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Expert Point of View: Ignatius Ou, MD, PhD


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Ignatius Ou, MD, PhD

Ignatius Ou, MD, PhD

Ignatius Ou, MD, PhD, Health Science Clinical Professor at the University of California Irvine, was invited to discuss the new data from the phase I trials evaluating the antibody drug conjugates patritumab deruxtecan (HER3-DXd)1 and datopotamab deruxtecan (Dato-DXd).2 He noted that TROP2 antibody-drug conjugates are emerging as interesting compounds in advanced cancer. In 2020, sacituzumab govitecan-hziy received accelerated approval by the U.S. Food and Drug Administration for metastatic triple-negative breast cancer in 2020 and is now in use. This antibody-drug conjugate might also prove beneficial in non–small cell lung cancer (NSCLC), he said.

“TROP2 has an EGF domain, so it may affect the cycling of NRG1, which may be interesting in the future. The expression of TROP2 seems to be associated with poor survival,” Dr. Ou noted.

Questions Emerge About TROP2 Antibody-Drug Conjugates

In the phase III TROPION-Lung01 trial of patritumab deruxtecan, antitumor activity was shown, especially with “the sweet spot” of 6 mg/kg, commented Dr. Ou. A registration trial will compare this TROP2 antibody-drug conjugate vs docetaxel at 75 mg/m2. Meanwhile, Dr. Ou had several questions about this TROP2 antibody-drug conjugate:

  • What is the relationship between TROP2 and expression of PD-L1?
  • Is TROP2–antibody-drug conjugate expression prognostic and/or predictive?
  • What is the best way to measure TROP2 expression? Which antibody? How should such expression be graded? Is TROP2 a new biomarker?
  • Do all NSCLCs have the same level of TROP2 expression?

Dr. Ou also questioned how TROP2 antibody-drug conjugates will fit into a front-line strategy for NSCLC. He suggested these possibilities for evaluation: chemotherapy plus immunotherapy with or without a TROP2 antibody-drug conjugate and a TROP2 antibody-drug conjugate vs chemotherapy plus immunotherapy vs immunotherapy doublets.

In heavily pretreated patients with NSCLC with EGFR mutations, the HER3-directed antibody-drug conjugate patritumab deruxtecan also showed promising activity at a recommended dose of 5.6 mg/kg in the phase I study reported by Yu et al. “These important findings also show this HER3 antibody-drug conjugate is effective, and the duration of response was good. We have more data here showing HER3-DXd works on almost all EGFR mutations,” Dr. Ou commented. He said he will be interested in seeing the design of the pivotal trial of this compound. 

DISCLOSURE: Dr. Ou reported financial associations with Pfizer, AstraZeneca, Takeda, Roche/Genentech, Janssen/JNJ, Daiichi Sankyo, Eisai, Elevation Oncology, Turning Point Therapeutics, AnHeart Therapeutics, and Beta-Pharma.

REFERENCES

1. Spira A, Lisberg AE, Sands JM, et al: Datopotamab deruxtecan (Dato-DXd; DS-1062), a TROP2 ADC, in patients with advanced NSCLC: Updated results of TROPION-PanTumor01 phase 1 study. 2020 World Conference on Lung Cancer. Abstract OA03.03. Presented January 29, 2021.

2. Helena YA, Baik C, Gold K, et al: Efficacy and safety of the novel HER3 directed antibody drug conjugate patritumab deruxtecan (HER3-DXd; U3-1402) in EGFR-mutated NSCLC. 2020 World Conference on Lung Cancer. Abstract OA03.04. Presented January 29, 2021.


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