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

Jänne, Pasi A.; Baik, Christina S.; Su, Wu‐Chou; Johnson, Melissa L.; Hayashi, Hidetoshi; Nishio, Makoto; Kim, Dong‐Wan; Koczywas, Marianna; Gold, Kathryn A.; Steuer, Conor E.; Murakami, Haruyasu; Yang, James Chih‐Hsin; Kim, Sang‐We; Vigliotti, Michele; Shi, Rong; Qi, Zhenhao; Qiu, Yang; Zhao, Lihui; Sternberg, David; Yu, Channing; Yu, Helena A.

doi:10.1158/2159-8290.cd-21-0715

Cited by 158 publications

(112 citation statements)

References 42 publications

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“…These compounds take advantage of the targeting ability of the mAb, as well as the therapeutic effects described above for mAbs, and add the cytotoxic action of the attached drug. There is currently one HER3-targeting ADC in clinical development, patritumab deruxtecan, and it has shown promising results in a phase I/II trial [ 15 ]. Compared to patritumab deruxtecan, Z HER3 -ABD-mcDM1 is considerably smaller, and should thus penetrate solid tumors more efficiently, possibly resulting in more efficient therapy [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, severe side-effects occur for some patients; most commonly liver damage from off-target uptake of the ADC, and a low blood count from premature release of the cytotoxic drug from the mAb [ 14 ]. Patritumab deruxtecan is a HER3-targeting ADC in phase I/II clinical trials for patients suffering from NSCLC and breast carcinoma, and has shown promising results [ 15 ]. Compared to other ADCs, patritumab deruxtecan has a relatively weak affinity for its receptor and a relatively high rate of internalization [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules

et al. 2022

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Increasing evidence suggests that therapy targeting the human epidermal growth factor receptor 3 (HER3) could be a viable route for targeted cancer therapy. Here, we studied a novel drug conjugate, ZHER3-ABD-mcDM1, consisting of a HER3-targeting affibody molecule, coupled to the cytotoxic tubulin polymerization inhibitor DM1, and an albumin-binding domain for in vivo half-life extension. ZHER3-ABD-mcDM1 showed a strong affinity to the extracellular domain of HER3 (KD 6 nM), and an even stronger affinity (KD 0.2 nM) to the HER3-overexpressing pancreatic carcinoma cell line, BxPC-3. The drug conjugate showed a potent cytotoxic effect on BxPC-3 cells with an IC50 value of 7 nM. Evaluation of a radiolabeled version, [99mTc]Tc-ZHER3-ABD-mcDM1, showed a relatively high rate of internalization, with a 27% internalized fraction after 8 h. Further in vivo evaluation showed that it could target BxPC-3 (pancreatic carcinoma) and DU145 (prostate carcinoma) xenografts in mice, with an uptake peaking at 6.3 ± 0.4% IA/g at 6 h post-injection for the BxPC-3 xenografts. The general biodistribution showed uptake in the liver, lung, salivary gland, stomach, and small intestine, organs known to express murine ErbB3 naturally. The results from the study show that ZHER3-ABD-mcDM1 is a highly potent and selective drug conjugate with the ability to specifically target HER3 overexpressing cells. Further pre-clinical and clinical development is discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules

et al. 2022

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“…HER3‐DXd has shown the most promising effects and tolerable safety in NSCLC with EGFR mutations in a phase I clinical trial, with a disease control rate of 70% and median duration of 6.9 months. 381 The efficacy of HER3‐DXd will be confirmed in a phase II trial, HERTHENA‐Lung01 (NCT04619004). Other mAbs targeting HER3, including patritumab and lumretuzumab, are under evaluation in early clinical trials.…”

Section: Other Promising Therapies For Nsclcmentioning

confidence: 96%

Therapeutic advances in non‐small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy

Yuan

Zhang

2021

MedComm

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Lung cancer still contributes to nearly one‐quarter cancer‐related deaths in the past decades, despite the rapid development of targeted therapy and immunotherapy in non‐small cell lung cancer (NSCLC). The development and availability of comprehensive genomic profiling make the classification of NSCLC more precise and personalized. Most treatment decisions of advanced‐stage NSCLC have been made based on the genetic features and PD‐L1 expression of patients. For the past 2 years, more than 10 therapeutic strategies have been approved as first‐line treatment for certain subgroups of NSCLC. However, some major challenges remain, including drug resistance and low rate of overall survival. Therefore, we discuss and review the therapeutic strategies of NSCLC, and focus on the development of targeted therapy and immunotherapy in advanced‐stage NSCLC. Based on the latest guidelines, we provide an updated summary on the standard treatment for NSCLC. At last, we discussed several potential therapies for NSCLC. The development of new drugs and combination therapies both provide promising therapeutic effects on NSCLC.

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“…Nevertheless, patritumab deruxtecan, in a phase I clinical trials in osimertinibresistant patients, achieved a response rate of 39%, irrespective of the underlying resistance mechanism. HER3-directed ADC might provide a future agnostic treatment alternative for the TKI resistance mechanism of EGFR [74]. A prospective clinical trial is currently ongoing, testing patrimumab deruxtecan in combination with osimertinib in patients progressing to first-line osimertinib (NCT04676477).…”

Section: Other Mechanismsmentioning

confidence: 99%

Acquired Resistance to Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer: How Do We Overcome It?

Bertoli

Carlo

Conte

et al. 2022

IJMS

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Osimertinib is currently the preferred first-line therapy in patients with non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutation and the standard second-line therapy in T790M-positive patients in progression to previous EGFR tyrosine kinase inhibitor. Osimertinib is a highly effective treatment that shows a high response rate and long-lasting disease control. However, a resistance to the treatment inevitably develops among patients. Understanding the secondary mechanisms of resistance and the possible therapeutic options available is crucial to define the best management of patients in progression to osimertinib. We provide a comprehensive review of the emerging molecular resistance mechanism in EGFR-mutated NSCLC pre-treated with osimertinib and its future treatment applications.

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

Abstract: Kim has received travel accommodations from and/or had expenses paid by Daiichi Sankyo and Amgen; and D.-W.K.'s institution has received research funding from Alpha Biopharma,

Cited by 158 publications

References 42 publications

Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules

Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules

Therapeutic advances in non‐small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy

Acquired Resistance to Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer: How Do We Overcome It?

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