AstraZeneca and Daiichi Sankyo on Friday announced that data from three mid-stage studies of Enhertu (trastuzumab deruxtecan) in patients with HER2-positive colorectal, gastric and non-small-cell lung (NSCLC) cancer were presented at the virtual scientific programme of the American Society of Clinical Oncology (ASCO) annual meeting, supporting potential broader use of the antibody drug conjugate. Enhertu is currently approved for the treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received at least two prior anti-HER2-based regimens in the metastatic setting.
José Baselga, executive vice president of oncology R&D at AstraZeneca, said "Enhertu has now demonstrated impressive clinical activity in four different cancer settings, reinforcing the potential of this…medicine to transform patient outcomes across a range of HER2-targetable tumours."
Colorectal cancer: tumour response of 45.3%
The DESTINY-CRC01 study enrolled 78 patients with HER2-expressing, unresectable and/or metastatic colorectal cancer, excluding those with RAS or BRAF gene mutations. The main goal is objective response rate (ORR) in the primary cohort, which consists of 53 patients with HER2-positive disease, defined as IHC3+ or IHC2+/ISH+ tumours. Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Two additional exploratory cohorts enrolled patients whose tumours had lower levels of HER2-expression.
Results showed that 45.3% of patients achieved a tumour response after treatment with Enhertu. Meanwhile, a DCR of 83% was observed with median PFS of 6.9 months.
Summary of results:
|Total evaluable in primary cohort (n=53)|
|Confirmed ORR (95% CI)||45.3% (31.6-59.6)|
|DCR (95% CI)||83% (70.2-91.9)|
|Median DoR (months) (95% CI)||NE (4.2-NE)|
|Median PFS (months) (95% CI)||6.9 (4.1-NE)|
|Median OS (months) (95% CI)||NE (0.74-NE)|
CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; NE, not estimable
The most common grade 3 or higher treatment-emergent adverse events in DESTINY-CRC01 were decreased neutrophil count and anaemia. There were also five cases of interstitial lung disease (ILD) and pneumonitis, with two deaths determined to be due to ILD.
Gastric cancer: 41% lower risk of death
The DESTINY-Gastric01 trial included 189 patients from Japan and South Korea with HER2-expressing advanced gastric cancer or gastroesophageal junction adenocarcinoma who have progressed on two or more prior treatment regimens, including fluoropyrimidine and platinum chemotherapy, and Roche's Herceptin (trastuzumab). Subjects were randomised to receive Enhertu monotherapy or investigator's choice of paclitaxel or irinotecan. In January, AstraZeneca and Daiichi Sankyo said the study had met the primary endpoint of ORR, while secondary goals included OS, PFS, DoR, DCR and time to treatment failure.
AstraZeneca and Daiichi Sankyo noted that the confirmed ORR was 42.9% with Enhertu compared to 12.5% with investigator's choice of chemotherapy. In addition, subjects treated with Enhertu had a 41% reduction in the risk of death versus patients treated with chemotherapy at a pre-specified interim analysis. Median OS was 12.5 months versus 8.4 months with chemotherapy, with an estimated OS rate at one year of 52.1% and 28.9%, respectively, in the Enhertu and chemotherapy arms.
Principal investigator Kohei Shitara suggested that based on the results, Enhertu "has the potential to become a new standard of care for these patients."
Summary of results:
|Enhertu||Investigator's choice of chemotherapy|
|Confirmed ORR (95% CI)||42.9%
|Confirmed DCR (95% CI)||85.7% (78.1-91.5)||62.5% (48.5-75.1)|
|Confirmed median DoR (months) (95% CI)||11.3 (5.6- NE)||3.9 (3.0-4.9)|
The most common grade 3 or higher treatment-emergent adverse events were decreased neutrophil count, anaemia, lower white blood cell count and reduce appetite. There were 12 cases of confirmed treatment-related ILD and pneumonitis, with no ILD-related deaths.
NSCLC: objective response of 61.9%
The DESTINY-Lung01 trial evaluated Enhertu in 170 patients with unresectable and metastatic non-squamous NSCLC who have HER2-mutant or HER2-overexpressing disease, defined as having IHC 3+ or IHC 2+ tumours. Patients had progressed after one or more systemic therapies including chemotherapy, molecular targeted therapy or immunotherapy. The study's main goal is ORR, while key secondary endpoints include DoR, DCR, PFS and OS.
Results showed that the confirmed ORR was 61.9% for patients treated with Enhertu monotherapy. Meanwhile, a DCR of 90.5% was seen, with a median PFS of 14 months.
"While the role of anti-HER2 treatment is well-established in breast and gastric cancers, there are no HER2-directed therapies specifically approved for lung cancer," noted Antoine Yver, global head of oncology R&D at Daiichi Sankyo. He added "these results validate HER2 mutations as actionable targets in lung cancer."
Summary of results:
|HER2 mutated total evaluable (n=42)|
|ORR (95% CI)||61.9% (45.6-76.4)|
|DCR (95% CI)||90.5% (77.4-97.3)|
|Median DoR (months) (95% CI)||NE (5.3-NE)|
|Median PFS (months) (95% CI)||14 months (6.4-14.0)|
|Median OS (months) (95% CI)||NE (11.8-NE)|
The most common grade 3 or higher treatment-emergent adverse events were decreased neutrophil count and anaemia. There were five cases of confirmed treatment-related ILD and pneumonitis.
Enhertu was recently granted a breakthrough therapy by the FDA for use in this setting.
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