Trastuzumab-Emtansine and Osimertinib Combination Therapy to Target Bypass Track Resistance in Mutation-Positive NSCLC.

Introduction: tyrosine kinase inhibitor improved the survival of patients with metastatic mutation-positive () NSCLC. Despite high response rates, resistance develops inevitably in every patient. In up to 13%, protein overexpression is found on progression. We hypothesized that dual blockade of and 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 NSCLC, progressing on osimertinib and 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 NSCLC to target 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.