Ph1b/2 Study of the Safety and Efficacy of T-DXd Combinations in Advanced HER2-expressing Gastric Cancer (DESTINY-Gastric03)

• Fluorouracil (5-FU) (Drug): 5-FU: administered as an IV infusion
• Capecitabine (Drug): Capecitabine: administered orally
• Durvalumab (Biological), also known as MEDI4736: Durvalumab: administered as an IV infusion
• Oxaliplatin (Drug): Oxaliplatin: administered as an IV infusion
• Trastuzumab (Biological): Trastuzumab: administered as an IV infusion
• Trastuzumab deruxtecan (Drug), also known as DS-8201a, Enhertu: T-DXd: administered as an IV infusion
• Cisplatin (Drug): Cisplatin: administered as an IV infusion
• Pembrolizumab (Biological): Pembrolizumab: administered as an IV infusion
• Volrustomig (Biological), also known as MEDI5752: Volrustomig: administered as an IV infusion
• Rilvegostomig (Biological), also known as AZD2936: Rilvegostomig: administered as an IV infusion

Primary outcomes

• Part 1: Occurrence of adverse events (AEs) and serious adverse events (SAEs), graded according to NCI CTCAE v5.0 [Safety will be assessed up to the follow-up period, approximately 24 months.]: Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0
• Part 1: Ocurrence of dose-limiting toxicities (DLTs) [Safety will be assessed up to the follow-up period, approximately 24 months.]: Occurrence of dose limiting toxicities
• Part 1: Changes from baseline in laboratory parameters [Safety will be assessed up to the follow-up period, approximately 24 months.]: Changes in laboratory parameters (every in appropriate units) compared to baseline results.
• Part 1: Changes from baseline in vital signs [Safety will be assessed up to the follow-up period, approximately 24 months.]: Changes in vital signs results compared to baseline results.
• Part 1: Changes from baseline in electrocardiogram (ECG) results [Safety will be assessed up to the follow-up period, approximately 24 months.]: Changes in ECG results compared to baseline results.
• Part 2, Part 3, Part 4 and Part 5: Endpoint assessed by Investigator per RECIST v1.1: Confirmed Objective Response Rate (ORR) [(Endpoint: ORR) Efficacy will be assessed at an average of approximately 12 months]: Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.

Secondary outcomes

• Part 1: Objective Response Rate (ORR) [Efficacy will be assessed at an average of approximately 12 months]: Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed.
• Part 2, Part 3, Part 4 and Part 5: Occurrence of adverse events (AEs) and serious adverse events (SAEs) [Safety will be assessed up to follow-up period, approximately 24 months]: Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0
• Part 2, Part 3, Part 4 and Part 5: Changes from baseline in laboratory parameters [Safety will be assessed up to follow-up period, approximately 24 months]: Changes in laboratory parameters (every in appropriate units) compared to baseline results.
• Part 2, Part 3, Part 4 and Part 5: Changes from baseline in vital signs [Safety will be assessed up to follow-up period, approximately 24 months]: Changes in vital signs results compared to baseline results.
• Part 2, Part 3 , Part 4 and Part 5: Changes from baseline in body weight [Safety will be assessed up to follow-up period, approximately 24 months]: Changes in body weight in kilograms compared to baseline results.
• Part 2, Part 3, Part 4 and Part 5: Changes from baseline in electrocardiogram (ECG) results [Safety will be assessed up to follow-up period, approximately 24 months]: Changes in ECG results compared to baseline results.
• Duration of Response (DoR) [Until progression or death, efficacy (DoR) will be assessed up to approximately 24 months]: DOR is defined as the time from the date of first documented response until the date of documented progression or death
• Disease Control Rate (DCR) [Efficacy will be assessed at an average of approximately 12 months]: DCR is the percentage of subjects who have a best overall response of complete response (CR) or partial response (PR) or stable disease (SD)
• Progression Free Survival (PFS) [Until progression or death, efficacy (PFS) will be assessed up to approximately 24 months]: PFS is the time from date of first dose until the date of objective disease progression or death
• Overall survival (OS) [Until death, efficacy (OS) will be assessed up to approximately 24 months]: OS is the time from date of first dose until death due to any cause
• Serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181a in all arms [While on study drug up to study completion, approximately 24 months]: Individual participant data and descriptive statistics will be provided for serum concentration data at each time point for each dose level for T-DXd, total anti-HER2 antibody, MAAA-1181a
• Serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab [While on study drug up to study completion, approximately 24 months]: Individual participant data and descriptive statistics will be provided for serum concentration data at each time point for durvalumab.
• Presence of ADAs for T-DXD, durvalumab, volrustomig and rilvegostomig (in study arms including T-DXd and durvalumab, and T-DXd and volrustomig, and T-DXd and rilvegostomig respectively) [While on study drug up to study completion, approximately 24 months]: Individual participant data and descriptive statistics will be provided for data at each time point for each dose level for T-DXd and durvalumab.
• Serum concentrations of volrustomig and rilvegostomig in study arms including T-DXd in combination with volrustomig and T-DXd in combination with rilvegostomig [While on study drug up to study completion, approximately 24 months]: Individual participant data and descriptive statistics will be provided for data at each time point for rilvegostomig and volrustomig
• Comparison of ORR [While on study drug up to study completion, approximately 24 months]: Comparison of objective response rate between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results
• Comparison of DCR [While on study drug up to study completion, approximately 24 months]: Comparison of disease control rate between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results
• Comparison of DoR [While on study drug up to study completion, approximately 24 months]: Comparison of duration of response between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results
• Comparison of PFS [While on study drug up to study completion, approximately 24 months]: Comparison of progression-free survival between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results
• Comparison of OS [While on study drug up to study completion, approximately 24 months]: Comparison of overall survival between participants using local HER2 test results and central HER2 test results from tumor samples with evaluable results

Sex: All, ages: 18 Years to 130 Years

Inclusion criteria:

1. Male and female participants must be at least 18 years of age. Other age restrictions may apply as per local regulations
2. Disease Characteristics:

   1. Locally advanced, unresectable, or metastatic disease based on most recent imaging
   2. For Part 1, 2, 3a, 4a pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-positive (IHC 3+ or IHC 2+/ISH+) based on local tissue testing results
   3. For Part 3b,4b and Part 5, pathologically documented adenocarcinoma of the stomach/GEJ/esophagus, HER2-low (IHC 2+/ISH-negative or IHC 1+) based on local tissue testing results
3. For Part 1, progression on or after at least one prior trastuzumabcontaining regimen For Part 2, Part 3, Part 4 and Part 5, previously untreated for unresectable or metastatic adenocarcinoma of the stomach/GEJ/ esophagus with with HER2-positive (Part 2 and Part 3 \[Arm 3A\] and Part 4 \[Arm 4A\]) or HER2-low (Part 3 \[Arm 3B\], Part 4 \[Arm 4B\] and Part 5)) status
4. Has measurable target disease assessed by the Investigator based on RECIST version 1.1
5. Has protocol defined adequate bone marrow and organ function including cardiac, renal and hepatic function
6. If of reproductive potential, agrees to use a highly effective form of contraception or avoid intercourse during and upon completion of the study.

Exclusion criteria:

1. Part 1 to 4: History of active primary immunodeficiency, known HIV, active chronic, or past hepatitis B infection, or hepatitis C infection. Part 5: evidence of active, uncontroled HIV, HBV or HCV infection.
2. Uncontrolled intercurrent illness.
3. History of non-infectious pneumonitis/ILD, current ILD, or where suspected ILD that cannot be ruled out by imaging at screening.
4. Lung-specific intercurrent clinically significant severe illnesses.
5. Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
6. Pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).
7. Has spinal cord compression or clinically active central nervous system metastases.

• Results publication: Yu J, Mehta R. Biomarker-Driven Approach to the Treatment of Metastatic Gastric or Gastroesophageal Adenocarcinoma. J Natl Compr Canc Netw. 2025 May;23(5):e257036. doi: 10.6004/jnccn.2025.7036. PMID 40341124

NIH grants: 2019