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Daiichi Sankyo has submitted a supplemental New Drug Application (sNDA) to Japan’s Ministry of Health, Labour and Welfare (MHLW) for Enhertu (trastuzumab deruxtecan) for the treatment of adult patients with HER2 positive advanced or recurrent solid tumours refractory or intolerant to standard treatments.
HER2 directed therapies currently are approved to treat breast, colorectal, gastric, lung and salivary gland cancer in Japan. However, there are no HER2 directed therapies approved for other cancers that are HER2 overexpressed (IHC 3+) or amplified (ERBB2).
The sNDA is based on data from four phase 2 trials including HERALD, an investigator-initiated trial conducted in Japan, DESTINY-PanTumor02, DESTINY-CRC02 and DESTINY-Lung01 where Enhertu demonstrated clinically meaningful responses across a broad range of tumours.
“The clinical benefit seen across several studies supports the potential of Enhertu to treat any type of HER2 positive metastatic solid cancer,” said Yuki Abe, PhD, Head of R&D Division in Japan and Head of Research, Daiichi Sankyo. “We look forward to working with the Japan health authority to bring the first antibody drug conjugate with a tumour agnostic indication to patients.”
HERALD is a multicenter, open-label, single-arm phase 2 trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) in patients with unresectable, advanced or recurrent solid tumors refractory or intolerant to standard treatments and have HER2 gene amplification in circulating tumour DNA, including biliary tract, cervical, colorectal, endometrial, esophageal, gastric, melanoma, non-small cell lung, ovarian, pancreatic, prostate, salivary gland, small intestine, urothelial cancer or other tumours.
The primary endpoint of HERALD is confirmed objective response rate (ORR) as assessed by investigator.
Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), time to treatment failure, overall survival (OS), ORR by independent central review and safety. Results from HERALD were published in the Journal of Clinical Oncology.
HERALD enrolled 62 patients at seven sites in Japan. For more information about the trial, visit Japan’s Registry of Clinical Trials.
DESTINY-PanTumor02 is a global, multicenter, multi-cohort, open-label phase 2 trial evaluating the efficacy and safety of Enhertu (5.4 mg/kg) for the treatment of previously treated HER2 expressing tumours, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancer or other tumours.
The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed ORR as assessed by investigator.
Secondary endpoints include DOR, DCR, PFS, OS, safety, tolerability and pharmacokinetics. Results from DESTINY-PanTumor02 were published in the Journal of Clinical Oncology.
DESTINY-PanTumor02 enrolled 267 patients, including 75 HER2 positive (IHC 3+) adult patients, at multiple sites in Asia, Europe and North America.
DESTINY-Lung01 is a global phase 2, open-label, two-cohort trial evaluating the efficacy and safety of Enhertu (6.4 mg/kg and 5.4 mg/kg) in patients with HER2 mutant (cohort 2, n=91) or HER2 overexpressing (defined as IHC 3+ or IHC 2+) (cohort 1 and 1a, n=90) unresectable or metastatic NSCLC who had progressed after one or more systemic therapies.
The primary endpoint is confirmed ORR by independent central review. Key secondary endpoints include DOR, DCR, PFS, OS and safety. Results from the HER2 mutant cohort were published in The New England Journal of Medicine. Full results from the HER2 overexpressing cohort were published in The Lancet Oncology.
DESTINY-Lung01 enrolled 181 patients, including 17 HER2 positive (IHC 3+) adult patients, at multiple sites, including Asia, Europe and North America.
DESTINY-CRC02 is a global, randomized, two arm, parallel, multicenter phase 2 trial evaluating the efficacy and safety of two doses (5.4 mg/kg or 6.4 mg/kg) of Enhertu in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, RAS wild-type or RAS mutant tumour types previously treated with standard therapy. The trial was conducted in two stages. In the first stage, patients (n=80) were randomized 1:1 to receive either 5.4 mg/kg or 6.4 mg/kg of Enhertu. In the second stage, additional patients (n=42) were enrolled in the 5.4 mg/kg arm.
The primary endpoint is confirmed ORR as assessed by blinded independent central review. Secondary endpoints include DOR, DCR, investigator-assessed confirmed ORR, clinical benefit ratio, PFS, OS and safety. Results from DESTINY-CRC02 were published in The Lancet Oncology.
DESTINY-CRC02 enrolled 122 patients, including 64 HER2 positive (IHC 3+) adult patients, at multiple sites in Asia, Europe and North America.
HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of various tissue cells throughout the body and is involved in normal cell growth. In some cancers, the HER2 gene is amplified or the cells have activating mutations.
HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis. HER2 directed therapies have been used to treat breast, colorectal, gastric, lung and salivary gland cancers.
Although HER2 is expressed or amplified in solid tumour types including biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers, testing is not routinely performed in these additional tumour types and as a result, available literature is limited.
Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform. Enhertu consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
Enhertu (5.4 mg/kg) is approved in more than 75 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization (ISH)+) breast cancer who have received a prior anti-HER2-based regimen, either in the metastatic setting or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within six months of completing therapy based on the results from the DESTINY-Breast03 trial.
Enhertu (5.4 mg/kg) is approved in more than 75 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.
Enhertu (5.4 mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic hormone receptor (HR) positive, HER2 low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer, as determined by a locally or regionally approved test, that have progressed on one or more endocrine therapies in the metastatic setting based on the results from the DESTINY-Breast06 trial.
Enhertu (5.4 mg/kg) is approved in more than 50 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 and/or DESTINY-Lung05 trials. Continued approval in China and the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (6.4 mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Continued approval in China for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Enhertu (5.4 mg/kg) is approved in Brazil, Israel, Russia, Taiwan, UK and the US for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumours who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
A comprehensive global clinical development program is underway evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2 targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize Enhertu in March 2019 and Datroway in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and Datroway.
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo.
The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of Enhertu, a HER2 directed ADC, and Datroway, a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck & Co., Inc, Rahway, NJ, USA. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.
The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.
Ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
Daiichi Sankyo is an innovative global healthcare company contributing to the sustainable development of society that discovers, develops and delivers new standards of care to enrich the quality of life around the world.
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