Interim results from the phase 1b DS8201-A-U106 study demonstrate promising efficacy for the combination of trastuzumab deruxtecan (T-DXd) and pembrolizumab in patients with HER2-positive non-small cell lung cancer (NSCLC), particularly in the first-line setting.
The study, presented at the 2024 ESMO Immuno-Oncology Congress, showed remarkable response rates across different patient populations. In previously untreated patients with HER2-mutant NSCLC, the combination achieved an impressive 80% confirmed objective response rate (cORR), including a 10% complete response rate.
"Combination therapy with T-DXd plus pembrolizumab showed preliminary antitumor activity in patients with IO-naive, HER2-expressing and HER2-mutant NSCLC," stated Dr. Antoine Italiano of Institut Bergonié and University of Bordeaux, who presented the findings.
Efficacy Across Patient Populations
The study evaluated two key patient cohorts: HER2-expressing NSCLC (cohort 3) and HER2-mutant NSCLC (cohort 4). In the overall population, including both treatment-naive and previously treated patients, the combination demonstrated robust efficacy:
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HER2-expressing NSCLC (n=22):
- 54.5% confirmed objective response rate
- 86.4% disease control rate
- 15.1 months median progression-free survival
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HER2-mutant NSCLC (n=33):
- 66.7% confirmed objective response rate
- 90.9% disease control rate
- 11.3 months median progression-free survival
First-Line Treatment Results
The combination showed particularly strong results in previously untreated patients:
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Treatment-naive HER2-expressing NSCLC (n=8):
- 62.5% confirmed objective response rate
- 87.5% disease control rate
- 23.5 months median progression-free survival
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Treatment-naive HER2-mutant NSCLC (n=20):
- 80% confirmed objective response rate
- 95% disease control rate
- 21.3 months median progression-free survival
Safety Profile and Monitoring
The safety profile was generally consistent with the known profiles of both drugs, though careful monitoring was required. Key safety findings included:
- Grade 3 or higher drug-related adverse events occurred in 38.2% of all NSCLC patients
- Interstitial lung disease (ILD) or pneumonitis was observed in both cohorts:
- 9.1% in HER2-expressing NSCLC patients
- 27.3% in HER2-mutant NSCLC patients, including one grade 5 event
Dr. Italiano emphasized that ILD remains an important risk associated with T-DXd treatment, requiring careful patient monitoring.
Study Design and Dosing
The open-label study determined 5.4 mg/kg of T-DXd plus 200 mg of pembrolizumab every three weeks as the recommended dose for expansion. The median treatment duration was 6.9 months across all NSCLC patients, with median follow-up of 12.9 months.
These encouraging results, particularly in the first-line setting, suggest that this combination could potentially offer a new treatment option for patients with HER2-positive NSCLC. However, as Dr. Italiano noted, further research with a larger dataset will be necessary to fully understand the potential of this therapeutic approach.
