作者: Lui, Allan J.W. ; Dematteo, Raymond G. ; Febres-Aldana, Christopher A. ; Tipping, Murray J. ; Ladanyi, Marc ; Gili, Leo ; Zhang, Tom ; Odintsov, Igor ; Kwong, Charlene ; Mattar, Marissa S. ; Khodos, Inna ; Liu, Zebing ; Lisanti, Jeanine ; Dix, Jenna-Marie ; Somwar, Romel ; de Stanchina, Elisa ; Cheng, Ryan ; Linkov, Irina

Abstract:

Purpose::

Desmoplastic small round cell tumor (DSRCT) is a rare but highly aggressive soft tissue sarcoma that arises in the abdominopelvic cavity of young males. Since the discovery of EWSR1::WT1 fusion as the driver of DSRCT, no actionable genomic alterations have been identified, limiting disease management to a combination of surgery, chemotherapy, and radiation, with very poor outcomes. Herein, we evaluated ERBB2/HER2 expression in DSRCT as a therapeutic target.

Experimental Design::

ERBB2/HER2 expression was assessed in clinical samples and patient-derived xenografts (PDX) using RNA sequencing, RT-qPCR, and a newly developed HER2 IHC assay (clone 29D8). Responses to HER2 antibody–drug conjugates (ADC)—trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine—were evaluated in DSRCT PDX, cell line, and organoid models. Drug internalization was demonstrated by live microscopy. Apoptosis was evaluated by Western blotting and caspase activity assays.

Results::

ERBB2/HER2 was detectable in DSRCT samples from patients and PDXs, with higher sensitivity RNA assays and improved IHC detectability using clone 29D8. Treatment of ERBB2/HER2-expressing DSRCT PDX, cell line, and organoid models with T-DXd or trastuzumab emtansine resulted in tumor regression. This therapeutic response was long-lasting in T-DXd–treated xenografts and was mediated by rapid HER2 ADC complex internalization and cytotoxicity, triggering p53-mediated apoptosis and growth arrest. Xenograft regression was associated with bystander payload effects triggering global tumor niche responses proportional to HER2 status.

Conclusions::

ERBB2/HER2 is a therapeutic target in DSRCT. HER2 ADCs may represent novel options for managing this exceptionally aggressive sarcoma, possibly fulfilling an urgent and historically unmet need for more effective clinical therapy.

2024-10-01·JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS

Towards a platform quantitative systems pharmacology (QSP) model for preclinical to clinical translation of antibody drug conjugates (ADCs)

Article

作者: Ghusinga, Khem Raj ; Nowak, Maksymilian ; McGirr, Kimiko ; Betts, Alison ; Subramanian, Kalyanasundaram ; Apgar, Joshua ; Scheuher, Bruna ; Panday, Sheetal

Abstract:

A next generation multiscale quantitative systems pharmacology (QSP) model for antibody drug conjugates (ADCs) is presented, for preclinical to clinical translation of ADC efficacy. Two HER2 ADCs (trastuzumab-DM1 and trastuzumab-DXd) were used for model development, calibration, and validation. The model integrates drug specific experimental data including in vitro cellular disposition data, pharmacokinetic (PK) and tumor growth inhibition (TGI) data for T-DM1 and T-DXd, as well as system specific data such as properties of HER2, tumor growth rates, and volumes. The model incorporates mechanistic detail at the intracellular level, to account for different mechanisms of ADC processing and payload release. It describes the disposition of the ADC, antibody, and payload inside and outside of the tumor, including binding to off-tumor, on-target sinks. The resulting multiscale PK model predicts plasma and tumor concentrations of ADC and payload. Tumor payload concentrations predicted by the model were linked to a TGI model and used to describe responses following ADC administration to xenograft mice. The model was translated to humans and virtual clinical trial simulations were performed that successfully predicted progression free survival response for T-DM1 and T-DXd for the treatment of HER2+ metastatic breast cancer, including differential efficacy based upon HER2 expression status. In conclusion, the presented model is a step toward a platform QSP model and strategy for ADCs, integrating multiple types of data and knowledge to predict ADC efficacy. The model has potential application to facilitate ADC design, lead candidate selection, and clinical dosing schedule optimization.

2024-09-01·CANCER

Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody‐drug conjugates–induced interstitial lung disease/pneumonitis: An expert consensus in China

Article

作者: Wu, Weizhu ; Si, Lu ; Shi, Yanxia ; Wang, Hongxia ; Chen, Zhanhong ; Zhang, Weiping ; Miao, Liyun ; Li, Hengyu ; Shen, Shurong ; Chen, Wenyan ; Zhang, Bin ; Lu, Yuanzhi ; Wang, Feng ; Zhong, Wenzhao ; Wan, Bing ; Wang, Ting ; Shu, Jingde ; Min, Lingfeng ; Song, Zhengbo ; Liu, Hongbing ; Lv, Tangfeng ; Wang, Lin ; Fu, Peifen ; Li, Qun ; Xie, Yanru ; Chen, Yiding ; Wang, Qian ; Hao, Yue ; Zhang, Zhang ; Xia, Yuanli ; Zhu, Youcai ; Wang, Xian ; Xu, Chunwei ; Zhou, Jianya ; Luo, Ting ; Wang, Dong ; Zhang, Yongchang ; Wang, Ouchen ; Huang, Liming ; Fang, Wenfeng ; Huang, Long ; Zhang, Lili ; Xie, Bojian ; Wang, Xiaojia ; Meng, Rui ; Lv, Donglai ; Li, Ziming ; Zhan, Ping ; Wang, Wenxian ; Song, Yong ; Fu, Jianfei ; Fang, Meiyu

Abstract:

Antibody–drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)‐positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2‐expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2‐positive and HER2‐low breast cancer, HER2‐positive gastric cancer, and HER2‐mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti‐HER2 ADC therapy. Studies on anti‐HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti‐HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti‐HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti‐HER2 ADC therapy in clinical practice.

项与 ADCs directed against HER2(Syntarga) 相关的新闻（医药）

2023-12-06

·FiercePharma

SABCS: Seagen outlines Tukysa's value alongside Roche's ADC in breast cancer. But FDA path remains unclear

Overall survival data on the combination of Tukysa and Kadcyla remain mature, and the company will continue to evaluate the trial data, Seagen said. As antibody-drug conjugates (ADCs) grow their importance in the oncology treatment space, efforts are underway to combine them with other agents. Enter Seagen. The ADC pioneer showed that its small-molecule drug Tukysa could offer additional tumor progression benefits on top of Roche’s ADC Kadcyla in HER2-positive breast cancer. When used as a second-line treatment, Tukysa and Kadcyla reduced the risk of disease progression or death by 24.1% compared with Kadcyla alone, according to phase 3 data presented at the 2023 San Antonio Breast Cancer Symposium. Patients who took the combination went a median 9.5 months without disease progression, versus 7.4 months for those in the control arm. “The results from the HER2CLIMB-02 study reinforce the clinical activity of Tukysa in patients with HER2-positive metastatic breast cancer,” Seagen’s R&D chief, Roger Dansey, M.D., said in a statement. But Seagen appears not ready to file for an FDA approval. Data on whether Tukysa’s addition can extend patients’ lives is not mature, and the company will continue to evaluate the trial data, Seagen said in response to Fierce Pharma’s inquiry about the company’s regulatory plan. Unlike the positive tumor progression signal, the Tukysa-Kadcyla regimen preliminarily showed a 23% increased risk of death after a median follow-up of 24.4 months. By the interim data cutoff, 134 patients in the 463-subject trial have died. Among the deaths, 71 (31%) happened in the combo arm and 63 (27%) belonged to the Kadcyla group. According to the overall survival curves presented at SABCS, differences started to show between the two treatment arms after about 18 months. Around that time, more patients on Kadcyla alone were alive compared with those on the Tukysa combo. In a relatively positive sign for the Seagen regimen, the combo started to perform better than Kadcyla monotherapy around month 33. The final overall survival analysis is planned for when 253 patients have passed away. A negative overall survival trend has become a big no-no at the FDA lately. The agency has required long-term data, limited the scope of an approval, or forced market withdrawals based on any hint of data suggesting a potential harm to survival. Having witnessed the agency’s actions, drugmakers have also learned not to push their luck when the survival data didn’t land in their favor. In HER2CLIMB-02, grade 3 or above treatment-emergent adverse events were higher at 69% in the combo arm, versus 41% in control. There’s another weakness in the HER2CLIMB-02 trial, the American Association for Cancer Research, the organizer of SABCS, noted in its own release. The Tukysa combo was not pitted against AstraZeneca and Daiichi Sankyo’s Enhertu, which has recently become the preferred agent over Kadcyla in the second-line HER2-positive setting. In the phase 3 DESTINY-Breast03 trial, Enhertu cut the risk of disease progression or death by a massive 72% over Kadcyla in patients pretreated with Roche’s Herceptin and chemo. Both Enhertu and Kadcyla are HER2-directed ADCs. Despite the availability of the ADCs, Tukysa has been holding onto a share of the second-line market mainly thanks to its ability to control brain metastases. Sara Hurvitz, M.D., from the Fred Hutchinson Cancer Center, who presented the HER2CLIMB-02 data at SABCS, also suggested that Tukysa could make a major difference in patients with brain metastases. Among about 44% of HER2CLIMB-02 patients who had brain metastases at baseline, the Tukysa-Kadcyla regimen cut the risk of progression or death by 36.1% over Kadcyla alone. The median progression-free survival was 7.8 months and 5.7 months, respectively. As for the proper ADC partner with Tukysa, Seagen is running a small phase 2 trial coded HER2CLIMB-04 that combines Tukysa with Enhertu in the second-line setting. The trial has a primary completion date in January 2024, according to ClinicalTrials.gov. Seagen also has its own HER2 ADC, disitamab vedotin, in-licensed from RemeGen. Seagen is currently being acquired by Pfizer in a $43 billion deal.