NCT04686305

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 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)

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 304 (estimated)
• Sponsor: AstraZeneca · Industry
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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.

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.

Conditions

• Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Interventions

Type	Name	Description
DRUG	T-DXd	T-DXd: administered as an IV infusion
BIOLOGICAL	Durvalumab	Durvalumab: administered as an IV infusion
DRUG	Cisplatin	Cisplatin: administered as an IV infusion
DRUG	Carboplatin	Carboplatin: administered as an IV infusion
DRUG	Pemetrexed	Pemetrexed: administered as an IV infusion (drug not used)
DRUG	Volrustomig	Volrustomig: administered as an IV infusion
DRUG	Rilvegostomig	Rilvegostomig: administered as an IV infusion

Timeline

• Start date: 2021-03-09
• Primary completion: 2027-06-30
• Completion: 2027-06-30
• First posted: 2020-12-28
• Last updated: 2026-04-13

Locations

91 sites across 19 countries: United States, Australia, Belgium, Brazil, Canada, China, France, Israel, Italy, Malaysia, Netherlands, Philippines, Poland, Singapore, South Korea, Spain, Taiwan, Thailand, Turkey (Türkiye)

Regulatory

• FDA-regulated drug study