Trial: Study of Dato-Dxd as Monotherapy and in…

Trial Details

Sponsor: AstraZeneca (industry)

Phase: 2

Start date: Sept. 6, 2022

Planned enrollment: 582

Trial ID: NCT05489211

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Datopotamab deruxtecan (Dato-DXd, DS-1062)

Overview

Datopotamab deruxtecan (Dato-DXd, DS-1062) is an investigational antibody-drug conjugate (ADC) targeting trophoblast cell-surface antigen-2 (TROP2). It is being developed by Daiichi Sankyo and AstraZeneca for the treatment of various cancers, including non–small cell lung cancer (NSCLC) and breast cancer.

Mechanism of Action

Dato-DXd comprises a humanized anti-TROP2 monoclonal antibody linked to a potent topoisomerase I inhibitor payload. Upon binding to TROP2-expressing tumor cells, the ADC is internalized, releasing the cytotoxic agent to induce DNA damage and cell death.

Efficacy

Non–Small Cell Lung Cancer (NSCLC):

TROPION-Lung05 Phase II Trial: In patients with advanced/metastatic NSCLC harboring actionable genomic alterations, Dato-DXd demonstrated an objective response rate (ORR) of 35.8%, with a median progression-free survival (PFS) of 5.4 months. (ascopubs.org)
TROPION-Lung01 Phase III Trial: Dato-DXd showed a statistically significant improvement in PFS compared to docetaxel in previously treated patients with locally advanced or metastatic NSCLC. (cms.dsi.com)

Breast Cancer:

TROPION-Breast01 Phase III Trial: In patients with inoperable or metastatic hormone receptor–positive, HER2-negative breast cancer, Dato-DXd significantly reduced the risk of disease progression or death by 37% compared to chemotherapy (hazard ratio [HR], 0.63; P < .0001). (ascopubs.org)
BEGONIA Phase 1b/2 Trial: In previously untreated metastatic triple-negative breast cancer, Dato-DXd combined with durvalumab achieved a confirmed ORR of 79%, including complete responses. (daiichisankyo.us)

Safety

In the TROPION-Breast01 trial, Dato-DXd exhibited a favorable safety profile, with grade ≥3 treatment-related adverse events (TRAEs) occurring in 20.8% of patients, compared to 44.7% in the chemotherapy group. Common TRAEs included nausea (51.1%; grade ≥3: 1.4%) and stomatitis (50%; grade ≥3: 6.4%). (ascopubs.org)

In the TROPION-Lung05 trial, grade ≥3 TRAEs were reported in 28.5% of patients, with stomatitis (10%) being the most common. There were five cases (3.6%) of treatment-related interstitial lung disease/pneumonitis, including one grade 5 event. (ascopubs.org)

Show for: Volrustomig (MEDI5752, PD-1/CTLA-4 DuetMab, MEDI-5752)

Overview

Volrustomig, also known as MEDI5752 or PD-1/CTLA-4 DuetMab, is an investigational bispecific monoclonal antibody targeting both PD-1 and CTLA-4 immune checkpoints. It is designed to fully inhibit PD-1 while preferentially inhibiting CTLA-4 on activated PD-1–positive T cells, aiming to enhance antitumor immune responses. (oncologypro.esmo.org)

Mechanism of Action

Volrustomig's bispecific nature allows it to simultaneously block PD-1 and CTLA-4 pathways. This dual inhibition is intended to restore and amplify T-cell activity against tumor cells, potentially leading to improved therapeutic outcomes compared to targeting either checkpoint alone. (aacrjournals.org)

Efficacy

In a Phase 1 study involving treatment-naïve patients with advanced clear cell renal cell carcinoma (ccRCC), volrustomig demonstrated promising efficacy:

750 mg dose cohort (V750):
Objective response rate (ORR): 48.4%
Complete response (CR) rate: 9.7%
Disease control rate (DCR): 90.3%
Median duration of response (DOR): 17.0 months
Median progression-free survival (PFS): 12.3 months
500 mg dose cohort (V500):
ORR: 45.5%
CR rate: 6.1%
DCR: 69.7%
Median DOR: 11.5 months
Median PFS: 9.7 months

These results suggest that volrustomig has the potential to improve outcomes in patients with advanced RCC. (onclive.com)

Safety

The safety profile of volrustomig is consistent with dual checkpoint inhibition:

750 mg dose cohort (V750):
Treatment-related adverse events (TRAEs) occurred in 96.9% of patients, with grade 3 or 4 TRAEs in 62.5%.
Common TRAEs included pruritus (50%), hyperthyroidism (34.4%), and diarrhea (25%).
46.9% of patients discontinued treatment due to TRAEs.
500 mg dose cohort (V500):
TRAEs occurred in 93.9% of patients, with grade 3 or 4 TRAEs in 42.4%.
Common TRAEs included pruritus (39.4%), hyperthyroidism (21.2%), and diarrhea (21.2%).
30.4% of patients discontinued treatment due to TRAEs.

One treatment-related death occurred in the V500 cohort due to bronchopulmonary aspergillosis with immune neutropenia. (onclive.com)

Show for: Rilvegostomig (AZD2936)

HealthScout AI Analysis

Goal: Evaluate the antitumor activity, safety, and recommended Phase II doses of datopotamab deruxtecan (Dato-DXd) given as monotherapy and in combinations across multiple advanced/metastatic solid tumor types using a modular master protocol.

Patients: Adults (≥18 years) with documented advanced or metastatic solid tumors, ECOG 0–1, adequate organ function, and at least one measurable lesion (nonmeasurable bone-only disease allowed in mCRPC). Tumor cohorts include endometrial, gastric, metastatic castration-resistant prostate, ovarian, colorectal, urothelial, and biliary tract cancers. Key exclusions include active/untreated CNS disease, uncontrolled infections (including active HBV/HCV, TB), significant cardiac risk/QT prolongation, prior TROP2-directed therapies or deruxtecan-based ADCs, clinically significant ILD/pneumonitis history, and uncontrolled comorbidities.

Design: Phase II, multicenter, open-label, nonrandomized master protocol with independent tumor- and regimen-specific substudies. Uncontrolled cohorts assess safety, preliminary efficacy, and dose selection for monotherapy and combinations within each disease setting.

Treatments: Dato-DXd is investigated across all substudies as monotherapy or in combination. Dato-DXd is an anti-TROP2 antibody-drug conjugate linked to a topoisomerase I inhibitor (DXd) via a cleavable linker; it delivers intracellular cytotoxic payload after TROP2-mediated internalization with potential bystander effect. In the phase III TROPION-Lung01 study versus docetaxel in previously treated NSCLC, Dato-DXd improved PFS (median 4.4 vs 3.7 months; HR 0.75) and ORR (26.4% vs 12.8%) with a manageable safety profile; OS was not statistically superior. In HR+/HER2- metastatic breast cancer, a phase III trial met PFS but not OS significance; ILD/pneumonitis remains an adverse event of special interest. Combinations under evaluation include: with capecitabine or 5-FU in gastric and colorectal cancer; with bevacizumab ± platinum (carboplatin) in ovarian and colorectal cancer; with prednisone/prednisolone in mCRPC; with platinum (carboplatin or cisplatin) in urothelial cancer; and with novel immunotherapies in urothelial cancer. Volrustomig (MEDI5752) is a bispecific PD-1/CTLA-4 antibody designed to enhance intratumoral checkpoint blockade with potentially reduced peripheral toxicity; early-phase data show promising activity, particularly in RCC, with dose-dependent immune-related AEs. Rilvegostomig (AZD2936) is a bispecific PD-1/TIGIT antibody engineered with reduced Fc effector function; phase I data in pretreated NSCLC show tolerability and disease control with a 750 mg Q3W RP2D.

Outcomes: Primary endpoints: objective response rate per RECIST 1.1 across most cohorts; safety and serious adverse events; PSA50 response in the mCRPC substudy; and PFS in the ovarian combination substudy. Secondary endpoints include PFS, duration of response, disease control rate at 12 and 24 weeks, best percentage change in tumor size, pharmacokinetics (Cmax, Tmax, AUC) of Dato-DXd and, in urothelial combinations, volrustomig and rilvegostomig; anti-drug antibodies; total anti-TROP2 antibody and MAAA-1181a levels; rPFS, PSA progression (mCRPC); CA-125 response and overall survival (ovarian).

Burden on patient: Moderate to high. Participants will undergo mandatory baseline tumor tissue submission and serial imaging for response assessments. Open-label Phase II substudies typically require frequent clinic visits, safety labs, and adverse event monitoring; combinations add infusion chair time for multi-agent regimens. Pharmacokinetic and immunogenicity sampling across cycles increases blood draw frequency, especially in early cycles and in immunotherapy combination cohorts. Ovarian and colorectal bevacizumab- and platinum-containing arms, and urothelial platinum combinations, entail additional infusion visits and toxicity monitoring. Monitoring for ILD/pneumonitis with clinical assessments and potential imaging adds vigilance. Travel and time burdens are higher than standard single-agent therapy, though generally consistent with combination/ADC trial expectations over approximately one year of follow-up.

Eligibility

Show Criteria

Key Inclusion Criteria:

* Male and female, ≥ 18 years

* Documented advanced or metastatic malignancy

* Eastern Cooperative Oncology Group performance status of 0 or 1 with no deterioration over the 2 weeks prior to baseline or day of first dosing

* All participants must provide a tumour sample for tissue-based analysis

* At least 1 measurable lesion not previously irradiated, except Substudy 3 (Prostate Cancer) which allows participants with non measurable bone metastatic disease

* Adequate bone marrow reserve and organ function

* Minimum life expectancy of 12 weeks

* At the time of screening, contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies

* All women of childbearing potential must have a negative serum pregnancy test documented during screening

* Female participants must be 1 year post-menopausal, surgically sterile, or using 1 highly effective form of birth control. Female participants must not donate, or retrieve for their own use, ova at any time during this study

* Male participants who intend to be sexually active with a female partner of childbearing potential must be surgically sterile, avoid intercourse, or use a highly effective method of contraception. Male participants must not freeze or donate sperm at any time during this study.

* Capable of giving signed informed consent

* Provision of signed and dated written optional genetic research informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative

Key Exclusion Criteria:

* Any evidence of diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol

* History of another primary malignancy except for adequately resected basal cell carcinoma or in situ squamous cell carcinoma of the skin, or other solid malignancy treated with curative intent

* Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved

* Irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator, for example hearing loss

* Spinal cord compression or brain metastases unless treated

* Leptomeningeal carcinomatosis

* Clinically significant corneal disease

* Active hepatitis or uncontrolled hepatitis B or C virus infection

* Uncontrolled infection requiring IV antibiotics, antivirals or antifungals, for example prodromal symptoms

* Known HIV infection that is not well controlled

* Known active tuberculosis infection

* Mean resting corrected QTcF \> 470 ms

* In the judgement of the investigator, history of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause TdP

* In the judgement of the investigator, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives

* Uncontrolled or significant cardiac diseases

* History of non-infectious Interstitial lung disease (ILD)/pneumonitis that required steroids

* Has severe pulmonary function compromise

* Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period

* Receipt of live, attenuated vaccine within 30 days prior to the first dose of study intervention

* Prior exposure to anticancer therapies without an adequate treatment washout period prior to enrolment or any concurrent anticancer treatment

* Palliative radiotherapy with a limited field of radiation within ≤ 2 weeks or to more than 30% of the bone marrow within ≤ 4 weeks before the first dose of study intervention

* Major surgical procedure or significant traumatic injury within ≤ 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study

* Prior treatment with TROP2-directed therapies or other antibody-drug conjugate (ADCs) with deruxtecan payload

* Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention

* Previous treatment in the present study

* Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to first dose of study intervention or concurrent enrolment in another clinical study

* Severe hypersensitivity to Dato-DXd or any of the excipients, including but not limited to polysorbate 80 or other monoclonal antibodies

* Involvement in the planning and/or conduct of the study

* Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements

* Females that are pregnant, breastfeeding, or planning to become pregnant

Trial Details

Show Summary from Sponsor

More details:

Investigational Drug AI Analysis

Show for: Datopotamab deruxtecan (Dato-DXd, DS-1062)

Overview

Mechanism of Action

Efficacy

Safety

Further Reading

Show for: Volrustomig (MEDI5752, PD-1/CTLA-4 DuetMab, MEDI-5752)

Overview

Mechanism of Action

Efficacy

Safety

Further Reading

Show for: Rilvegostomig (AZD2936)

Overview

Mechanism of Action

Efficacy

Safety

Further Reading

HealthScout AI Analysis

Eligibility

Show Criteria

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