022, 

 at a recommended dose of 5.4 mg/kg for the treatment of patients with 

In DESTINY-Lung01, patients with HER2 overexpression (classified as HER2 expression of 2+ or 3+ per immunohistochemistry) who received T-DXd at 6.4 mg/kg had a lower ORR of 26.5% (95% CI, 15.0%-41.1%) compared with those in the 

-mutated cohort, he continues. Both DESTINY-Lung01 and DESTINY-Lung02 administered T-DXd in the second line and beyond. There is a growing interest in using ADCs like T-DXd as frontline therapy for patients with HER2 overexpression or mutations, Ashraf states.

In the HER2 overexpression cohorts of DESTINY-Lung01, 49 patients received T-DXd at 6.4 mg/kg and 41 patients received the agent at 5.4 mg/kg. Efficacy outcomes were similar across doses, but the 5.4-mg/kg dose was associated with a lower incidence of toxicity. ADC-related toxicities generally mimic those seen with chemotherapy, including cytopenias and alopecia, according to Ashraf. However, a unique risk associated with ADCs is interstitial lung disease (ILD), which can be fatal in some cases, he says. Thus, managing and minimizing ILD risk remains crucial to optimize patient outcomes when balancing therapeutic efficacy and safety, Ashraf concludes.

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Noman Ashraf, MD, discusses notable data seen with T-DXd treatment in previously treated HER2-mutated and -overexpressing non–small cell lung cancer.

Dr Ashraf on Ivonescimab vs Pembrolizumab as a First-Line Treatment for PD-L1+ Advanced NSCLC

Noman Ashraf, MD, hematologist-oncologist, Tampa General Hospital, associate professor, medicine, Division of Hematology/Oncology, University of South Florida Health Morsani College discusses the primary 

findings from the phase 3 HARMONi-2 trial

 (NCT05899608) evaluating ivonescimab (AK112) vs pembrolizumab (Keytruda) as a first-line treatment for patients with PD-L1–positive, advanced non-small cell lung cancer (NSCLC).

The primary end point of the trial was progression-free survival (PFS), Ashraf explains. Patients treated with ivonescimab achieved a median PFS of 11.14 months (95% CI, 7.33-not evaluable), which was more than double the 5.82-month (95% CI, 5.03-8.21) median PFS observed in the pembrolizumab arm. This PFS improvement translated to a hazard ratio of 0.51 (95% CI, 0.38-0.69; 

< .0001), indicating a 49% reduction in the risk of progression with ivonescimab vs pembrolizumab, he states.

Additionally, the objective response rate was higher in the ivonescimab arm, at 50.0% (95% CI, 42.8%-57.2%) compared with 38.5% (95% CI, 31.7%-45.6%) in the pembrolizumab arm, Ashraf continues. Although the overall survival (OS) data remain immature, early results show a promising trend favoring ivonescimab, he adds.

The trial stratified patients by multiple subgroups, including squamous vs nonsquamous histology and different PD-L1 expression levels. Ashraf explained that ivonescimab demonstrated robust and consistent efficacy across all these subgroups, indicating its broad therapeutic potential in patients with NSCLC regardless of histological type or PD-L1 expression. This finding underscores ivonescimab’s versatility in treating diverse presentations of PD-L1–positive, advanced NSCLC.

Notably, patients with brain metastases represented approximately 16% to 19% of the study population. Despite having asymptomatic brain metastases, these patients also derived benefit from ivonescimab treatment. This finding is particularly important, as brain metastases are generally associated with a poor prognosis and represent a challenge in lung cancer management, Ashraf reports. Ashraf highlights that even in this high-risk subgroup, ivonescimab demonstrated efficacy, further supporting its potential as a first-line treatment option for a wide range of patients with PD-L1-positive, advanced NSCLC.

Overall, the HARMONi-2 trial findings indicate that ivonescimab offers improvement in PFS compared with pembrolizumab for PD-L1–positive, advanced NSCLC. Further analysis will be required to assess the agent’s effect on OS, however, early data show that ivonescimab may be a valuable new first-line treatment option in this setting, Ashraf concludes.

Noman Ashraf, MD, discusses ivonescimab vs pembrolizumab as a first-line treatment for PD-L1-positive, advanced non-small cell lung cancer.

Noman Ashraf, MD

Articles

Dr Ashraf on the Utility of T-DXd in HER2-Mutated NSCLC

Dr Ashraf on Ivonescimab vs Pembrolizumab as a First-Line Treatment for PD-L1+ Advanced NSCLC