AstraZeneca and Daiichi Sankyo’s Enhertu has demonstrated a six-month improvement in median progression-free survival compared with the current global standard of care in patients with HER2-mutant advanced non-small cell lung cancer (NSCLC).

 

This marks a potentially significant shift in the first-line treatment landscape.

 

Results from the Phase III DESTINY-Lung04 trial showed that Enhertu (trastuzumab deruxtecan) reduced the risk of disease progression or death by 37% compared with pembrolizumab plus platinum-pemetrexed chemotherapy.

 

Patients treated with Enhertu achieved a median progression-free survival of 14.3 months, compared with 8.3 months for those receiving pembrolizumab plus chemotherapy. The difference was statistically significant, with a hazard ratio of 0.63 and p<0.0001.

 

The findings position Enhertu as the first HER2-directed therapy to demonstrate superior progression-free survival over standard of care in a Phase III trial in this setting.

 

The benefit extended beyond delaying disease progression. Enhertu produced an objective response rate of 70.0%, compared with 44.5% for pembrolizumab plus chemotherapy.

 

Responses also lasted longer with Enhertu, with a median duration of response of 13.4 months, compared with 9.7 months in the standard-of-care arm.

 

A favourable progression-free survival trend was observed across key patient subgroups, including patients with brain or liver metastases, different smoking histories, HER2 exon 19 or exon 20 mutations, and de novo or recurrent disease.

 

Julia Rotow, Assistant Professor of Medicine, Dana-Farber Cancer Institute and lead investigator of the trial, said: “HER2-mutant non-small cell lung cancer is an aggressive disease with limited responses to current first-line standard of care, and many patients experience disease progression within a year of starting treatment. 

 

"With seventy per cent of patients responding and a median progression-free survival of 14.3 months, trastuzumab deruxtecan has the potential to become an important new first-line treatment option for these patients.”

 

The results could have particular significance because HER2-mutant NSCLC remains an aggressive form of lung cancer with limited first-line treatment options. HER2 mutations occur in approximately 2–4% of patients with non-squamous NSCLC and are associated with tumour growth, poor prognosis and an increased incidence of brain metastases.

 

The current global first-line standard of care combines immunotherapy with platinum-based chemotherapy. However, many patients do not respond adequately and can experience disease progression within a year, highlighting the need for more effective targeted approaches.

 

Susan Galbraith, Executive Vice President, Oncology Haematology R&D, AstraZeneca, said: “DESTINY-Lung04 is the first Phase III trial to demonstrate superior progression-free survival versus the global first-line standard of care in patients with HER2-mutant advanced non-small cell lung cancer. 

 

"These results add to the growing body of evidence supporting Enhertu as an important treatment for patients with HER2 alterations and underscore its potential role at the time of metastatic diagnosis, when treatment has the greatest opportunity to improve outcomes.”

 

John Tsai, Global Head, R&D, Daiichi Sankyo, said: “Enhertu was the first HER2-directed medicine and antibody drug conjugate approved for patients with HER2-mutant non-small cell lung cancer and has become a second-line standard-of-care treatment. 

 

"The progression-free survival benefit of six months and strong response rates seen in DESTINY-Lung04 reinforce the importance of targeting HER2 directly in these patients and support the potential of Enhertu in the first-line setting where delaying disease progression for as long as possible is a critical goal.”

 

The next key question will be whether the progression-free survival advantage ultimately translates into a meaningful overall survival benefit as the DESTINY-Lung04 trial matures.