Locally Advanced or Metastatic Non-Small Cell Lung CancerPhase 1DL03NCT04686305
Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents With and Without Chemotherapy in Advanced or Metastatic HER2+, Non-squamous NSCLC
A Phase 1 study testing T-DXd, Durvalumab and Cisplatin in people with Locally Advanced or Metastatic Non-Small Cell Lung Cancer, run by AstraZeneca at 91 sites in 19 countries.
Trial summary
DESTINY-Lung03 will investigate the safety and tolerability of trastuzumab deruxtecan in combination with Immunotherapy Agents with and without chemotherapy in patients with HER2 over-expressing non-small cell lung cancer. The efficacy will be also analyzed as a secondary endpoint. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Locally Advanced or Metastatic Non-Small Cell Lung Cancer
- What is being tested?
- T-DXd, Durvalumab and Cisplatin
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 304 participants
- Where
- 91 sitesin 19 countries
- Study dates
- 9 Mar 2021to 30 Jun 2027
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically documented unresectable locally advanced/metastatic non-squamous NSCLC
- Part 1: Progression after 1 or 2 lines of systemic therapy for recurrent or metastatic setting.
- Part 3, Part 4 and Part 5: Patients must have tumors that do not harbor known genomic alterations or actionable driver kinases, for which approved therapies are available are allowed.
- Part 3, Part 4 and Part 5: Patient must be treatment-naïve for advanced or metastatic NSCLC. Patients who have received prior adjuvant, or neoadjuvant chemotherapy, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred > 6 months from end of last therapy
- HER2overexpression status as determined by central review of tumor tissue
- WHO / ECOG performance status of 0 or 1
Show all 9Show fewer
- Measurable target disease assessed by the investigator using RECIST 1.1
- Has protocol defined adequate organ and bone marrow function
- Part 3, Part 4 and Part 5: Minimum body weight of 35 kg.
Who cannot join
- HER2 mutation if previously known
- 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
- Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder and prior pneumonectomy
- Active primary immunodeficiency known HIV infection, or active chronic and resolved hepatitis B (positive hepatitis B virus surface antigen [HBsAg+ve] or hepatitis B virus core antibody (anti-HBc +ve) regardless of HBV DNA level)) or hepatitis C infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients should be tested for HIV prior to treatment assignment if required by local regulations or IRB/EC
- Active infection including tuberculosis and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
Show all 15Show fewer
- Medical history of myocardial infarction within 6 months before treatment assignment, symptomatic CHF (New York Heart Association Class II to IV), clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke
- For Part 3, Part 4 and Part 5: Cardiomyopathy of any etiology, symptomatic CHF (as defined by New York Heart Association Class > II), unstable angina pectoris, history of MI within the past 12 months, or cardiac arrhythmia are to be excluded. Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before treatment assignment to rule out acute cardiopulmonary events.
- Ascites or pericardial effusion that requires drainage, peritoneal shunt, Pleuroperitoneal shunt or CART (Concentrated Ascites Reinfusion Therapy)
- For Part 3, Part 4 and Part 5: Active non-infectious skin disease (including any grade rash, urticarial, dermatitis, ulceration, or psoriasis) requiring systemic treatment, active or prior documented autoimmune or inflammatory disorders requiring chronic treatment with steroids or other immunosuppressive treatment.
- Unresolved toxicities not yet resolved to Grade ≤ 1 or baseline from previous anticancer therapy OR prior discontinuation of any planned study therapy due to toxicity.
- must not have any medical contraindication to platinum-based chemotherapy.
- Part 3, Part 4 and Part 5 patients must not have had prior exposure to anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-TIGIT or any other experimental immunotherapy in any setting.
- For Part 3, Part 4 and Part 5: History of substance abuse or any other medical or psychological conditions that may, in the opinion of the Investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results
- For Part 3, Part 4 and Part 5: History of thromboembolic events within 3 months before the first dose of IP (limited to pulmonary embolism, deep vein thrombosis, or cerebral venous sinus thrombosis).
Trial locations and contacts
91 sites in 19 countries. Contact the study team or a site near you to ask about taking part.
AstraZeneca Clinical Study Information Center contact
91 sites in 19 countries
United States13 sites, 4 recruiting
- Recruiting
Research Site
Baltimore, Maryland, 21287
- Withdrawn
Research Site
Buffalo, New York, 14263
- Withdrawn
Research Site
Detroit, Michigan, 48201
- Withdrawn
Research Site
Duarte, California, 91010
- Recruiting
Research Site
Fairfax, Virginia, 22031
- Recruiting
Research Site
Houston, Texas, 77030
- Withdrawn
Research Site
New York, New York, 10029
- Withdrawn
Research Site
Newport Beach, California, 92663
- Recruiting
Research Site
Orange, California, 92868
- Withdrawn
Research Site
Santa Rosa, California, 95403
- Withdrawn
Research Site
Tacoma, Washington, 98405
- Withdrawn
Research Site
The Bronx, New York, 10461
- Withdrawn
Research Site
Westwood, Kansas, 66205
Philippines9 sites, 3 recruiting
- Recruiting
Research Site
Bacolod, 6100
- Withdrawn
Research Site
Cebu City, 6000
- Withdrawn
Research Site
City of Taguig, 1634
- Terminated
Research Site
Davao City, PH-8000
- Terminated
Research Site
Manila, 1000
- Withdrawn
Research Site
Manila, 1015
- Recruiting
Research Site
Quezon City, 1100
- Recruiting
Research Site
Quezon City, 1112
- Terminated
Research Site
San Juan City, 1500
Taiwan8 sites, 8 recruiting
- Recruiting
Research Site
Kaohsiung City, 833
- Recruiting
Research Site
Taichung, 402
- Recruiting
Research Site
Taichung, 40705
- Recruiting
Research Site
Tainan, 70403
- Recruiting
Research Site
Taipei, 100
- Recruiting
Research Site
Taipei, 11217
- Recruiting
Research Site
Taipei, 235
- Recruiting
Research Site
Taoyuan, 333
China6 sites, 6 recruiting
- Not yet recruiting
Research Site
Changchun, 130000
- Not yet recruiting
Research Site
Chengdu, 610041
- Not yet recruiting
Research Site
Fuzhou, 350011
- Not yet recruiting
Research Site
Shandong
- Recruiting
Research Site
Shanghai, 200433
- Not yet recruiting
Research Site
Zhengzhou, 450000
South Korea6 sites, 5 recruiting
- Recruiting
Research Site
Cheongju-si, 28644
- Recruiting
Research Site
Goyang-si, 10408
- Recruiting
Research Site
Jinju, 52727
- Recruiting
Research Site
Seoul, 03722
- Withdrawn
Research Site
Seoul, 05505
- Recruiting
Research Site
Seoul, 06351
Thailand6 sites, 3 recruiting
- Recruiting
Research Site
Bangkok, 10300
- Completed
Research Site
Bangkok, 10330
- Completed
Research Site
Hat Yai, 90110
- Completed
Research Site
Khon Kaen, 40002
- Not yet recruiting
Research Site
Muang, 22000
- Recruiting
Research Site
Muang, 50200
France5 sites, 4 recruiting
- Withdrawn
Research Site
Bordeaux, 33075
- Recruiting
Research Site
Dijon, 21079
- Recruiting
Research Site
Pierre-Bénite, 69495
- Recruiting
Research Site
Saint-Herblain, 44800
- Recruiting
Research Site
Villejuif, 94805
Italy5 sites, 3 recruiting
- Completed
Research Site
Milan, 20133
- Recruiting
Research Site
Milan, 20162
- Recruiting
Research Site
Monza, 20052
- Recruiting
Research Site
Naples, 80131
- Withdrawn
Research Site
Padova, 35128
Poland5 sites, 3 recruiting
- Recruiting
Research Site
Gdansk, 80-214
- Suspended
Research Site
Krakow, 30-727
- Recruiting
Research Site
Olsztyn, 10-357
- Terminated
Research Site
Tomaszów Mazowiecki, 97-200
- Recruiting
Research Site
Warsaw, 02-781
Malaysia4 sites, 4 recruiting
- Recruiting
Research Site
George Town, 10450
- Recruiting
Research Site
Kuala Lumpur, 59100
- Recruiting
Research Site
Kuala Selangor, 62250
- Recruiting
Research Site
Kuching, 93586
Spain4 sites
- Withdrawn
Research Site
Badalona, 08013
- Withdrawn
Research Site
Madrid, 28041
- Withdrawn
Research Site
Seville, 41013
- Withdrawn
Research Site
Valencia, 46010
Turkey (Türkiye)4 sites, 3 recruiting
- Recruiting
Research Site
Ankara, 06800
- Recruiting
Research Site
Ankara, 6200
- Active, not recruiting
Research Site
Bornova-Izmir, 35100
- Recruiting
Research Site
Istanbul, 31755
Australia3 sites, 1 recruiting
- Terminated
Research Site
Adelaide, 5000
- Withdrawn
Research Site
Heidelberg, 3084
- Recruiting
Research Site
Nedlands, 6009
Brazil3 sites, 3 recruiting
- Recruiting
Research Site
Barretos, 14784-400
- Recruiting
Research Site
Porto Alegre, 90035-903
- Recruiting
Research Site
São Paulo, 05652-900
Canada3 sites, 1 recruiting
- Withdrawn
Research Site
London, Ontario, N6A 5W9
- Recruiting
Research Site
Montreal, Quebec, H3T 1E2
- Withdrawn
Research Site
Winnipeg, Manitoba, R3E 0V9
Singapore3 sites
- Completed
Research Site
Singapore, 119228
- Completed
Research Site
Singapore, 168583
- Completed
Research Site
Singapore, 308433
Israel2 sites, 2 recruiting
- Recruiting
Research Site
Kfar Saba, 4428164
- Recruiting
Research Site
Tel HaShomer, 52620
About this study
Official title: A Phase Ib Multicenter, Open-label Study to Evaluate the Safety and Tolerability of Trastuzumab Deruxtecan (T-DXd) and Immunotherapy Agents With and Without Chemotherapy Agents in First-line Treatment of Patients With Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) and Human Epidermal Growth Factor Receptor 2 (HER2) Overexpression (OE) (DESTINY-Lung03)
DESTINY-Lung03 will investigate the safety and tolerability of trastuzumab deruxtecan in combination with Immunotherapy Agents with and without chemotherapy in patients with HER2 over-expressing non-small cell lung cancer. The efficacy will be also analyzed as a secondary endpoint.
Read the detailed description
Part 1 is a dose escalation study by design, allowing the assessment of safety, tolerability, and recommended dose levels of the combination of T-DXd and durvalumab plus cisplatin, carboplatin, or pemetrexed. No more patients will be enrolled in this part of the study. Part 2, expansions in the treatment-naïve setting on any recommended dose level, will not be initiated.
The evaluation of T-DXd combination treatment with immunotherapy continues in Part 3, Part 4, and Part 5. In Part 3, T-DXd is assessed in combination with volrustomig, with carboplatin (Arm 3B) or without carboplatin (Arm 3A). Part 4 examines T-DXd with rilvegostomig, either with carboplatin (Arm 4B) or without carboplatin (Arm 4A). In Part 5, T-DXd is evaluated with volrustomig, given with or without a priming dose followed by a fixed dose in Arm 5A. There is also an optional Arm 5B at the Sponsor's discretion. These parts focus on further dose optimization for first-line HER2-overexpressing NSCLC.
For Part 3, patients will be randomized to Arms 3A and 3B, beginning with the cohorts receiving the volrustomig starting dose (SD). A total of 6 DLT-evaluable patients will be enrolled to the SD cohorts in each arm. If the combination of T-DXd with volrustomig at the starting dose is deemed safe, a dose escalation (E1) cohort will be opened for 6 DLT-evaluable patients. Once all open dose confirmation cohorts have 6 DLT-evaluable patients, the SRC will convene to select the volrustomig RP2D to be used in the dose-expansion (DE) cohorts of each arm (n=34). Part 3 is now permanently closed to recruitment; no further patients will be enrolled.
In Part 4, once a total of 6 DLT-evaluable patients/arm have been enrolled into Arm 4A and Arm 4B safety-run in (SR) cohorts and deemed safe, an additional 34 patients per arm will be enrolled in Arms 4A and 4B in dose expansion cohorts.
Part 5 involves additional dosing regimens of T-DXd in combination with volrustomig. The objective of Part 5 is to evaluate the safety and efficacy of priming and flat dosing regimens in 2 different cohorts of up to 30 patients per arm.
The target population of interest (for Part 3, 4 and 5) are patients with advanced or metastatic non-small cell lung cancer measurable disease by RECIST 1.1 criteria, HER2 overexpression, ECOG PS of 0 to 1, patients who are treatment naïve for recurrent, unresectable or metastatic disease. Patients with tumors that harbor a known genomic alteration or driver for which approved therapies are available are excluded.
- Being tested
- T-DXd, Durvalumab, Cisplatin, Carboplatin, Pemetrexed
- Keywords
- HER2+, HER2 expression, DS-8201a, T-DXd, Trastuzumab Deruxtecan, Volrustomig (MEDI5752), Antibody - drug conjugate, bispecific antibody, Volrustomig, Rilvegostomig, Carboplatin, First line, Locally advanced and unresectable non-squamous NSCLC, Metastatic non-squamous NSCLC, Non-small cell lung cancer
- Medical subject headings
- Carcinoma, Non-Small-Cell Lung
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
T-DXdDrug
Also called DS-8201a, Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
DurvalumabBiological
Also called MEDI4736
Durvalumab: administered as an IV infusion
CisplatinDrug
Cisplatin: administered as an IV infusion
CarboplatinDrug
Carboplatin: administered as an IV infusion
PemetrexedDrug
Pemetrexed: administered as an IV infusion (drug not used)
VolrustomigDrug
Also called Other Name: MEDI5752
Volrustomig: administered as an IV infusion
RilvegostomigDrug
Also called Other Name: AZD2936
Rilvegostomig: administered as an IV infusion
| Study group | Role | What they receive |
|---|---|---|
| Arm 1A: T-DXd, Durvalumab and Cisplatin | Experimental | T-DXd, Durvalumab and Cisplatin Receives: Drug: T-DXd; Biological: Durvalumab; Drug: Cisplatin |
| Arm 1B: T-DXd, Durvalumab and Carboplatin | Experimental | T-DXd, Durvalumab and Carboplatin Receives: Drug: T-DXd; Biological: Durvalumab; Drug: Carboplatin |
| Arm 1C: T-DXd, Durvalumab and Pemetrexed | Experimental | T-DXd, Durvalumab and Pemetrexed (Arm not initiated) Receives: Drug: T-DXd; Biological: Durvalumab; Drug: Pemetrexed |
| Arm 1D: T-DXd | Experimental | T-DXd Receives: Drug: T-DXd |
| Arm 3A: T-DXd and Volrustomig | Experimental | Drug: T-DXd and Volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Receives: Drug: T-DXd; Drug: Volrustomig |
| Arm 3B: T-DXd, Volrustomig and Carboplatin | Experimental | Drug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion Receives: Drug: T-DXd; Drug: Carboplatin; Drug: Volrustomig |
| Arm 4A: T-DXd and Rilvegostomig | Experimental | T-DXd and Rilvegostomig Drug: T-DXd, Rilvegostomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Receives: Drug: T-DXd; Drug: Rilvegostomig |
| Arm 4B T-DXd and Rilvegostomig with Carboplatin | Experimental | Drug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion Receives: Drug: T-DXd; Drug: Carboplatin; Drug: Rilvegostomig |
| Arm 5A: T-DXd and Volrustomig | Experimental | Drug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (priming dose in first cycle, fixed dose in subsequent cycles) Other Name: volrustomig Receives: Drug: T-DXd; Drug: Volrustomig |
| Arm 5B: T-DXd and Volrustomig | Experimental | Drug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (fixed dose from first cycle onward) Other Name: volrustomig Receives: Drug: T-DXd; Drug: Volrustomig |
What is being measured
The primary outcome is the main question the study is designed to answer.
Frequency of AEs and SAEs
Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0
Measured: Safety and tolerability (and to determine RP2D) will be assessed for approximately 20 months from informed consent
Secondary outcomes (10)
Confirmed Objective Response Rate (ORR)
Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed, based on investigator assessment
Measured: An average of approximately 12 months
Duration of Response (DoR)
DOR is defined as the time from the date of first documented response until the date of documented progression or death, based on RECIST 1.1 assessment
Measured: An average of approximately 20 months
Disease Control Rate (DCR)
DCR is the percentage of patients who have a best overall response of complete response (CR) or partial response (PR) or stable disease (SD), based on RECIST 1.1 assessment. DCR is assessed at 6 and 12 weeks
Measured: An average of approximately 12 months
Progression-free survival (PFS)
PFS is the time from first dose of study treatment until the date of objective disease progression or death, based on RECIST 1.1 assessment
Measured: An average of approximately 20 months
Overall survival (OS)
OS is the time form the date of first dose of study treatment until death due to any cause
Measured: An average of approximately 20 months
Pharmacokinetics (PK) assessed by the serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181 in all arms
Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for T-DXd, total anti-HER2 antibody and MAAA-1181a
Measured: An average of approximately 20 months
Pharmacokinetics (PK) assessed by the serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab
Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for durvalumab, including T-DXd in combination with durvalumab
Measured: An average of approximately 20 months
Pharmacokinetics (PK) assessed by the serum concentration of volrustomig in study arms including T-DXd in combination with volrustomig
Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for volrustomig, including T-DXd in combination with volrustomig
Measured: An average of approximately 20 months
Pharmacokinetics (PK) assessed by the serum concentration of rilvegostomig in study arms including T-DXd in combination with rilvegostomig
Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for rilvegostomig, including T- DXd in combination with rilvegostomig
Measured: An average of approximately 20 months
The immunogenicity of T-DXd, durvalumab, volrustomig and rilvegostomig assessed by the presence of ADAs for T-DXd, durvalumab, volrustomig, or rilvegostomig
Individual participant data and descriptive statistics will be provided for data at each time point for each dose level for T-DXd, durvalumab or volrustomig, or rilvegostomig
Measured: An average of approximately 20 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Dec 2020
- Study start9 Mar 2021
- Primary completion30 Jun 2027 (estimated)
- Study completion30 Jun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Locally Advanced or Metastatic Non-Small Cell Lung CancerStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- DL-03 aims to identify T-DXd-based combination therapies for patients with previously untreated, advanced, HER2-overexpressing NSCLC. Across all study parts, the primary objectives are to assess safety and tolerability. Secondary objectives include assessing preliminary efficacy based on ORR, DoR, DCR, PFS, and OS. Part 5 will consist of two arms evaluating T-DXd plus volrustomig, without chemotherapy. Arm 5A will assess T-DXd plus volrustomig as a single priming dose, followed by a lower, fixed maintenance dose. Arm 5B will evaluate T-DXd plus volrustomig as fixed doses. Part 4 consists of two arms utilizing T-DXd plus rilvegostomig, without or with carboplatin (first 4 cycles in Arm 4B only). Part 3 consists of two arms utilizing T-DXd plus volrustomig, without or with carboplatin (first 4 cycles in Arm 3B only), and assesses two different volrustomig doses. Part 3 is closed to recruitment and enrolment. Part 2 was not initiated. Part 1 is complete.
- Masking
- None (open label)
- Enrolment
- 304 participants (estimated)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Daiichi Sankyo
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04686305
- Sponsor's protocol ID
- D967YC00001
- Other IDs
- 2023-504949-31-00, 2020-003260-31, 2023
- Acronym
- DL03
- Status last verified
- Feb 2026
- First submitted
- 8 Dec 2020
- Last updated
- 13 Apr 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Publications
Planchard D, Kim HR, Suksombooncharoen T, Li R, Cortinovis D, Han JY, Samol J, Runglodvatana Y, Lee KY, Chang GC, Lee CH, Kowalski D, Saw SPL, Huang Y, Ruiter G, Ahn MJ, Yang TY, Yang CT, Sookprasert A, Nakajima EC, Alfon J, McEwen R, Chang YT, Yang JC. Trastuzumab Deruxtecan in Patients With HER2-Overexpressing NSCLC: Results From Part 1 of the Open-Label, Multicenter, Phase 1b DESTINY-Lung03 Trial. J Thorac Oncol. 2026 May;21(5):103541. doi: 10.1016/j.jtho.2025.12.080. Epub 2025 Dec 23.
PubMed 41448488
Study at a glance
From the registry record, last updated by the sponsor on 13 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase Ib Multicenter, Open-label Study to Evaluate the Safety and Tolerability of Trastuzumab Deruxtecan (T-DXd) and Immunotherapy Agents With and Without Chemotherapy Agents in First-line Treatment of Patients With Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) and Human Epidermal Growth Factor Receptor 2 (HER2) Overexpression (OE) (DESTINY-Lung03)
- ClinicalTrials.gov ID
- NCT04686305
- Acronym / sponsor ID
- DL03 / D967YC00001
- Keywords
- HER2+, HER2 expression, DS-8201a, T-DXd, Trastuzumab Deruxtecan, Volrustomig (MEDI5752), Antibody - drug conjugate, bispecific antibody
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 304 participants (estimated)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Collaborators
- Daiichi Sankyo
- Study start
- 9 Mar 2021 (actual)
- Primary completion
- 30 Jun 2027 (estimated)
- Study completion
- 30 Jun 2027 (estimated)
- First posted
- 28 Dec 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
DESTINY-Lung03 will investigate the safety and tolerability of trastuzumab deruxtecan in combination with Immunotherapy Agents with and without chemotherapy in patients with HER2 over-expressing non-small cell lung cancer. The efficacy will be also analyzed as a secondary endpoint.
Detailed description
Part 1 is a dose escalation study by design, allowing the assessment of safety, tolerability, and recommended dose levels of the combination of T-DXd and durvalumab plus cisplatin, carboplatin, or pemetrexed. No more patients will be enrolled in this part of the study. Part 2, expansions in the treatment-naïve setting on any recommended dose level, will not be initiated.
The evaluation of T-DXd combination treatment with immunotherapy continues in Part 3, Part 4, and Part 5. In Part 3, T-DXd is assessed in combination with volrustomig, with carboplatin (Arm 3B) or without carboplatin (Arm 3A). Part 4 examines T-DXd with rilvegostomig, either with carboplatin (Arm 4B) or without carboplatin (Arm 4A). In Part 5, T-DXd is evaluated with volrustomig, given with or without a priming dose followed by a fixed dose in Arm 5A. There is also an optional Arm 5B at the Sponsor's discretion. These parts focus on further dose optimization for first-line HER2-overexpressing NSCLC.
For Part 3, patients will be randomized to Arms 3A and 3B, beginning with the cohorts receiving the volrustomig starting dose (SD). A total of 6 DLT-evaluable patients will be enrolled to the SD cohorts in each arm. If the combination of T-DXd with volrustomig at the starting dose is deemed safe, a dose escalation (E1) cohort will be opened for 6 DLT-evaluable patients. Once all open dose confirmation cohorts have 6 DLT-evaluable patients, the SRC will convene to select the volrustomig RP2D to be used in the dose-expansion (DE) cohorts of each arm (n=34). Part 3 is now permanently closed to recruitment; no further patients will be enrolled.
In Part 4, once a total of 6 DLT-evaluable patients/arm have been enrolled into Arm 4A and Arm 4B safety-run in (SR) cohorts and deemed safe, an additional 34 patients per arm will be enrolled in Arms 4A and 4B in dose expansion cohorts.
Part 5 involves additional dosing regimens of T-DXd in combination with volrustomig. The objective of Part 5 is to evaluate the safety and efficacy of priming and flat dosing regimens in 2 different cohorts of up to 30 patients per arm.
The target population of interest (for Part 3, 4 and 5) are patients with advanced or metastatic non-small cell lung cancer measurable disease by RECIST 1.1 criteria, HER2 overexpression, ECOG PS of 0 to 1, patients who are treatment naïve for recurrent, unresectable or metastatic disease. Patients with tumors that harbor a known genomic alteration or driver for which approved therapies are available are excluded.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 10
- Model description
- DL-03 aims to identify T-DXd-based combination therapies for patients with previously untreated, advanced, HER2-overexpressing NSCLC. Across all study parts, the primary objectives are to assess safety and tolerability. Secondary objectives include assessing preliminary efficacy based on ORR, DoR, DCR, PFS, and OS. Part 5 will consist of two arms evaluating T-DXd plus volrustomig, without chemotherapy. Arm 5A will assess T-DXd plus volrustomig as a single priming dose, followed by a lower, fixed maintenance dose. Arm 5B will evaluate T-DXd plus volrustomig as fixed doses. Part 4 consists of two arms utilizing T-DXd plus rilvegostomig, without or with carboplatin (first 4 cycles in Arm 4B only). Part 3 consists of two arms utilizing T-DXd plus volrustomig, without or with carboplatin (first 4 cycles in Arm 3B only), and assesses two different volrustomig doses. Part 3 is closed to recruitment and enrolment. Part 2 was not initiated. Part 1 is complete.
| Arm | Type | Receives |
|---|---|---|
| Arm 1A: T-DXd, Durvalumab and Cisplatin | Experimental | Drug: T-DXd, Biological: Durvalumab, Drug: CisplatinT-DXd, Durvalumab and Cisplatin |
| Arm 1B: T-DXd, Durvalumab and Carboplatin | Experimental | Drug: T-DXd, Biological: Durvalumab, Drug: CarboplatinT-DXd, Durvalumab and Carboplatin |
| Arm 1C: T-DXd, Durvalumab and Pemetrexed | Experimental | Drug: T-DXd, Biological: Durvalumab, Drug: PemetrexedT-DXd, Durvalumab and Pemetrexed (Arm not initiated) |
| Arm 1D: T-DXd | Experimental | Drug: T-DXdT-DXd |
| Arm 3A: T-DXd and Volrustomig | Experimental | Drug: T-DXd, Drug: VolrustomigDrug: T-DXd and Volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig |
| Arm 3B: T-DXd, Volrustomig and Carboplatin | Experimental | Drug: T-DXd, Drug: Carboplatin, Drug: VolrustomigDrug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion |
| Arm 4A: T-DXd and Rilvegostomig | Experimental | Drug: T-DXd, Drug: RilvegostomigT-DXd and Rilvegostomig Drug: T-DXd, Rilvegostomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 |
| Arm 4B T-DXd and Rilvegostomig with Carboplatin | Experimental | Drug: T-DXd, Drug: Carboplatin, Drug: RilvegostomigDrug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion |
| Arm 5A: T-DXd and Volrustomig | Experimental | Drug: T-DXd, Drug: VolrustomigDrug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (priming dose in first cycle, fixed dose in subsequent cycles) Other Name: volrustomig |
| Arm 5B: T-DXd and Volrustomig | Experimental | Drug: T-DXd, Drug: VolrustomigDrug: T-DXd and volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion (fixed dose from first cycle onward) Other Name: volrustomig |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Histologically documented unresectable locally advanced/metastatic non-squamous NSCLC
- Part 1: Progression after 1 or 2 lines of systemic therapy for recurrent or metastatic setting.
- Part 3, Part 4 and Part 5: Patients must have tumors that do not harbor known genomic alterations or actionable driver kinases, for which approved therapies are available are allowed.
- Part 3, Part 4 and Part 5: Patient must be treatment-naïve for advanced or metastatic NSCLC. Patients who have received prior adjuvant, or neoadjuvant chemotherapy, or definitive chemoradiation for advanced disease are eligible, provided that progression has occurred > 6 months from end of last therapy
- HER2overexpression status as determined by central review of tumor tissue
Key exclusion criteria (15 listed)
- HER2 mutation if previously known
- 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
- Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder and prior pneumonectomy
- Active primary immunodeficiency known HIV infection, or active chronic and resolved hepatitis B (positive hepatitis B virus surface antigen [HBsAg+ve] or hepatitis B virus core antibody (anti-HBc +ve) regardless of HBV DNA level)) or hepatitis C infection. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Patients should be tested for HIV prior to treatment assignment if required by local regulations or IRB/EC
- Active infection including tuberculosis and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| T-DXdAlso: DS-8201a, Trastuzumab deruxtecanT-DXd: administered as an IV infusion | Drug | Arm 1A: T-DXd, Durvalumab and Cisplatin, Arm 1B: T-DXd, Durvalumab and Carboplatin, Arm 1C: T-DXd, Durvalumab and Pemetrexed, Arm 1D: T-DXd, Arm 3A: T-DXd and Volrustomig, Arm 3B: T-DXd, Volrustomig and Carboplatin, Arm 4A: T-DXd and Rilvegostomig, Arm 4B T-DXd and Rilvegostomig with Carboplatin, Arm 5A: T-DXd and Volrustomig, Arm 5B: T-DXd and Volrustomig |
| DurvalumabAlso: MEDI4736Durvalumab: administered as an IV infusion | Biological | Arm 1A: T-DXd, Durvalumab and Cisplatin, Arm 1B: T-DXd, Durvalumab and Carboplatin, Arm 1C: T-DXd, Durvalumab and Pemetrexed |
| CisplatinCisplatin: administered as an IV infusion | Drug | Arm 1A: T-DXd, Durvalumab and Cisplatin |
| CarboplatinCarboplatin: administered as an IV infusion | Drug | Arm 1B: T-DXd, Durvalumab and Carboplatin, Arm 3B: T-DXd, Volrustomig and Carboplatin, Arm 4B T-DXd and Rilvegostomig with Carboplatin |
| PemetrexedPemetrexed: administered as an IV infusion (drug not used) | Drug | Arm 1C: T-DXd, Durvalumab and Pemetrexed |
| VolrustomigAlso: Other Name: MEDI5752Volrustomig: administered as an IV infusion | Drug | Arm 3A: T-DXd and Volrustomig, Arm 3B: T-DXd, Volrustomig and Carboplatin, Arm 5A: T-DXd and Volrustomig, Arm 5B: T-DXd and Volrustomig |
| RilvegostomigAlso: Other Name: AZD2936Rilvegostomig: administered as an IV infusion | Drug | Arm 4A: T-DXd and Rilvegostomig, Arm 4B T-DXd and Rilvegostomig with Carboplatin |
Primary outcome
Frequency of AEs and SAEs
Time frame: Safety and tolerability (and to determine RP2D) will be assessed for approximately 20 months from informed consent
Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0
10 secondary outcomes
Confirmed Objective Response Rate (ORR)
Time frame: An average of approximately 12 months
Duration of Response (DoR)
Time frame: An average of approximately 20 months
Disease Control Rate (DCR)
Time frame: An average of approximately 12 months
Progression-free survival (PFS)
Time frame: An average of approximately 20 months
Overall survival (OS)
Time frame: An average of approximately 20 months
Pharmacokinetics (PK) assessed by the serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181 in all arms
Time frame: An average of approximately 20 months
Pharmacokinetics (PK) assessed by the serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab
Time frame: An average of approximately 20 months
Pharmacokinetics (PK) assessed by the serum concentration of volrustomig in study arms including T-DXd in combination with volrustomig
Time frame: An average of approximately 20 months
Pharmacokinetics (PK) assessed by the serum concentration of rilvegostomig in study arms including T-DXd in combination with rilvegostomig
Time frame: An average of approximately 20 months
The immunogenicity of T-DXd, durvalumab, volrustomig and rilvegostomig assessed by the presence of ADAs for T-DXd, durvalumab, volrustomig, or rilvegostomig
Time frame: An average of approximately 20 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Apr 2026.
- Derived from this study: PubMed 41448488Planchard D, Kim HR, Suksombooncharoen T, Li R, Cortinovis D, Han JY, Samol J, Runglodvatana Y, Lee KY, Chang GC, Lee CH, Kowalski D, Saw SPL, Huang Y, Ruiter G, Ahn MJ, Yang TY, Yang CT, Sookprasert A, Nakajima EC, Alfon J, McEwen R, Chang YT, Yang JC. Trastuzumab Deruxtecan in Patients With HER2-Overexpressing NSCLC: Results From Part 1 of the Open-Label, Multicenter, Phase 1b DESTINY-Lung03 Trial. J Thorac Oncol. 2026 May;21(5):103541. doi: 10.1016/j.jtho.2025.12.080. Epub 2025 Dec 23.
- Lung Cancer Study Locator details (for US)Link provided by the sponsor.
- Individual participant dataSharing planned: Yes. Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
AstraZeneca Clinical Study Information Center contact
91 sites in 19 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing T-DXd, Durvalumab and Cisplatin in people with Locally Advanced or Metastatic Non-Small Cell Lung Cancer, run by AstraZeneca at 91 sites in 19 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 13 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 91 sites in United States, Philippines, Taiwan, China, South Korea and 14 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact AstraZeneca Clinical Study Information Center (1-877-240-9479, information.center@astrazeneca.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Frequency of AEs and SAEs (time frame: Safety and tolerability (and to determine RP2D) will be assessed for approximately 20 months from informed consent). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04686305, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Apr 2026.