Home › Trials › NCT06899126

Trastuzumab deruxtecan plus pembrolizumab versus platinum chemotherapy plus pembrolizumab for first-line HER2‑overexpressing non‑squamous NSCLC

A Phase 3, Multicenter, Randomized, Open-label Trial of Trastuzumab Deruxtecan in Combination With Pembrolizumab Versus Platinum-based Chemotherapy in Combination With Pembrolizumab, as First-line Therapy in Participants With Locally Advanced Unresectable or Metastatic HER2 Overexpressing and PD-L1 TPS <50% Non-squamous Non-small Cell Lung Cancer (DESTINY-Lung06)

Phase 3 Interventional Daiichi Sankyo · NCT06899126

This trial will test whether combining trastuzumab deruxtecan with pembrolizumab works better than standard platinum‑based chemotherapy plus pembrolizumab as first treatment for adults with HER2‑overexpressing, PD‑L1 low (<50%) advanced non‑squamous NSCLC.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment686 (estimated)
Ages18 Years and up
SexAll
SponsorDaiichi Sankyo Industry-sponsored
Drugs / interventionstrastuzumab, pembrolizumab, chemotherapy
Locations100 sites (Anchorage, Alaska and 99 other locations)
Trial IDNCT06899126 on ClinicalTrials.gov

What this trial studies

This is a phase 3 randomized comparison of trastuzumab deruxtecan (T‑DXd) plus pembrolizumab versus pemetrexed‑containing platinum chemotherapy plus pembrolizumab in patients with treatment‑naive, locally advanced unresectable or metastatic non‑squamous NSCLC that overexpresses HER2 and has PD‑L1 TPS <50% without known actionable genomic alterations with available local therapies. Eligible participants undergo tissue screening to confirm HER2 overexpression and other entry criteria before randomization. The trial measures clinical efficacy endpoints such as progression‑free survival and overall survival along with safety and tolerability of the combinations. Patients receive regular imaging and clinical monitoring during and after treatment per protocol.

Who should consider this trial

Good fit: Adults (≥18) with no prior systemic therapy for locally advanced unresectable or metastatic non‑squamous NSCLC whose tumors overexpress HER2, have PD‑L1 TPS <50%, and lack actionable genomic alterations with locally available targeted therapies.

Not a fit: Patients with squamous histology, prior systemic treatment for advanced disease, high PD‑L1 expression (≥50%), known actionable genomic alterations with available targeted therapies, or insufficient HER2 expression are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, this regimen could provide a more effective first‑line option that improves tumor responses and survival for patients with HER2‑overexpressing advanced non‑squamous NSCLC.

How similar studies have performed: Trastuzumab deruxtecan has shown promising activity in HER2‑altered lung cancers and pembrolizumab plus chemotherapy is an established first‑line approach, but the specific combination in this HER2‑overexpressing, PD‑L1 low population is novel and is being tested in phase 3.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

1. Sign and date the Tissue Screening ICF, prior to any Tissue Screening procedure. Sign and date the Main ICF, prior to the start of any trial-specific qualification procedures.

   Sign and date the Optional PGx ICF (included in the Main Screening ICF) prior to any PGx procedure, and the Pregnant Partner ICF, if applicable.
2. Adults ≥18 years of age on the day of signing the ICF. Follow local regulatory requirements if the legal age of consent for trial participation is \>18 years old.
3. Histologically documented non-squamous locally advanced unresectable or metastatic

   NSCLC and meets all of the following criteria:

   Has Stage IV NSCLC disease or Stage IIIB or IIIC disease but is not a candidate for surgical resection or definitive chemoradiation at the time of randomization (based on the American Joint Committee on Cancer, Eighth Edition). Has no known AGAs (based on existing test result of local test) that have locally available therapies targeting their AGAs in the first-line advanced/metastatic setting. Has no known HER2 mutation based on existing test results (if approved or validated local test is available). Note: Participants with mixed histology are eligible if adenocarcinoma is the predominant histology. Mixed tumors will be classified based on the predominant cell type.
4. Has not been treated with systemic anticancer therapy for advanced or metastatic non-squamous NSCLC. Participants who received adjuvant or neoadjuvant therapy other than those listed below, including ICI (ie, anti-PD-1/PD-L1) or a platinum-based regimen, are eligible if the last dose of adjuvant/neoadjuvant therapy was given at least 6 months before the date of the first trial dose and should not have progressed on or within 6 months of the last dose date of adjuvant/neoadjuvant therapy.

   1. Any agent, including an ADC, containing a chemotherapeutic agent targeting topoisomerase I.
   2. HER2-targeted antibody-based anticancer therapy.
5. Has adequate tumor tissue sample (not previously irradiated) available for assessment of HER2 and PD-L1 expression by central or Sponsor-specified laboratory. A new biopsy is required if the participant's most recent archival tumor tissue sample cannot be supplied.

Details pertaining to tumor tissue submission can be found in the Trial Laboratory Manual.

Exclusion Criteria:

1. Has a medical history of MI within 6 months before randomization/enrollment or symptomatic CHF (NYHA Class II to Class IV). Participants with troponin levels above the ULN at Screening (as defined by the manufacturer) and without any MI-related symptoms should have a cardiologic consultation during the Screening Period to rule out MI.
2. Has a QTc prolongation to \>480 ms based on the average of the Screening triplicate 12- lead ECG.
3. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
4. Has lung-specific, intercurrent, clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the trial randomization, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.).
5. Had a prior complete pneumonectomy.

Where this trial is running

Anchorage, Alaska and 99 other locations

+50 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions Non-small Cell Lung CancerDESTINYNSCLC
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.