Enhertu demonstrated clinically meaningful and durable responses in patients across multiple HER2-expressing advanced solid tumours.- AstraZeneca + Daiichi Sankyo

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.”

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%).