Results from a global Phase 3 trial demonstrated that trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca) can delay disease progression longer than standard chemoimmunotherapy as first-line treatment for patients with HER2-mutant advanced or metastatic non-small cell lung cancer (NSCLC).
The DESTINY-Lung04 (NCT05048797) results, presented at the 2026 World Conference on Lung Cancer (WCLC) held September 12–15, 2026, in Seoul, South Korea, showed a statistically significant improvement in progression-free survival (PFS) with trastuzumab deruxtecan compared with pembrolizumab (Keytruda®; Merck & Co/MSD) plus platinum-based chemotherapy. Median PFS was 14.3 months with T-DXd versus 8.3 months with chemoimmunotherapy, corresponding to a 37% reduction in the risk of disease progression or death.[1][2]
Key Takeaways
- Trastuzumab deruxtecan reduced the risk of disease progression or death by 37% compared with pembrolizumab plus platinum-based chemotherapy in previously untreated patients with HER2-mutant advanced or metastatic non-squamous NSCLC.[1][2]
- Median PFS was 14.3 months with trastuzumab deruxtecan versus 8.3 months with pembrolizumab plus chemotherapy, an absolute difference of 6 months.[1][2]
- Objective response rates were 70.0% with trastuzumab deruxtecan and 44.5% with chemoimmunotherapy, while median duration of response was 13.4 and 9.7 months, respectively.[1][2]
- The interim OS analysis numerically favored chemoimmunotherapy, with median OS of 33.1 months versus 29.3 months and an HR of 1.15. The analysis was immature and was not formally tested.[1][2]
- Subsequent HER2-directed therapy was more common in the comparator arm, an imbalance that complicates interpretation of the interim OS findings.[1][2]
- ILD/pneumonitis remains a significant clinical concern with trastuzumab deruxtecan, occurring in 20.8% of patients receiving the ADC, including fatal events.[1][2]
- The first-line treatment landscape has changed during the development of DESTINY-Lung04, with FDA accelerated approvals for the HER2-directed tyrosine kinase inhibitors zongertinib and sevabertinib in patients with specific HER2 tyrosine kinase domain activating mutations.[3][4]
A Genetically Defined Subgroup of NSCLC
HER2 mutations occur in a relatively small proportion of NSCLC patients, generally estimated at approximately 2% to 4%.[5] The alterations are particularly relevant in non-squamous NSCLC and represent a molecularly distinct subset of lung cancer. HER2-mutant disease should not be equated with HER2 overexpression or HER2 amplification. In lung cancer, the specific molecular alteration matters because different HER2-directed therapies target different aspects of HER2 biology. DESTINY-Lung04 enrolled patients with HER2 exon 19 or exon 20 mutations.[1][6]
Patients with HER2-mutant NSCLC have historically been treated according to the broader treatment paradigm for advanced non-squamous NSCLC, including platinum-based chemotherapy and immunotherapy. Trastuzumab deruxtecan changed that landscape after demonstrating clinically meaningful activity in previously treated HER2-mutant disease.
The randomized Phase 2 DESTINY-Lung02 (NCT04644237) study provided evidence supporting T-DXd in patients whose disease progressed after prior treatment.[7] DESTINY-Lung04 moved the question into the first-line setting: Could HER2-directed therapy provide better disease control if given before conventional chemoimmunotherapy?
DESTINY-Lung04 Trial Design
DESTINY-Lung04 (NCT05048797) is a global, open-label, randomized Phase 3 trial evaluating trastuzumab deruxtecan against pembrolizumab plus platinum-based chemotherapy in patients with unresectable, locally advanced, or metastatic non-squamous NSCLC harboring HER2 exon 19 or exon 20 mutations.[1][6] The study enrolled 454 treatment-naive patients, who were randomized 1:1 to receive either trastuzumab deruxtecan 5.4 mg/kg intravenously every three weeks, or pembrolizumab plus platinum-based chemotherapy and pemetrexed, followed by pemetrexed maintenance.[1][2] Randomization was stratified by smoking history and brain metastasis status.
The primary endpoint was PFS assessed by blinded independent central review. Secondary endpoints included objective response rate (ORR), duration of response (DoR), PFS after subsequent therapy (PFS2), overall survival, and safety.[1][2] Patients with asymptomatic or medically stable brain metastases were eligible. This is clinically relevant because central nervous system involvement is an important consideration in HER2-mutant NSCLC.
Trastuzumab deruxtecan Produced a Six-Month Improvement in Median PFS
At the June 9, 2026, data cutoff, median follow-up was 21.6 months in the trastuzumab deruxtecan arm and 20.4 months in the pembrolizumab-plus-chemotherapy arm.[1][2] The primary endpoint favored trastuzumab deruxtecan. Median PFS was 14.3 months with trastuzumab deruxtecan and 8.3 months with pembrolizumab plus chemotherapy. The hazard ratio for disease progression or death was 0.63 (95% CI, 0.50-0.79; P<0.0001).[1][2] The result represents a 37% reduction in the relative risk of progression or death.
The PFS advantage was reported across prespecified subgroups, including patients with and without brain metastases, patients with exon 19 or exon 20 mutations, patients with and without liver metastases, different smoking histories, and those with de novo or recurrent disease.[1][2] For the primary endpoint, the conclusion is straightforward: first-line trastuzumab deruxtecan produced significantly longer PFS than pembrolizumab plus platinum-based chemotherapy in the study population.
Higher Response Rates and Longer Duration of Response
Tumor response also favored trastuzumab deruxtecan. The objective response rate was 70.0% with trastuzumab deruxtecan compared with 44.5% with pembrolizumab plus chemotherapy.[1][2] The complete response rate was 1.8% in both treatment groups, while partial responses accounted for most of the observed responses.[2]
Median duration of response was 13.4 months with trastuzumab deruxtecan versus 9.7 months with chemoimmunotherapy.[1][2] PFS2 was 22.7 months with trastuzumab deruxtecan and 17.3 months with pembrolizumab plus chemotherapy, with a hazard ratio of 0.80 (95% CI, 0.62-1.02).[1][2] The efficacy results therefore show a consistent pattern for initial disease control. Trastuzumab deruxtecan produced a higher response rate, longer duration of response, and significantly longer PFS than the comparator regimen. The overall-survival result, however, requires a separate assessment.
The Interim Overall-Survival Result Requires Caution
At the interim OS analysis, 213 patients had died: 115 patients in the trastuzumab deruxtecan group and 98 in the pembrolizumab-plus-chemotherapy group.[1][2] Median OS was 29.3 months with trastuzumab deruxtecan and 33.1 months with pembrolizumab plus chemotherapy. The hazard ratio was 1.15 (95% CI, 0.88-1.52).[1][2]
The OS data were 46.9% mature, and the endpoint had not undergone formal statistical hypothesis testing at this analysis.[1][2] The confidence interval also crosses 1.0. Consequently, the interim result does not establish that trastuzumab deruxtecan is inferior to chemoimmunotherapy for overall survival. These results establish an unresolved discrepancy between the trial’s primary endpoint and its current OS trend: PFS significantly favors trastuzumab deruxtecan, while the numerical OS estimate currently favors the comparator.
The timing of the separation is also notable. In the interim presentation, the OS curves began to favor the comparator at approximately 20 months after randomization.[8] This is a descriptive observation from the current analysis rather than a statistically established difference. Longer follow-up and the planned formal OS analyses will be needed to determine whether the current numerical difference persists.
Subsequent HER2-Directed Treatment Complicates the OS Comparison
One important consideration is the treatment patients received after discontinuing their assigned study regimen. Approximately 72% of patients who discontinued protocol treatment subsequently received anticancer therapy in each treatment group.[8] However, subsequent treatments differed. Among all randomized patients, subsequent HER2-directed therapy was reported in about 48.0% of patients in the pembrolizumab-plus-chemotherapy arm compared with about 23% in the trastuzumab deruxtecan arm.[1][2][8]
Among patients who received subsequent therapy, HER2-directed treatment was also more common among those initially assigned to chemoimmunotherapy.[8] This imbalance is clinically relevant because patients in the comparator group were more likely to receive HER2-directed treatment after progression, whereas many patients initially treated with trastuzumab deruxtecan had already received a HER2-directed therapy.
The difference does not establish that subsequent treatment caused the OS difference. It does, however, make a simple comparison of overall survival between the randomized groups more difficult to interpret. The investigators and sponsors have identified differences in subsequent treatment as an important consideration in interpreting the immature OS findings.[1][2] The appropriate conclusion at this stage is therefore measured: DESTINY-Lung04 has demonstrated a PFS benefit, but the effect of first-line trastuzumab deruxtecan on overall survival remains unresolved.
Safety: ILD Remains a Central Clinical Issue
The overall safety profile of trastuzumab deruxtecan was consistent with its established profile, with no new safety signals identified.[1][2] Despite longer median treatment exposure with trastuzumab deruxtecan—12.3 months compared with 7.1 months in the comparator arm—grade 3 or higher treatment-related adverse events occurred at similar rates, 34.1% with trastuzumab deruxtecan and 33.6% with pembrolizumab plus chemotherapy[1][2]
Neutropenia was among the more common grade 3 or higher treatment-related adverse events, occurring in 11.1% of patients receiving trastuzumab deruxtecan and 14.1% of patients receiving chemoimmunotherapy.[1] The safety issue most specifically associated with T-DXd was interstitial lung disease (ILD) or pneumonitis. An independent adjudication committee identified ILD or pneumonitis in 20.8% of patients receiving trastuzumab deruxtecan, compared with 2.3% in the comparator group.[1][2]
Among patients receiving trastuzumab deruxtecan, reported events included: Grade 1: 3.1%; Grade 2: 13.3%; Grade 3: 2.2%; Grade 4: 0.4%; and Grade 5: 1.8%.[1][2]. Four grade 5 ILD/pneumonitis events occurred in the trastuzumab deruxtecan arm in the primary safety analysis.[1][2] The presentation also reported that most ILD/pneumonitis events were grade 1 or 2. Nevertheless, the fatal events underscore that ILD remains a potentially serious and sometimes fatal complication of trastuzumab deruxtecan treatment.
The current prescribing information recommends monitoring for respiratory symptoms and promptly evaluating suspected ILD/pneumonitis. For symptomatic grade 2 or higher ILD/pneumonitis, trastuzumab deruxtecan should be permanently discontinued and systemic corticosteroids initiated.[9] The sponsor subsequently reported that nearly all grade 5 ILD cases in DESTINY-Lung04 involved delayed initiation and/or suboptimal steroid dosing.[8] That statement should be understood as the sponsor’s assessment of the reported cases and not as a general causal conclusion applicable to all patients receiving trastuzumab deruxtecan.
The First-Line HER2 Treatment Landscape Is Changing
DESTINY-Lung04 is being interpreted in a treatment environment that has changed considerably since the study began. Trastuzumab deruxtecan became the first FDA-approved HER2-directed therapy for previously treated HER2-mutant NSCLC. Since then, HER2-directed oral tyrosine kinase inhibitors have entered the treatment landscape.
In February 2026, the FDA granted accelerated approval to zongertinib (Hernexeos®; Boehringer Ingelheim Pharmaceuticals) for adults with unresectable or metastatic non-squamous NSCLC whose tumors harbor HER2/ERBB2 tyrosine kinase domain activating mutations.[3] In September 2026, the FDA expanded the accelerated approval of sevabertinib (Hyrnuo®; Bayer) to include adults with locally advanced or metastatic non-squamous NSCLC harboring HER2/ERBB2 tyrosine kinase domain activating mutations.[4] These therapies are relevant to interpreting DESTINY-Lung04, but they should not be considered interchangeable with trastuzumab deruxtecan across all HER2-mutant NSCLC.
The FDA indications for zongertinib and sevabertinib specifically address HER2 tyrosine kinase domain activating mutations.[3][4] DESTINY-Lung04, by comparison, enrolled patients with HER2 exon 19 or exon 20 mutations.[1]
The clinical development programs also differ. Zongertinib demonstrated a 76% objective response rate in previously untreated patients in the Phase 1 Beamion LUNG-1 study, but that evidence came from a single-arm study rather than a randomized Phase 3 comparison with standard therapy.[10] Those results therefore should not be directly compared with the DESTINY-Lung04 efficacy results as though the trials had identical populations, designs, or endpoints. Their importance, however, is broader. The treatment choice for HER2-mutant NSCLC is no longer limited to deciding between chemotherapy, immunotherapy, and a HER2-directed ADC. For patients whose tumors harbor specific HER2 tyrosine kinase domain activating mutations, oral HER2-directed therapies are now also part of the treatment landscape.
What DESTINY-Lung04 Does—and Does Not—Show
DESTINY-Lung04 establishes randomized Phase 3 evidence that first-line trastuzumab deruxtecan can produce significantly longer PFS than pembrolizumab plus platinum-based chemotherapy in patients with HER2-mutant advanced or metastatic non-squamous NSCLC. The six-month improvement in median PFS, higher response rate, and longer duration of response represent a consistent pattern of improved initial disease control.[1][2]
The trial has not yet demonstrated an overall-survival benefit. Instead, the current interim OS analysis shows a numerical difference favoring the comparator. Because the data are immature, the analysis was not formally tested, and the confidence interval crosses 1.0, the finding does not establish an OS disadvantage for trastuzumab deruxtecan.[1][2]
The unequal use of subsequent HER2-directed treatment is another important consideration. Patients originally assigned to chemoimmunotherapy were substantially more likely to receive a HER2-directed treatment after progression than those initially treated with trastuzumab deruxtecan.[1][2][8] At the same time, trastuzumab deruxtecan carries a clinically important ILD/pneumonitis risk, including fatal events.[1][2] These findings need to be considered together when assessing the clinical profile of first-line trastuzumab deruxtecan.
A First-Line Benchmark With Important Questions Remaining
DESTINY-Lung04 is an important milestone in developing HER2-directed therapy for lung cancer. It is the first global Phase 3 study to demonstrate a statistically significant PFS advantage for a HER2-directed therapy over standard first-line chemoimmunotherapy in HER2-mutant NSCLC.[1][2] The trial establishes that trastuzumab deruxtecan can provide longer initial disease control in this molecularly defined population. It does not yet establish that earlier treatment with trastuzumab deruxtecan prolongs overall survival.
That distinction will matter as the data mature. The emergence of zongertinib and sevabertinib also makes the clinical question more specific. The field is moving from simply identifying HER2-mutant NSCLC to determining which HER2 alteration is present and which targeted strategy fits that molecular subtype.[3][4] For clinicians, the DESTINY-Lung04 results reinforce the importance of comprehensive molecular testing and precise characterization of HER2 alterations. For patients, the study provides evidence that a HER2-directed ADC can deliver substantially longer initial disease control than pembrolizumab plus platinum-based chemotherapy.
Whether that advantage ultimately translates into longer overall survival remains an open question. As of the WCLC 2026 presentation, first-line trastuzumab deruxtecan for HER2-mutant NSCLC remains an investigational indication in the United States.
What is established today is narrower—and more defensible. In previously untreated patients with HER2-mutant advanced or metastatic non-squamous NSCLC, trastuzumab deruxtecan significantly prolonged progression-free survival compared with pembrolizumab plus platinum-based chemotherapy. The next question is whether that PFS advantage will translate into an overall-survival benefit.
That answer is still pending.
Clinical trials
A Study to Investigate the Efficacy and Safety of Trastuzumab Deruxtecan as the First Treatment Option for Unresectable, Locally Advanced/Metastatic Non-Small Cell Lung Cancer With HER2 Mutations – ClinicalTrials.gov ID NCT05048797
Beamion LUNG-1: A Study to Test Different Doses of Zongertinib in People With Different Types of Advanced Cancer (Solid Tumours With Changes in the HER2 Gene) – ClinicalTrials.gov ID NCT04886804
Trastuzumab Deruxtecan in Participants With HER2-mutated Metastatic Non-small Cell Lung Cancer (NSCLC) (DESTINY-LUNG02) – ClinicalTrials.gov ID NCT04644237
Highlights of Prescribing Information
Trastuzumab deruxtecan (T-DXd; Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]
Zongertinib (Hernexeos®; Boehringer Ingelheim Pharmaceuticals)[Prescribing Information]
Sevabertinib (Hyrnuo®; Bayer)[Prescribing Information]
References
[1] International Association for the Study of Lung Cancer. Phase 3 DESTINY-Lung04 Trial Shows First-Line Trastuzumab Deruxtecan Significantly Improves Progression-Free Survival in HER2-Mutant NSCLC. Presented at: IASLC 2026 World Conference on Lung Cancer; September 14, 2026; Seoul, South Korea.
[2] AstraZeneca. Enhertu demonstrated a median progression-free survival of 14.3 months as 1st-line therapy in patients with HER2-mutant advanced non-small cell lung cancer in DESTINY-Lung04 Phase III trial. Published September 14, 2026.
[3] U.S. Food and Drug Administration. FDA grants accelerated approval to zongertinib for unresectable or metastatic non-squamous non-small cell lung cancer. February 2026. Online. Last accessed on September 14, 2026.
[4] U.S. Food and Drug Administration. FDA grants accelerated approval to sevabertinib for locally advanced or metastatic non-small cell lung cancer. September 2026. Online. Last accessed on September 14, 2026.
[5] Mazières J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, Besse B, Blons H, Mansuet-Lupo A, Urban T, Moro-Sibilot D, Dansin E, Chouaid C, Wislez M, Diebold J, Felip E, Rouquette I, Milia JD, Gautschi O. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013 Jun 1;31(16):1997-2003. doi: 10.1200/JCO.2012.45.6095. Epub 2013 Apr 22. PMID: 23610105.
[6] ClinicalTrials.gov. An open-label, randomized, multicenter, Phase 3 study to assess the efficacy and safety of trastuzumab deruxtecan as first-line treatment of unresectable, locally advanced, or metastatic NSCLC harboring HER2 exon 19 or 20 mutations (DESTINY-Lung04). NCT05048797.
[7] Goto K, Goto Y, Kubo T, Ninomiya K, Kim SW, Planchard D, Ahn MJ, Smit EF, de Langen AJ, Pérol M, Pons-Tostivint E, Novello S, Hayashi H, Shimizu J, Kim DW, Kuo CH, Yang JC, Pereira K, Cheng FC, Taguchi A, Cheng Y, Feng W, Tsuchihashi Z, Jänne PA. Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic Non-Small-Cell Lung Cancer: Primary Results From the Randomized, Phase II DESTINY-Lung02 Trial. J Clin Oncol. 2023 Nov 1;41(31):4852-4863. doi: 10.1200/JCO.23.01361. Epub 2023 Sep 11. Erratum in: J Clin Oncol. 2024 Feb 1;42(4):485. doi: 10.1200/JCO.23.02574. Erratum in: J Clin Oncol. 2024 Oct 20;42(30):3635. doi: 10.1200/JCO-24-01883. PMID: 37694347; PMCID: PMC10617843.
[8] Rotow J, Okamoto I, Goto K, et al. First-line trastuzumab deruxtecan (T-DXd) in patients with metastatic HER2-mutant NSCLC: DESTINY-Lung04 primary results. Presented at: IASLC 2026 World Conference on Lung Cancer; September 14, 2026; Seoul, South Korea. Abstract PL03.08.
[9] AstraZeneca. ENHERTU (fam-trastuzumab deruxtecan-nxki) prescribing information. Interstitial Lung Disease/Pneumonitis.
[10] Heymach JV, Yamamoto N, Girard N, Ruiter G, Smit EF, Planchard D, Nadal E, Wu YL, Zugazagoitia J, Tu HY, Baik CS, Yoh K, Soo RA, Zhao Y, Sabari JK, Wermke M, Scheffler M, Ahn MJ, Fernamberg K, Schroeter L, Sadrolhefazi B, Thamer C, Eigenbrod-Giese S, Popat S; Beamion LUNG-1 Investigators. First-Line Zongertinib in Advanced HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2026 Apr 30;394(17):1675-1684. doi: 10.1056/NEJMoa2516969. Epub 2026 Apr 15. PMID: 41985129.
This article is intended for informational purposes for healthcare professionals and does not constitute medical advice. The DESTINY-Lung04 results discussed here were presented at the 2026 World Conference on Lung Cancer and reported in company and conference communications; full peer-reviewed publication of the Phase 3 trial is pending. First-line trastuzumab deruxtecan for HER2-mutant NSCLC remains investigational unless and until approved by the applicable regulatory authority. Treatment decisions should be based on current regulatory labeling, clinical guidelines, and individual patient circumstances.
Featured image: © 2017 – 2026 Fotolia/Adobe. Used with permission.
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