Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer

  • Cancer Discov. 2022 Jan;12(1):74-89. doi: 10.1158/2159-8290.CD-21-0715.
Pasi A Jänne  1 ,  Christina Baik  2 ,  Wu-Chou Su  3 ,  Melissa L Johnson  4 ,  Hidetoshi Hayashi  5 ,  Makoto Nishio  6 ,  Dong-Wan Kim  7 ,  Marianna Koczywas  8 ,  Kathryn A Gold  9 ,  Conor E Steuer  10 ,  Haruyasu Murakami  11 ,  James Chih-Hsin Yang  12 ,  Sang-We Kim  13 ,  Michele Vigliotti  14 ,  Rong Shi  14 ,  Zhenhao Qi  14 ,  Yang Qiu  14 ,  Lihui Zhao  14 ,  David Sternberg  14 ,  Channing Yu  14 ,  Helena A Yu  15
Affiliations
  • 1. Dana-Farber Cancer Institute, Boston, Massachusetts. [email protected].
  • 2. Seattle Cancer Care Alliance, Seattle, Washington.
  • 3. National Cheng Kung University Hospital, Tainan, Taiwan.
  • 4. Sarah Cannon Research Institute/Tennessee Oncology, PLCC, Nashville, Tennessee.
  • 5. Kindai University Hospital, Osaka-Sayama City, Japan.
  • 6. The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Japan.
  • 7. Seoul National University College of Medicine and Seoul National University Hospital, Seoul, South Korea.
  • 8. City of Hope Medical Center, Duarte, California.
  • 9. University of California, San Diego, San Diego, California.
  • 10. Winship Cancer Institute of Emory University, Atlanta, Georgia.
  • 11. Shizuoka Cancer Center, Sunto-gun, Japan.
  • 12. National Taiwan University Cancer Center, Taipei, Taiwan.
  • 13. Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • 14. Daiichi Sankyo, Inc., Basking Ridge, New Jersey.
  • 15. Memorial Sloan Kettering Cancer Center, New York, New York.
PMID: 34548309 DOI: 10.1158/2159-8290.CD-21-0715
Abstract

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody-drug conjugate consisting of a HER3 antibody attached to a Topoisomerase I inhibitor payload via a tetrapeptide-based Cleavable Linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0-52.4], and median progression-free survival was 8.2 (95% CI, 4.4-8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI-resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. SIGNIFICANCE: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.See related commentary by Lim et al., p. 16.This article is highlighted in the In This Issue feature, p. 1.

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