AstraZeneca and Daiichi's Enhertu lung cancer bid clouded by survival setback

AstraZeneca (AZN) and Daiichi Sankyo (DSNKY) face a harder path to establishing their blockbuster antibody-drug conjugate Enhertu as a first-line treatment for HER2-mutant non-small cell lung cancer, after a late-stage trial showed an unfavorable trend in overall survival.

Patients treated with Enhertu had a preliminary 15 percent higher risk of death than those given Merck's (MRK) Keytruda plus chemotherapy in the phase 3 Destiny-Lung04 study, according to results presented at the 2026 World Conference on Lung Cancer.

At an interim analysis, median survival was 29.3 months in the Enhertu arm against 33.1 months for the Keytruda-chemotherapy group. By that point, 213 patients, or 46.9 percent of those enrolled, had died, including 115 in the Enhertu arm and 98 in the control arm.

The survival figures were assessed when the trial met its primary endpoint of progression-free survival. Enhertu reduced the risk of disease progression or death by 37 percent, extending median progression-free survival by six months to 14.3 months. The drug also produced a higher objective response rate, of 70 percent compared with 44.5 percent, and responses lasted longer, at a median 13.4 months versus 9.7 months. Complete response rates were identical, at 1.8 percent, in both arms.

Julia Rotow, an oncologist at the Dana-Farber Cancer Institute and an investigator on the study, said the progression and response data supported Enhertu as a new first-line option for a patient population in need of more effective HER2-directed therapies.

Susan Galbraith, AstraZeneca's executive vice-president of oncology hematology R&D, noted that Destiny-Lung04 was the first phase 3 study to demonstrate a progression-free survival benefit over the existing first-line standard in this disease. The results, she said, strengthened the case for using Enhertu at the point of metastatic diagnosis, "when treatment has the greatest opportunity to improve outcomes."

The adverse survival trend, however, could make approval discussions with the US Food and Drug Administration difficult, even though overall survival had not yet been formally tested. In recent years, companies including Novartis (NVS), Eli Lilly (LLY) and Roche (RHHBY) have seen regulatory plans delayed or derailed over survival data. AstraZeneca said it intends to share the results with the FDA and other regulators.

The survival curves began to favor the control arm roughly 20 months after randomization, with no sign of the gap narrowing through the follow-up period. Rotow suggested an imbalance in subsequent treatments might explain the result. About 72 percent of patients in both arms who stopped their assigned therapy went on to receive further treatment, but only 39 percent of those in the Enhertu arm received a HER2-directed agent, against 72 percent in the control group.

Drug-related deaths were also more frequent with Enhertu. All four treatment-related fatal adverse events in the Enhertu arm were linked to pneumonitis or interstitial lung disease, a known risk of Enhertu and other conjugates built on Daiichi's DXd platform. A fifth death was later adjudicated as drug-related lung disease after the safety database was locked. No such cases were linked to the Keytruda arm.

AstraZeneca said nearly all fatal cases involved delayed or insufficient steroid treatment. Overall, adjudicated drug-related lung inflammation occurred in 20.8 percent of Enhertu patients, most of it mild or moderate, compared with 2.3 percent in the comparator group. Although two-thirds of cases resolved, the investigators cautioned that the condition remained an important risk requiring careful monitoring. The company said the drug's safety profile was otherwise consistent with previous findings.

HER2-mutant disease is an aggressive but rare form of lung cancer, accounting for about 2 to 4 percent of cases. Checkpoint inhibitors such as Keytruda, combined with chemotherapy, are not specifically indicated for these tumors but fall under broad first-line labels.

Enhertu became the first HER2-directed therapy approved by the FDA for the disease in 2022, through an accelerated clearance for previously treated patients that has yet to be converted into full approval. Since then, the agency has cleared two oral tyrosine kinase inhibitors, Boehringer Ingelheim's Hernexeos and Bayer's (BAYRY) Hyrnuo, both of which gained first-line accelerated approvals this year, in February and last week respectively, on the strength of response rates of 76 percent and 75 percent in small trials.

The arrival of these rivals could further weaken the case for Enhertu in the front-line setting, given the survival concerns now hanging over the drug.