Trastuzumab-Emtansine and Osimertinib Combination Therapy to Target HER2 Bypass Track Resistance in EGFR
M Jebbink1, A J de Langen1, K Monkhorst2
1Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
Introduction:
EGFR tyrosine kinase inhibitor improved the survival of patients with metastatic EGFR mutation-positive (EGFRm+) NSCLC. Despite high response rates, resistance develops inevitably in every patient. In up to 13%, HER2 protein overexpression is found on progression. We hypothesized that dual blockade of EGFR and HER2 by osimertinib combined with trastuzumab-emtansine (T-DM1) could reinduce tumor responses.
Methods:
In this multicenter, single-arm, phase 1-2 study (NCT03784599), patients with EGFRm+ NSCLC, progressing on osimertinib and HER2 overexpression were included. Patients were treated with T-DM1 3.6 mg/kg (intravenously) every 3 weeks and osimertinib 80 mg once a day. Primary end points were objective response rate (ORR) at 12 weeks and safety. Responses were assessed every 6 weeks (Response Evaluation Criteria in Solid Tumors 1.1). Sample size was calculated using Simon's two-stage minimax design (H0 = 41%, H1 > 55%, 80% power, one-sided type I error 10%: a ORR 16 of 36 was needed to proceed to 58 patients).
Results:
From January 2019 to April 2021, 27 patients were enrolled. ORR after 12 weeks of treatment was 4% (1 of 27). Median progression-free survival was 2.8 months (95% confidence interval: 1.4-4.6 mo). Most frequent treatment-related adverse events of any grade were fatigue, diarrhea, and nausea, among these, grade 3 in four patients. There were no grade 4 or 5 therapy-related adverse events.
Conclusions:
TRAEMOS (Trastuzumab-Emtansine and Osimertinib) is the first trial combining T-DM1 and osimertinib in patients with EGFRm+ NSCLC to target HER2 overexpression at osimertinib resistance. Safety profile was favorable compared with cytotoxic chemotherapy; but treatment revealed limited efficacy. Further clinical evaluation of this regimen is not warranted.
Insights
This study found that combining trastuzumab-emtansine (T-DM1) with osimertinib showed limited efficacy in patients with EGFR mutation-positive NSCLC resistant to osimertinib. The dual blockade strategy did not significantly improve outcomes despite a favorable safety profile.
Area of Science:
- Oncology
- Medical Research
- Clinical Trials
Background:
- EGFR tyrosine kinase inhibitors (TKIs) improve survival in EGFR mutation-positive (EGFRm+) NSCLC.
- Resistance to EGFR TKIs, including osimertinib, is inevitable.
- HER2 protein overexpression occurs in up to 13% of NSCLC cases upon progression.
Purpose of the Study:
- To evaluate the efficacy and safety of combining trastuzumab-emtansine (T-DM1) with osimertinib in patients with EGFRm+ NSCLC who developed resistance to osimertinib and exhibit HER2 overexpression.
- To determine if dual blockade of EGFR and HER2 can reinduce tumor responses.
Main Methods:
- A multicenter, single-arm, phase 1-2 study (NCT03784599) enrolled patients with EGFRm+ NSCLC progressing on osimertinib with HER2 overexpression.
- Patients received T-DM1 (3.6 mg/kg IV every 3 weeks) and osimertinib (80 mg daily).
- Primary endpoints were objective response rate (ORR) at 12 weeks and safety. Responses were assessed per RECIST 1.1.
Main Results:
- The objective response rate (ORR) at 12 weeks was 4% (1 of 27 patients).
- Median progression-free survival was 2.8 months (95% CI: 1.4-4.6 months).
- The most frequent treatment-related adverse events were fatigue, diarrhea, and nausea; four patients experienced grade 3 events. No grade 4 or 5 events occurred.
Conclusions:
- The combination of T-DM1 and osimertinib (TRAEMOS trial) is the first to target HER2 overexpression in osimertinib-resistant EGFRm+ NSCLC.
- The regimen demonstrated a favorable safety profile compared to cytotoxic chemotherapy but showed limited clinical efficacy.
- Further clinical evaluation of this specific combination regimen is not warranted.
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