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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Developed by Daiichi Sankyo and licensed by AstraZeneca trastuzumab deruxtecan (Enhertu™) is approved for the treatment of unresectable or metastatic HER2-positive breast cancer in patients who have received two or more previous anti-HER2 therapies. This ADC consists of a HER2-targeted antibody joined to a topoisomerase I inhibiting payload (i.e., deruxtecan, a derivative of exatecan) through a cleavable peptidic linker (Figure 7.36). Structure of trastuzumab deruxtecan (Enhertu™) which consists of a HER2-targeted antibody joined to a topoisomerase I inhibiting payload (i.e., deruxtecan, a derivative of exatecan) through a cleavable peptidic linker (Figure reprinted with permission from Daiichi Sankyo. References: [1] Doi et al., Lancet Oncol. 2017;18:1512-1522; [2] Ogitani et al. Cancer Sci. 2016;107:1039–46; [3] Poon et al. Toxicol Appl Pharmacol. 2013;273:298–313; [4] Mitsui et al. Jpn J Cancer Res. 1995; 86: 776–782).
HER-2 as a Prognostic and Predictive Biomarker in Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Alexandra S. Zimmer, Suparna B. Wedamb, Stanley Lipkowitza
Trastuzumab deruxtecan is an ADC which couples a topoisomerase inhibitor (deruxtecan) to trastuzumab. A phase I trial of trastuzumab deruxtecan described activity of this drug in patients with HER-2 amplified tumors [244]. Recently, a non-randomized phase II study where 184 heavily pretreated patients with metastatic HER-2 amplified (defined as IHC of 3+ or amplification by in situ hybridization) breast cancer reported a response rate of 60.9% and a median PFS of 16.4 months [245]. Trastuzumab deruxtecan was granted accelerated approval by the FDA for patients with metastatic HER-2+ breast cancer who have received two or more prior anti-HER-2 based regimens in the metastatic setting. A randomized phase II study compared trastuzumab deruxtecan to chemotherapy in patients with HER-2 positive advanced gastric cancer who had previously received trastuzumab [246]. 187 patients were randomized 2:1 to trastuzumab deruxtecan vs. chemotherapy. Patients treated with trastuzumab deruxtecan had improved ORR (51% vs. 14%), duration of response (11.3 months vs. 3.9 months), and OS (12.5 months vs. 8.4 months) compared to those treated with chemotherapy. The FDA has granted orphan drug status for trastuzumab deruxtecan for the treatment of HER-2 positive unresectable or metastatic gastric cancer who have received 2 or more prior regimens including trastuzumab.
A systematic review of clinical trials of treatment regimens in HER2-amplified metastatic colorectal cancer
Published in Expert Review of Anticancer Therapy, 2023
Daniel Sur, Cristina Lungulescu, Elena Adriana Dumitrescu, Vlad Afrăsânie, Ștefan Spînu, Cristian Virgil Lungulescu, Hans- Joachim Schmoll
The most common treatment-related adverse events (AEs) of chemotherapy (capecitabine) in combination with lapatinib were fatigue (83%), hand-foot syndrome (69%), and diarrhea (59%). Lapatinib in combination with trastuzumab often caused diarrhea (78%), rash (48%), and fatigue (48%). In the FOCUS4-D trial skin rash occurred in 20% of the AZD8931 group versus none in the placebo group, and diarrhea occurred in 7% of the AZD8931 group versus 6% in the placebo group. The combination of trastuzumab and pertuzumab frequently caused fatigue (32%), diarrhea (34%), nausea (30%) in My-Pathway study, while the TRIUMPH trial found that infusion-related events, diarrhea, stomatitis, and malaise were the most common side effects. Trastuzumab-deruxtecan (T-DXd), an antibody–drug conjugate, was associated with a high incidence of nausea (60%), fatigue (33%), and diarrhea (28%), while ado-trastuzumab-emtansine (T-DM1) combined with pertuzumab-induced fatigue (18%), hyperbilirubinemia (9%), and thrombocytopenia (8%). Summaries of each of the seven papers included in this study are presented in Table 2.
Interstitial lung disease associated with anti-HER2 anti-body drug conjugates: results from clinical trials and the WHO's pharmacovigilance database
Published in Expert Review of Clinical Pharmacology, 2022
Zhuo Ma, Yi Zhang, Min Zhu, Lin Feng, Yuhui Zhang, Zhuoling An
In meta-analysis, 3 deaths from anti-HER2 ADC-related ILD events were reported in 2 RCTs [30,36], among which, 2 from TH3RESA trial [30] of patients treated with trastuzumab emtansine (0.2%, 1/403) and 1 from TULIP trial [36] of patients treated with trastuzumab duocarmazine (0.7%, 2/291). 11 deaths were reported in 4 SATs of patients treated with trastuzumab deruxtecan [22,24,38,51]. However, in pharmacovigilance analysis, there were 28 deaths attributed to anti-HER2 ADC-associated ILD/pneumonitis with a fatality rate of 18.79% (28/149), suggesting a heightened awareness of this potential life-threatening AEs. Anti-HER2 ADC-related ILD/pneumonitis was characterized by an early onset with a wide range (0 day to 800 days). A significant shorter TTO was found in trastuzumab deruxtecan compared with trastuzumab emtansine. The median TTO of ILD events related to trastuzumab deruxtecan that reported in a systematic review of clinical trials was 77–193 days [75]. Pooled analysis of the TTO of ILD induced by other anti-HER2 ADCs are still lacking. These results suggested that we should be aware of the onset of ILD/pneumonitis with trastuzumab deruxtecan over a wide range of time.
An overview of the preclinical discovery and development of trastuzumab deruxtecan: a novel gastric cancer therapeutic
Published in Expert Opinion on Drug Discovery, 2022
James Kalmuk, Dan Rinder, Carl Heltzel, Albert Craig Lockhart
Now that trastuzumab deruxtecan has successfully demonstrated evidence of clinical benefit in HER2 positive gastric cancer, there is certainly enthusiasm about combination therapeutic approaches. Iwata et al. suggested trastuzumab deruxtecan may lead to more immunologic tumor cytotoxicity than irinotecan given the potential immunomodulatory activity of topoisomerase inhibitors, the high degree of potency with Dxd compared to SN-38, and the selective activity of trastuzumab deruxtecan at the tumor site [37]. This suggests a potential synergistic role with checkpoint blockade, and as noted above trastuzumab deruxtecan is being evaluated in combination with durvalumab, avelumab, and nivolumab. However, such a combination also raises concerns about overlapping toxicity. Clinicians should remain cognizant of this possibility, particularly pulmonary toxicity given the risk of pneumonitis with checkpoint-targeting agents and the incidence of interstitial lung disease described in multiple trials including DESTINY-Gastric01 [49,55,57]. Nevertheless, the results of the DESTINY-Gastric01 study are encouraging given the ongoing unmet need for effective therapeutics for gastric cancer patients with all degrees of HER2 expression, and we look forward to the results of DESTINY-Gastric02 and DESTINY-Gastric-03.