Trastuzumab Deruxtecan: Changing the Destiny of HER2 Expressing Solid Tumors

HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors.

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The regulatory approval of anamorelin for treatment of cachexia in patients with non‐small cell lung cancer, gastric cancer, pancreatic cancer, and colorectal cancer in Japan: facts and numbers.

Journal of Cachexia Sarcopenia and Muscle ◽

10.1002/jcsm.12675 ◽

2020 ◽

Author(s):

Hidetaka Wakabayashi ◽

Hidenori Arai ◽

Akio Inui

Keyword(s):

Colorectal Cancer ◽

Gastric Cancer ◽

Lung Cancer ◽

Pancreatic Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Regulatory Approval ◽

Small Cell Lung

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Establishment of the first international large-scale, genomic screening platform to identify patients with rare oncogene drivers in non-small cell lung cancer (NSCLC) in East Asia.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.9605 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 9605-9605

Author(s):

Shingo Matsumoto ◽

Caicun Zhou ◽

Chih-Hsi Kuo ◽

Kiyotaka Yoh ◽

Terufumi Kato ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Small Cell Lung Cancer ◽

Targeted Therapies ◽

Large Scale ◽

East Asian ◽

Small Cell ◽

Small Cell Lung ◽

Genomic Screening ◽

Screening Platform

9605 Background: A rapidly increasing number of oncogenic drivers have been identified in non-small cell lung cancer (NSCLC), and most of them occur in less than 5% of patients. Large-scale genomic screening to identify patients with rare driver alterations is thus necessary to enable precision medicine and to support the development of novel targeted therapies and companion diagnostics (CDx). Methods: A lung cancer genomic screening project (LC-SCRUM-Asia) capturing clinical outcome was established in 2013 with 206 institutions in Japan and 5 in Taiwan currently participating. A separate genomic screening project with similar structure was established in China (LC-IRICA-China) in collaboration with LC-SCRUM-Asia in 2019 (3 institutions enrolling, 17 about to open, 63 undergoing review). Samples are analyzed by a multi-gene PCR panel and targeted next-generation sequencing. The target is to enroll 70000 NSCLC patients (20000 from LC-SCRUM-Asia and 50000 from LC-IRICA-China) by 2022. Results: From March 2013, a total of 9383 lung cancer patients were enrolled in LC-SCRUM-Asia, and from October 2019, 1649 pts were included in LC-IRICA-China (January 2020). The rates of genomic alterations in LC-SCRUM-Asia: EGFR (17%) of which ex20ins (2%), KRAS (13%) of which G12C (4%), ALK fusions (2%), ROS1 fusions (2%), RET fusions (2%), HER 2 ex20ins (3%), MET ex14skip (2%), BRAF V600E (1%), NRG1 fusions (0.2%) and NTRK3 fusions (0.03%). Corresponding rates in the initial 243 pts in LC-IRICA China: EGFR (45%) of which ex20ins (2%), KRAS (8%), ALK (5%), ROS1 (2%), RET (1%), HER2 (2%), MET ex14skip (1%), BRAFV600E (1%). Through the screening, 266 patients from Japan and Taiwan were enrolled into genotype-matched clinical trials of unapproved targeted drugs. In Japan, ROS1-, BRAF- and TRK-targeted therapies were successfully approved based on these clinical trials, and a NGS-based multi-gene CDx for EGFR/ALK/ROS1/BRAF targeted-therapies was approved based a concordance study using archival samples from the project. Conclusions: An East Asian international genomic screening platform has been established to enable precision medicine for patients, accelerate drug and diagnostic development in patients with very rare alterations and to help provide a deeper understanding of the underlying biology of NSCLC in East Asian patients. The screening network will be further expanded to other countries in East Asia in the near future.

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Comparative Efficacy of Targeted Therapies in Patients with Non-Small Cell Lung Cancer: A Network Meta-Analysis of Clinical Trials

Journal of Clinical Medicine ◽

10.3390/jcm9041063 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1063 ◽

Cited By ~ 1

Author(s):

Tung Hoang ◽

Seung-Kwon Myung ◽

Thu Thi Pham ◽

Jeongseon Kim ◽

Woong Ju

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Targeted Therapies ◽

Meta Analysis ◽

Small Cell ◽

Cochrane Library ◽

Comparative Efficacy ◽

Small Cell Lung

This study aims to investigate the efficacy of targeted therapies in the treatment of non-small cell lung cancer (NSCLC) by using a network meta-analysis of clinical trials. PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov were searched by using keywords related to the topic on 19 September 2018. Two investigators independently selected relevant trials by pre-determined criteria. A pooled response ratio (RR) for overall response rate (ORR) and a hazard ratio (HR) for progression-free survival (PFS) were calculated based on both the Bayesian and frequentist approaches. A total of 128 clinical trials with 39,501 participants were included in the final analysis of 14 therapeutic groups. Compared with chemotherapy, both ORR and PFS were significantly improved for afatinib, alectinib, and crizotinib, while only PFS was significantly improved for cabozantinib, ceritinib, gefitinib, and osimertinib. Consistency was observed between the direct and indirect comparisons based on the Bayesian approach statistically and the frequentist approach visually. Cabozantinib and alectinib showed the highest probability for the first-line treatment ranking in ORR (62.5%) and PFS (87.5%), respectively. The current network meta-analysis showed the comprehensive evidence-based comparative efficacy of different types of targeted therapies, which would help clinicians use targeted therapies in clinical practice.

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Criteria of tumor response used in clinical trials of chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.1985.3.6.870 ◽

1985 ◽

Vol 3 (6) ◽

pp. 870-875 ◽

Cited By ~ 38

Author(s):

K Tonkin ◽

D Tritchler ◽

I Tannock

Keyword(s):

Colorectal Cancer ◽

Lung Cancer ◽

Clinical Trials ◽

Head And Neck Cancer ◽

Small Cell Lung Cancer ◽

Metastatic Colorectal Cancer ◽

Tumor Response ◽

Senior Author ◽

Small Cell ◽

Small Cell Lung

We have studied 61 published reports of trials of cancer chemotherapy to evaluate the criteria for tumor response that were used and the adequacy of their description in the publication. Our sample comprised recent articles published in three major journals that addressed the influence of chemotherapy on patients with recurrent or metastatic colorectal cancer, non-small cell lung cancer, and head and neck cancer. Incomplete information was sought through a questionnaire mailed to the senior author of each paper, and 48 of them responded. We conclude that: no article contained all of the information required to define precisely criteria for tumor responses; criteria for tumor response are variable; and differences in response criteria contribute to the wide variation in reported rates of tumor response. Meaningful intercomparison of clinical trials will require the establishment of uniform criteria for assessing and reporting the response of tumors to chemotherapy.

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