Enhertu demonstrated clinically meaningful and durable responses in patients across multiple HER2-expressing advanced solid tumours

AstraZeneca and Daiichi Sankyo’s Enhertu showed an objective response rate of 37.1% in the overall population of the DESTINY-PanTumor02 Phase II trial. Enhertu is the first therapy to show broad activity across HER2-expressing advanced solid tumours where there are currently no approved HER2-directed therapies. DESTINY-CRC02 Phase II trial also demonstrated positive antitumour activity and consistent safety in patients with previously treated HER2-positive metastatic colorectal cancer.

Positive results from an interim analysis of the ongoing DESTINY-PanTumor02 Phase II trial showed that Enhertu (trastuzumab deruxtecan) demonstrated clinically meaningful and durable responses across a broad range of HER2-expressing advanced solid tumours in previously treated patients.

These results will be presented today as a late-breaking oral presentation at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA3000).

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo. 

In the trial, previously treated patients (2 median prior lines of therapy) with HER2-expressing advanced solid tumours including either biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers or other tumours treated with Enhertu showed a confirmed objective response rate (ORR) of 37.1%, as assessed by investigator at an interim analysis. A greater response was observed in patients with the highest level of HER2 expression (immunohistochemistry (IHC) 3+), where Enhertu demonstrated a confirmed ORR of 61.3% as confirmed by central testing. A complete response (CR) was observed in 15 (5.6%) patients in the overall trial population, with 84 (31.5%) partial responses (PR) observed, and 123 (46.1%) patients achieving stable disease. The disease control rate (DCR) in the overall trial population was 68.2%, as assessed by investigator.

Nearly half (49.6%) of all patients in DESTINY-PanTumor02 who achieved a response remained in response at one year. Median duration of response (DoR) was 11.8 months (95% confidence interval [CI] 9.8-NE) in the overall trial population and 22.1 months (CI 9.3-NE) in patients with IHC 3+ expression.

Funda Meric-Bernstam, MD, Chair of the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, US and principal investigator for the trial, said: “The DESTINY-PanTumor02 data showed encouraging and durable response rates across a broad range of HER2-expressing solid tumours where there are currently no approved HER2-targeted treatments. Based on these results, Enhertu has the potential to benefit specific patients with HER2-expressing advanced disease who currently have limited options and may face a poor prognosis.”

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: “While HER2 is an established biomarker in breast, gastric, lung and colorectal cancers, data from the DESTINY-PanTumor02 trial validate HER2 as an actionable biomarker across a broad range of tumour types. Enhertu is the first treatment to demonstrate broad activity across HER2-expressing solid tumours where there are currently no approved HER2-directed therapies. These data will support our ongoing conversations with global health authorities as we look to bring Enhertu to as many patients as possible.”

Mark Rutstein, MD, Global Head, Oncology Development, Daiichi Sankyo, said: “Nearly half of patients who achieved a response with Enhertu as a late-line treatment for HER2-expressing advanced solid tumours in DESTINY-PanTumor02 remained in response at one year, demonstrating the potential of this important medicine to provide benefit to patients with hard-to-treat cancers in need of new options. The results further reinforce the important role of antibody drug conjugates like Enhertu to provide potential new solutions to advance current standards of care in areas of high unmet need and improve the outcomes of patients.” 

Summary of results: DESTINY-PanTumor02

BTC, biliary tract cancer; CI, confidence interval; DCR, disease control rate; DoR, duration of response; IHC, immunohistochemistry; NE, not estimable; NR, not reached; ORR, objective response rate

ⁱResponses in extramammary Paget disease, head and neck cancer, oropharyngeal neoplasm, and salivary gland cancer.

ⁱⁱIHC based on central HER2 testing; 67 patients had IHC 1+ (n=25), IHC 0 (n=30) or unknown IHC status (n=12) by central testing

ⁱⁱⁱ Confirmed complete response, confirmed partial response or stable disease.

The safety profile of Enhertu was consistent with previous clinical trials, with no new safety concerns identified. The most common Grade 3 or higher treatment-related treatment-emergent adverse events (TEAEs) were neutropenia (19.1%), anaemia (8.6%), fatigue (6.0%) and thrombocytopenia (5.2%).

In DESTINY-PanTumor02, 20 patients (7.5%) experienced interstitial lung disease (ILD) or pneumonitis related to treatment with Enhertu as determined by an independent adjudication committee. The majority (6.7%) were low Grade (Grade 1 or 2) with one (0.4%) Grade 3 event, no Grade 4 events and one (0.4%) Grade 5 event observed.

DESTINY-CRC02 primary results support 5.4mg/kg as optimal dose of Enhertu in patients with HER2-positive metastatic colorectal cancer

Primary results from the DESTINY-CRC02 Phase II trial, which evaluated Enhertu at the 5.4mg/kg and 6.4mg/kg doses in patients with previously treated locally advanced, unresectable or metastatic HER2-positive (IHC 3+ or IHC 2+/in-situ hybridisation [ISH]+) colorectal cancer of BRAF wild-type, RAS wild-type or RAS mutant tumour types, were also presented at ASCO.

In the primary endpoint analysis, a confirmed ORR of 37.8% (95% CI 27.3-49.2) and 27.5% (95% CI 14.6-43.9) was seen in patients in the 5.4mg/kg and 6.4mg/kg arms respectively, as assessed by blinded independent central review (BICR). All responses (n=42) were partial, with 40 (48.8%) patients in the 5.4mg/kg arm and 23 (57.5%) patients in the 6.4mg/kg arm achieving stable disease. Greater efficacy (46.9% ORR (95% CI 34.3-59.8)) was observed in patients with the highest levels of HER2 expression (IHC 3+) compared to those with IHC 2+/ISH+ HER2 status in the 5.4mg/kg treatment arm (5.6% ORR (95% CI 0.1-27.3)). Anti-tumour efficacy was observed regardless of RAS mutation status (39.7% with RAS mutations; 28.6% without RAS mutations) and in those with prior HER2-directed therapy (41.2%) in the 5.4mg/kg arm.

Enhertu also demonstrated a median DoR of 5.5 months in both the 5.4mg/kg (95% CI 4.2-8.1) and 6.4mg/kg (95% CI 3.7-NE) arms with a median duration of follow-up of 8.9 months and 10.3 months in the two arms respectively. Median progression-free survival (PFS) was 5.8 months (95% CI 4.6-7.0) in the 5.4mg/kg arm and 5.5 months (95% CI 4.2-7.0) in the 6.4mg/kg arm. Median overall survival (OS) was 13.4 months (95% CI 12.5-16.8) in the 5.4mg/kg arm and not reached (95% CI 9.9-NE) in the 6.4mg/kg arm.

The safety profile observed in DESTINY-CRC02 at the 5.4mg/kg and 6.4mg/kg dose levels was consistent with other clinical trials of Enhertu, with no new safety signals identified at either dose. A more favourable benefit-risk profile was observed in patients treated with Enhertu 5.4mg/kg, resulting in its selection as the recommended dose. Grade 3 or higher treatment related TEAEs were numerically higher with Enhertu 6.4mg/kg versus 5.4mg/kg. Grade 3 or higher treatment related TEAEs occurred in 41.0% and 48.7% of patients receiving Enhertu 5.4mg/kg or 6.4mg/kg, respectively.

The most common Grade 3 or higher TEAEs occurring in greater than 10% of patients were neutropenia (16.9% (5.4mg/kg), 28.2% (6.4mg/kg)), anaemia (9.6% (5.4mg/kg), 23.1% (6.4mg/kg)) and thrombocytopenia (6.0% (5.4mg/kg); 12.8% (6.4mg/kg)). There were 12 cases (8.4% in the 5.4mg/kg arm and 12.8% in the 6.4mg/kg arm) of treatment related ILD or pneumonitis reported, as determined by an independent adjudication committee. The majority (5.4mg/kg: 8.4%, 6.4mg/kg: 10.2%) were low Grade (Grade 1 or 2) with no Grade 3, no Grade 4 and one Grade 5 event observed (6.4mg/kg: 2.6%).

Notes

HER2 expression in solid tumours

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.^1,2 In some cancers, HER2 expression is amplified or the cells have activating mutations.^1,3 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis.⁴

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 tumour types.^2,5,6

HER2 is an emerging biomarker in biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers.³ Testing is not routinely performed in these additional tumour types and as a result, available literature is limited. HER2 overexpression (IHC3+) has been observed at rates from 1% to 28% in these solid tumours.^7,8 There is an unmet need for effective therapies for certain HER2-expressing solid tumours, 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 these cancers.^2,9

Colorectal cancer is the third most common cancer 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 2020.¹⁰ 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.¹¹ For patients with metastatic disease, approximately 2 to 3% are HER2 overexpressing.^6,12

DESTINY-PanTumor02

DESTINY-PanTumor02 is a global, multicentre, multi-cohort, open-label Phase II trial evaluating the efficacy and safety of Enhertu (5.4mg/kg) for the treatment of previously treated HER2-expressing tumours, including biliary tract cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer and 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.

DESTINY-PanTumor02 has enrolled 267 patients at multiple sites in Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

DESTINY-CRC02

DESTINY-CRC02 is a global, randomised, two arm, parallel, multicentre Phase II trial evaluating the efficacy and safety of two doses (5.4mg/kg or 6.4mg/kg) of Enhertu in patients with locally advanced, unresectable or metastatic HER2 positive colorectal cancer of BRAF wild-type, or RAS wild-type and RAS mutant tumour types previously treated with standard therapy.

The trial was conducted in two stages. In the first stage, patients (n=80) were randomised 1:1 to receive either 5.4mg/kg or 6.4mg/kg of Enhertu. In the second stage, additional patients (n=42) were enrolled in the 5.4mg/kg arm.

The primary endpoint is confirmed ORR as assessed by BICR. 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.

Enhertu

Enhertu 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 topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Enhertu (5.4mg/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 (5.4mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridisation [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 (5.4mg/kg) is approved in Israel and under accelerated approval in the US for the treatment of adult patients with unresectable or metastatic non-small cell lung cancer whose tumours have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the US for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/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 trial and/or DESTINY-Gastric02 trial.

Enhertu development programme

A comprehensive global development programme 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, are also underway.

Daiichi Sankyo collaboration

Daiichi Sankyo Company, Limited (TSE: 4568) [referred to as Daiichi Sankyo] and AstraZeneca entered into a global collaboration to jointly develop and commercialise Enhertu (a HER2-directed ADC) in March 2019, and datopotamab deruxtecan (DS-1062; a TROP2-directed ADC) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for the manufacturing and supply of Enhertu and datopotamab deruxtecan.

AstraZeneca in oncology

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The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
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