In patients with advanced HER2-mutant non–small cell lung cancer (NSCLC), first-line monotherapy with the HER2-directed antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) significantly prolonged progression-free survival compared with standard-of-care chemoimmunotherapy. This was according to the primary results from the multicenter phase III DESTINY-Lung04 trial presented during the Presidential Symposium of the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer.1
Although T-DXd is approved in multiple countries for this patient population in the second-line setting, the global first-line standard of care remains immunotherapy plus doublet chemotherapy, which produces limited response rates, with many patients ultimately experiencing disease progression, presenting author Julia Rotow, MD, of Dana-Farber Cancer Institute, Boston, explained during the conference.
At the first interim analysis of DESTINY-Lung04, the primary endpoint was met, with first-line T-DXd reducing the risk of disease progression or death by 37% compared with standard-of-care treatment.
“The findings support T-DXd as a new first-line treatment option in this patient population, for whom more effective HER2-directed approaches are needed,” Dr. Rotow said.
About DESTINY-Lung04
DESTINY-Lung04 enrolled patients with treatment-naive, unresectable locally advanced or metastatic nonsquamous NSCLC with HER2 exon 19 or 20 mutations. Eligible patients had a World Health Organization/Eastern Cooperative Oncology Group performance status of 0 or 1; asymptomatic or stable brain metastases were permitted.
A total of 454 patients were randomly assigned in a 1:1 ratio to receive T-DXd at 5.4 mg/kg intravenously every 3 weeks or standard-of-care treatment with pembrolizumab plus platinum-based chemotherapy and pemetrexed. Randomization was stratified by the presence or history of brain metastases (yes vs no) and smoking status (ever vs never).
The findings support T-DXd as a new first-line treatment option in this patient population, for whom more effective HER2-directed approaches are needed.— JULIA ROTOW, MD
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Dr. Rotow described the patient demographics as “essentially what we would expect.” The median age was 62 years, about one-half of patients were enrolled from Asia, and more than 90% had exon 20 mutations. Approximately two-thirds of patients had never smoked, and among those with known PD-L1 status, a similar proportion tested negative.
The primary endpoint was progression-free survival assessed by blinded independent central review (BICR). Secondary endpoints included overall survival, BICR-assessed confirmed objective response rate and duration of response, investigator-assessed second progression-free survival (defined as the time from randomization to the earliest progression event following first subsequent therapy or death), and safety.
Median follow-up was 21.6 months with T-DXd and 20.4 months with chemoimmunotherapy.
Expanded Progression-Free Survival Findings
Median progression-free survival was 14.3 months with T-DXd vs 8.3 months with chemoimmunotherapy (hazard ratio [HR] = 0.63; P < .0001), a 6-month gain that Dr. Rotow described as a “striking” and clinically meaningful improvement.
The progression-free survival benefit with T-DXd was observed across all prespecified subgroups, including several, highlighted by Dr. Rotow, that may be more challenging to treat: patients with central nervous system involvement (HR = 0.62, 95% confidence interval [CI] = 0.41–0.93), liver involvement (HR = 0.41, 95% CI = 0.24–0.70), a history of tobacco use (HR = 0.70, 95% CI = 0.49–0.99), or age 65 years or older (HR = 0.66, 95% CI = 0.47–0.93).
Secondary Efficacy Endpoints
One “key finding,” according to Dr. Rotow, was the objective response rate: 70.0% with T-DXd—among the highest reported with an antibody-drug conjugate in NSCLC to date—vs 44.5% with chemoimmunotherapy (odds ratio = 2.93, 95% CI = 2.00–4.34). Median duration of response was 13.4 vs 9.7 months, respectively.
Dr. Rotow added that the overall response rate with chemoimmunotherapy, along with the progression-free survival results, was consistent with outcomes previously reported with chemoimmunotherapy in broader NSCLC populations. This, she said, “reflects appropriate performance of the control arm here as the comparator.”
Median second progression-free survival was 22.7 months with T-DXd vs 17.3 months with chemoimmunotherapy (HR = 0.80, 95% CI = 0.62–1.02).
Median overall survival was 29.3 months with T-DXd vs 33.1 months with chemoimmunotherapy (HR = 1.15, 95% CI = 0.88–1.52). These results were from an administrative analysis, and no formal hypothesis testing was performed. Dr. Rotow highlighted the notable overall survival on both arms of the study, relative to historical real-world cohorts from before the availability of HER2-targeted therapies that suggested a median overall survival of less than 2 years for patients with HER2-mutant lung cancer.
Although additional data are anticipated from the study’s second and final analyses, Dr. Rotow noted that the observed trend may in part reflect imbalances in subsequent therapies between the treatment groups.
Subsequent Therapy
At data cutoff, more patients in the T-DXd arm remained on any study treatment than in the chemoimmunotherapy arm (17.7% vs 4.5%). Among those who discontinued study treatment, similar proportions received subsequent anticancer therapy (71.5% and 72.4%, respectively), meaning that approximately 30% of those who discontinued study treatment received no further anticancer therapy. “This puts a lot of pressure on choosing the most effective treatments in the front-line setting,” Dr. Rotow said. “We don’t know how many patients will get to second line.”
KEY POINTS
- In the phase III DESTINY-Lung04 trial, first-line T-DXd improved progression-free survival and objective response rate compared with pembrolizumab plus platinum-based chemotherapy and pemetrexed.
- Overall survival with T-DXd did not appear to outperform that with chemoimmunotherapy.
- The safety profile of T-DXd was generally consistent with its known safety profile; interstitial lung disease remained an important adverse event requiring appropriate management.
- The findings support T-DXd as a new first-line treatment option for patients with HER2-mutant NSCLC.
The types of subsequent therapy received also differed between the treatment groups, she reported. More patients in the chemoimmunotherapy arm subsequently received HER2-directed therapy (48.0% vs 23.3% in the T-DXd arm). Although all patients in the chemoimmunotherapy arm received pembrolizumab as part of their first-line regimen, fewer than a quarter of patients in the T-DXd arm (23.8%) received chemoimmunotherapy at any point during their treatment course.
Against this backdrop, Misty D. Shields, MD, PhD, of Indiana University School of Medicine, Indianapolis, noted in a statement, “[It is] difficult to know how T-DXd will fit in the sequencing of an evolving HER2 landscape with available TKIs [tyrosine kinase inhibitors] zongertinib and sevabertinib.”
Addressing the role of oral TKIs, Dr. Rotow told The ASCO Post that these agents will likely be used extensively in the first-line setting given their convenience and toxicity profiles. For patients who would otherwise be considered for chemoimmunotherapy, however, she said T-DXd should be used instead, describing it as “far more effective.” She also noted that patterns of subsequent HER2-directed therapy in DESTINY-Lung04 reflected the treatment landscape at the time, when access to these agents was limited. However, “that is a changed state now. All these therapies are more readily available and should indeed be sequenced around each other to make sure patients get access to each effective class of treatment.” Looking ahead, she said combination strategies may offer another avenue for extending the durability of effect.
Safety Summary
Regarding the safety summary, Dr. Rotow highlighted that the rates of grade 3 or higher adverse events (34.1% vs 33.6%), adverse events leading to discontinuation of any drug (15.9% in both arms), and adverse events leading to dose reduction (17.7% vs 15.9%) were similar between the T-DXd and chemoimmunotherapy arms.
The most common adverse events were consistent with the known safety profiles of both regimens. Nausea, fatigue, and cytopenias were among the most frequently reported. Higher rates of grade 3 or higher neutropenia, anemia, and thrombocytopenia were observed with chemoimmunotherapy than with T-DXd, Dr. Rotow noted.
Among the adverse events of special interest, Dr. Rotow highlighted interstitial lung disease (ILD), a known potential toxicity of T-DXd. Although any-grade adjudicated ILD was reported in 20.8% of T-DXd–treated patients, 78.7% of cases were grade 1 or 2, and 66.0% had resolved. Approximately half of the adjudicated grade 2 events had been classified as grade 1 by investigators but were reclassified as grade 2 because of steroid use. This, Dr. Rotow stated, “reflects vigilance and increased knowledge for the investigators…about how best to manage ILD in patients receiving T-DXd, which typically includes early and aggressive use of steroid therapy to avoid progression to high-grade ILD.”
By contrast, delayed initiation or suboptimal dosing of steroids was observed in 90% of adjudicated grade 3 or higher ILD cases, including all four grade 5 cases. Dr. Rotow emphasized the importance of appropriate steroid management, saying the finding “again [highlights] the point of this educational management message.”
Taken together, Dr. Rotow concluded, “DESTINY-Lung04 is the first phase III trial to demonstrate the benefit of a HER2-directed therapy compared with a global standard of care in the first-line [setting] for patients with HER2-mutant [NSCLC]. … These data do indeed support T-DXd as our new front-line treatment option….”
DISCLOSURE: Dr. Rotow has received research funding from AbbVie, Altor BioScience, AstraZeneca, Bicycle Therapeutics, BioAtla, BioNTech, Black Diamond, BlossomHill, Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, DualityBio, Enliven Therapeutics, EpimAb, ImmunityBio, Loxo Oncology, ORIC Pharmaceuticals, Redcloudbio, Regeneron, Summit, and Synthekine; has served as a consultant for AbbVie, Amgen, AstraZeneca, BioAtla, BioNTech, BlossomHill, Boehringer Ingelheim, Bristol Myers Squibb, Caris, Catalyst, Daiichi Sankyo, G1 Therapeutics, Genentech, Gilead, Guardant Health, Jazz Pharmaceuticals, Johnson and Johnson, Merck, Merus, Novocure, Nuvalent, Nuvation Bio, Ottimo, Pfizer, Regeneron, Sanofi-Genzyme, Summit, and Takeda; and has received honoraria from AstraZeneca, Daiichi Sankyo, Johnson and Johnson, and Pfizer.
REFERENCE
1. Rotow J, Okamoto I, Goto K, et al: First-line trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant NSCLC: DESTINY-Lung04 primary results. 2026 World Conference on Lung Cancer. Abstract 1052. Presented September 14, 2026.
EXPERT POINT OF VIEW
During the Presidential Symposium of the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer, invited discussant and study investigator James Chih-Hsin Yang, MD, PhD, of National Taiwan University, Taipei, characterized DESTINY-Lung04 as a “landmark” study in HER2-mutant advanced non–small cell lung cancer (NSCLC), although he emphasized that important questions remain.1
James Chih-Hsin Yang, MD, PhD
Dr. Yang described the median progression-free survival of 14.3 months and 70.0% objective response rate with first-line fam-trastuzumab deruxtecan-nxki (T-DXd), an antibody drug conjugate as “unprecedented,” noting that both outcomes exceeded those reported in the second-line setting. He predicted that T-DXd and the EGFR-HER2–directed tyrosine kinase inhibitor (TKI) sevabertinib would join the HER2 TKI zongertinib as National Comprehensive Cancer Network (NCCN) Guidelines–recommended first-line options, while questioning whether the systemic therapy recommendation would remain; however, updated guidelines added only sevabertinib to the first-line setting, retaining T-DXd for subsequent therapy and the existing systemic therapy recommendation.2,3
In this context, Dr. Yang highlighted first-line objective response rates of 77% with zongertinib and 71% with sevabertinib in single-arm studies, noting that progression-free survival outcomes appeared comparable to those with T-DXd.4,5
Turning to overall survival, Dr. Yang described the findings, which numerically favored pembrolizumab plus chemotherapy (hazard ratio [HR] = 1.15), as “disturbing.” He noted that the median overall survival reached 33.1 months in the chemoimmunotherapy arm, substantially exceeding the 22.0 months reported with the same regimen in KEYNOTE-189, although the populations were not directly comparable.6 “Something must have happened during those 5 years [between the studies’ enrollment periods],” he remarked, suggesting that greater access to effective subsequent HER2-directed therapies may have contributed to improved outcomes.
Dr. Yang questioned the reliability of the overall survival estimate given that subsequent HER2-directed therapy was more than twice as common in the chemoimmunotherapy arm than in the T-DXd arm. “If it were balanced, then we can say this overall survival [HR] can be trusted,” he explained, predicting that “these [subsequent therapy] point estimates will change in future studies.”
Regarding safety, Dr. Yang questioned why T-DXd monotherapy had rates of nausea and vomiting similar to those of pembrolizumab plus chemotherapy. He suggested that established prophylaxis with the chemoimmunotherapy combination may partly explain this finding, whereas supportive care for T-DXd still has “room for improvement.” Given the potential for persistent neurotoxicity with platinum-based chemotherapy, he additionally highlighted the absence of comparative data, which “will make a great difference in choosing one regimen vs the other.”
Dr. Yang also observed that several adverse events were less frequent with first-line T-DXd than in second-line DESTINY studies of the agent in lung and breast cancers, except for interstitial lung disease or pneumonitis, which occurred in 20.8% of patients. Nevertheless, he noted that many of those affected were able to receive subsequent therapy.
Looking ahead, Dr. Yang said he anticipated more selective HER2-directed TKIs, antibody-drug conjugates with improved toxicity profiles, and potentially combination approaches. He also highlighted areas for further investigation, including optimal treatment sequencing—particularly in light of his observation of less favorable outcomes with HER2-directed TKIs following prior antibody-drug conjugate therapy—the role of immunotherapy, and therapeutic strategies for patients whose tumors express HER2 alterations.
Dr. Yang ultimately emphasized that despite the benefits observed with T-DXd, existing approaches remain important as the therapeutic landscape evolves. “We must allow patients to receive all active treatment in order to achieve the highest overall survival at the end of the day,” he concluded.
DISCLOSURE: Dr. Yang has reported personal fees from Amgen, AbbVie, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Merck Sharp & Dohme, Pfizer, Roche/Genentech, Janssen Pharmaceuticals, BioNTech, and Guardant Health; has received compensation for travel-related expenses from AstraZeneca, Merck KGaA, Pfizer, Roche/Genentech, Takeda Oncology, and Janssen Pharmaceuticals; and has other relationships with Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Merck KGaA, Merck Sharp & Dohme, Roche/Genentech, Takeda Oncology, Janssen Pharmaceuticals, ArriVent, Bayer, and Gilead. He is a coinvestigator of DESTINY-Lung04.
REFERENCES
1. Rotow J, Okamoto I, Goto K, et al: First-line trastuzumab deruxtecan (T-DXd) in patients with HER2-mutant NSCLC: DESTINY-Lung04 primary results. 2026 World Conference on Lung Cancer. Abstract 1052. Presented September 14, 2026.
2. Riely GJ, Wood DE, Aisner DL, et al: NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 7.2026 [View the most recent and complete version of the guideline at www.nccn.org].
3. Riely GJ, Wood DE, Aisner DL, et al: NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 9.2026. Available at www.nccn.org. Accessed October 16, 2026.
4. Popat S, Yamamoto N, Girard N, et al: Zongertinib as first-line treatment in patients with advanced HER2-mutant NSCLC: Beamion LUNG 1. ESMO Congress 2025. Abstract LBA74. Presented October 17, 2025.
5. Le X, Kim TM, Dong X, et al: Sevabertinib (BAY 2927088) in advanced HER2-mutant non-small cell lung cancer (NSCLC): Results from the SOHO-01 study. ESMO Congress 2025. Abstract LBA75. Presented October 17, 2025.
6. Garassino MC, Gadgeel S, Speranza G, et al: Pembrolizumab plus pemetrexed and platinum in nonsquamous non–small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study. J Clin Oncol 41:1992-1998, 2023.
