On August 31, 2023 Astrazeneca and Daiichi Sankyo reported that ENHERTU (fam-trastuzumab deruxtecan-nxki) has been granted two additional Breakthrough Therapy Designations (BTDs) in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, and for the treatment of patients with HER2 positive (IHC 3+) metastatic colorectal cancer who have received two or more prior regimens (Press release, AstraZeneca, AUG 31, 2023, View Source [SID1234634818]).
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ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN).
HER2 overexpression has been observed in 1% to 28% across various types of metastatic solid tumors and in up to 5% of patients with colorectal cancer.1,2,3,4 There is an unmet need for effective therapies for these tumor types, particularly for patients who have progressed on or are refractory to standard of care therapies.5,6
The U.S. Food and Drug Administration (FDA) BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat a serious condition and address a significant unmet medical need. The new medicine needs to have shown encouraging preliminary clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.
The FDA granted the BTD for the treatment of metastatic HER2 positive solid tumors based on results from the ongoing DESTINY-PanTumor02 phase 2 trial with supporting data from other trials in the ENHERTU clinical development program. Results from an interim analysis of DESTINY-PanTumor02 were presented as a late-breaking oral presentation at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in previously treated patients with HER2 expressing metastatic solid tumors including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic cancers and other tumors. The BTD for the treatment of HER2 positive metastatic colorectal cancer was based on final results from the DESTINY-CRC01 phase 2 trial presented at the 2022 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI) and primary results from the DESTINY-CRC02 phase 2 trial presented at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting.
"ENHERTU is the first HER2 directed therapy to demonstrate a potential benefit across a series of difficult-to-treat cancers and these designations are recognition of the continued potential of this innovative medicine," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "We remain committed to exploring additional opportunities for ENHERTU in these tumor types with the goal of bringing this treatment to more patients as soon as possible."
"This is an important step in bringing ENHERTU to patients with a broad range of HER2 expressing solid tumors who currently face a poor prognosis," said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. "We are encouraged by the recently reported results from our pan-tumor and colorectal cancer trials that contributed to these designations, and we look forward to working closely with the FDA to provide these patients with a potential new targeted treatment option."
ENHERTU has received seven BTDs and its designation in HER2 expressing metastatic solid tumors represents the first time ENHERTU has been granted this designation in a tumor agnostic setting. ENHERTU previously received BTDs for three indications in breast cancer, including HER2 low metastatic breast cancer, second-line HER2 positive metastatic breast cancer and later-line HER2 positive metastatic breast cancer. Two additional BTDs for ENHERTU were granted for HER2 (ERBB2) mutant metastatic non-small cell lung cancer (NSCLC) and HER2 positive metastatic gastric cancer.
About DESTINY-PanTumor02
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 HER2 expressing tumors (IHC 3+ or IHC 2+), including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer and other tumors.
The primary efficacy endpoint of DESTINY-PanTumor02 is confirmed objective response rate (ORR) as assessed by investigator. Secondary endpoints include duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), safety, tolerability and pharmacokinetics.
DESTINY-PanTumor02 has enrolled 268 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.
About DESTINY-CRC01
DESTINY-CRC01 is a global, phase 2, open-label, multicenter trial evaluating the efficacy and safety of ENHERTU (6.4 mg/kg) in patients with HER2 expressing unresectable and/or metastatic colorectal cancer.
The primary endpoint of the main cohort of DESTINY-CRC01, which enrolled 53 patients with HER2 positive (IHC 3+ or IHC 2+/in-situ hybridization [ISH]+) metastatic colorectal cancer, was confirmed ORR as assessed by independent central review. Secondary endpoints include DCR, DoR, PFS, OS and safety. Two additional exploratory cohorts enrolled patients whose tumors had lower levels of HER2 expression (HER2 IHC 2+/ISH- [n=15], and HER2 IHC 1+ [n=18], respectively).
DESTINY-CRC01 enrolled 86 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.
About DESTINY-CRC02
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 (IHC 3+ or IHC 2+/ISH+) colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumor 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.
DESTINY-CRC02 enrolled 122 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.
About HER2 Expression in Solid Tumors
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.5,7 In some cancers, HER2 expression is amplified or the cells have activating mutations.7,8 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.9
While HER2 directed therapies have been used to treat breast, gastric, lung and colorectal cancers, more research is needed evaluating their potential role in treating other HER2 expressing tumor types.3,5,10
HER2 is an emerging biomarker in biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers.8 Testing is not routinely performed in these additional tumor types and as a result, available literature is limited. HER2 overexpression has been observed at rates from 1% to 28% in these solid tumors.1,2 There is an unmet need for effective therapies for certain HER2 expressing solid tumors, particularly for those who have progressed on or are refractory to standard of care therapies as there are currently no approved HER2 directed therapies for biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers.5,6
Colorectal cancer is the third most common and second most common cause of cancer deaths worldwide with more than 1.9 million patients diagnosed and more than 935,000 deaths globally in 2020.11 Approximately 25% of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs and about 50% of patients with colorectal cancer will eventually develop metastases.12 For patients with metastatic disease, up to 5% are HER2 overexpressing.3,4
About ENHERTU
ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. 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 program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.
ENHERTU (5.4 mg/kg) is approved in more than 50 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a (or one or more) 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 40 countries 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 Israel, Japan and under accelerated approval in the U.S. for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors 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 trial. Continued approval in the U.S. 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 30 countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.
About the ENHERTU Clinical Development Program
A comprehensive global 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.