JTO Clinical and Research Reports (Apr 2023)

Trastuzumab-Emtansine and Osimertinib Combination Therapy to Target HER2 Bypass Track Resistance in EGFR Mutation-Positive NSCLC

  • M. Jebbink, MD,
  • A.J. de Langen, MD, PhD,
  • K. Monkhorst, MD, PhD,
  • M.C. Boelens, PhD,
  • D. van den Broek, PhD,
  • V. van der Noort, PhD,
  • C.J. de Gooijer, MD, PhD,
  • M. Mahn, MSc,
  • A.J. van der Wekken, MD, PhD,
  • L. Hendriks, MD, PhD,
  • S.M.S. Hashemi, MD, PhD,
  • M.S. Paats, MD, PhD,
  • A.C. Dingemans, MD, PhD,
  • E.F. Smit, MD, PhD

Journal volume & issue
Vol. 4, no. 4
p. 100481

Abstract

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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.

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