An unfavorable overall survival trend in a phase 3 trial threatens to thwart AstraZeneca and Daiichi Sankyo’s bid to establish their star antibody-drug conjugate Enhertu as a first-line treatment for patients with HER2-mutant non-small cell lung cancer.
Treatment with Enhertu showed a preliminary 15% increased risk of death compared with Keytruda plus chemotherapy in the phase 3 Destiny-Lung04 study, according to results shared at the 2026 World Conference on Lung Cancer.
At an interim analysis of the study, patients in the Enhertu arm lived a median 29.3 months, versus 33.1 months for the Keytruda-chemo arm. At that point, 213 patients (46.9%) enrolled in the study had passed away, including 115 (50.7%) in the Enhertu group and 98 (43.2%) in the control arm.
The early overall survival data were evaluated when the trial met its primary endpoint, progression-free survival. Enhertu cut the risk of progression or death by 37%, extending median PFS by six months to 14.3 months.
The HER2-targeted ADC also registered a higher objective response rate (ORR), reaching 70%, compared to 44.5% with Keytruda plus chemo, as well as a longer duration of response lasting a median 13.4 months, versus 9.7 months, respectively. The rate of complete responses was the same, at 1.8%, for both regimens.
Based on those positive PFS and tumor response signals, Julia Rotow, M.D., of the Dana-Farber Cancer Institute and investigator of the study, said the data “support [Enhertu] as a new first-line treatment option for this patient population, for whom more effective HER2-directed approaches are needed.”
In a statement, AZ’s executive vice president of oncology hematology R&D, Susan Galbraith, Ph.D., noted that Destiny-Lung04 is the first phase 3 trial to show a PFS benefit versus existing first-line standard in HER2-mutant NSCLC.
“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,” she said.
Still, the negative OS trend could make any approval discussions with the FDA difficult, even though the endpoint was not yet formally tested at this juncture. Many companies like Novartis, Eli Lilly and Roche have in recent years had their FDA plans delayed or derailed because of OS data.
An AZ spokesperson confirmed to Fierce that the company intends to share the Destiny-Lung04 data with the FDA and other regulatory authorities.
In Destiny-Lung04, OS curves started to favor the control arm over Enhertu at about 20 months post-randomization, with no sign of the gap closing up through the follow-up, according to Rotow’s presentation slides prepared for a WCLC press conference.
Rotow noted that an imbalance in subsequent HER2-directed treatments may explain the unfavorable OS results.
Among patients who had stopped their assigned treatments, roughly 72% of patients in both arms received a subsequent therapy. Among those who got later-line treatments, 39% in the Enhertu arm received a HER2-directed agent, versus 72% in the control arm.
In addition to follow-on therapies, more drug-related death events happened in the Enhertu arm. All four Enhertu-related grade 5 adverse events were tied to pneumonitis or interstitial lung disease (ILD), a known risk factor for Enhertu and other ADCs built with Daiichi’s DXd platform. Following the clinical database lock for the safety analysis, Enhertu recorded one additional death adjudicated as drug-related ILD. By comparison, no adjudicated ILD was linked to the Keytruda arm.
“Nearly all Grade 5 ILD cases in [Destiny-Lung04] had delayed initiation and/or suboptimal steroid dosing for ILD,” the AZ spokesperson said in an email statement to Fierce.
All told, adjudicated drug-related ILD or pneumonitis occurred in 20.8% of patients in the Enhertu arm—with 78.7% of the events classified as grade 1 or 2—compared with 2.3% for the comparator group.
Even as 66% cases of ILD in the Enhertu arm were resolved, the deaths highlighted that “ILD remains an important risk of [Enhertu] and should be monitored/managed appropriately,” Rotow and colleagues said in the presentation slides.
Overall, Enhertu showed a safety profile that was generally consistent with its known profile, with no new safety concerns identified, the AZ spokesperson pointed out.
HER2-mutant NSCLC is an aggressive but rare form of lung cancer associated with poor prognosis, accounting for approximately 2% to 4% of all NSCLC cases. Existing immune checkpoint inhibitors like Keytruda, used alongside chemo, are not specifically indicated for HER2-mutant tumors but are covered under broad first-line NSCLC labels.
In 2022, Enhertu became the first HER2-directed therapy approved by the FDA for HER2-mutant NSCLC. That accelerated approval, still awaiting conversion to a full nod, allows the ADC to be used in previously treated patients.
Since then, the FDA has cleared two oral tyrosine kinase inhibitors, Boehringer Ingelheim’s Hernexeos and Bayer’s Hyrnuo. Through two additional accelerated approvals, the two drugs entered the front-line setting in February and just this past week, respectively.
Availability of the two TKIs could also weaken AZ and Daiichi’s argument for Enhertu as a first-line option considering the unfavorable OS trend. Hernexeos and Hyrnuo got their latest go-aheads based on 76% and 75% ORR, respectively, including 11% and 6% complete responses, in small trial populations.
Editor's Note: The story was updated with a statement from AZ's Susan Galbraith, Ph.D., a description of Enhertu's overall safety profile, and new phrasing in the first paragraph.