What side effects are associated with this type of intervention?

Common treatments for Non-Small Cell Lung Cancer (NSCLC), particularly antibody-drug conjugates (ADCs) like HER3-DXd, often result in side effects such as fatigue, nausea, and increased liver function tests. Specific severe side effects reported include cardiac failure and pulmonary hemorrhage. Other targeted therapies, such as EGFR inhibitors, may cause rash, diarrhea, and interstitial lung disease. Additionally, treatments like ramucirumab can lead to bleeding, hypertension, and rare cases of intestinal perforation and arterial thrombosis.

What prior FDA approvals exist?

For the treatment of Non-Small Cell Lung Cancer (NSCLC), the FDA has approved several antibody-drug conjugates (ADCs) and targeted therapies. One notable ADC is fam-trastuzumab deruxtecan, approved for patients with unresectable or metastatic NSCLC with HER2 mutations who have received prior systemic therapy. Another ADC, ado-trastuzumab emtansine, has shown efficacy in HER2-mutant advanced lung cancer. These treatments, like HER3-DXd, deliver cytotoxic agents directly to cancer cells by targeting specific receptors, in this case, HER2. Additionally, other targeted therapies such as tyrosine kinase inhibitors (TKIs) are used for NSCLC with specific genetic mutations, including EGFR and ALK inhibitors.

What other types of research exist?

Promising alternatives to HER3-DXd for NSCLC patients include: 1) Selpercatinib and pralsetinib for RET fusion-positive tumors, 2) Dacomitinib for KRAS wild-type NSCLC, 3) Pembrolizumab combined with chemotherapy for advanced nonsquamous NSCLC, and 4) Enfortumab vedotin for metastatic urothelial carcinoma with potential application in NSCLC. These therapies have shown efficacy in clinical trials and represent novel approaches for treating NSCLC.

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Antibody-Drug Conjugate

U3-1402 for Non-Small Cell Lung Cancer

Phase 1

Recruiting

Research Sponsored by Daiichi Sankyo

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Has documentation of EGFR-activating mutation(s) detected from tumor tissue: G719X, exon deletion 19, L858R, or L861Q (Cohorts 1, 3a, 3b, and 4 of Dose Expansion)

Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib

Must not have

Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in Screening biopsy performed after progression

Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval

Timeline

Screening 3 weeks

Treatment Varies

Follow Up approximately within 36 months

Awards & highlights

Summary

This trial is testing HER3-DXd, a new drug for advanced lung cancer patients who haven't responded to other treatments. The drug targets a protein on cancer cells and delivers a toxic substance to destroy them.

Who is the study for?

This trial is for adults with advanced or inoperable non-small cell lung cancer (NSCLC) who have previously been treated with EGFR tyrosine kinase inhibitors. Participants must have at least one measurable lesion, be in good physical condition (ECOG status of 0 or 1), and not have other active cancers or serious heart conditions.

What is being tested?

The study tests U3-1402, a new drug for NSCLC. It has two parts: Dose Escalation to find the safe dosage for those with an EGFR mutation after TKI therapy failure, and Dose Expansion to assess effectiveness in broader NSCLC cases post systemic treatment failure.

What are the potential side effects?

While specific side effects are not listed here, common ones may include fatigue, nausea, skin reactions at the injection site, allergic reactions to the drug components, and potential impacts on blood pressure and heart rhythm.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My cancer has a specific EGFR mutation.

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I am currently taking a specific cancer medication but can stop if needed.

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I am fully active or restricted in physically strenuous activity but can do light work.

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My lung cancer cannot be cured with surgery or radiation.

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I benefited from EGFR treatment but my cancer progressed while still on it.

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I have been treated with a platinum-based chemotherapy for my advanced cancer.

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My cancer progressed after treatment with an EGFR inhibitor.

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My cancer progressed despite treatment with specific lung cancer medications.

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My cancer has worsened after my last treatment.

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My lung cancer is confirmed to be adenocarcinoma type.

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My lung cancer is confirmed by lab tests and does not have EGFR mutations.

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My lung cancer is confirmed to be adenocarcinoma type.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My cancer biopsy shows small cell or mixed small cell and non-small cell features.

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I cannot or will not stop taking medications that may affect my heart's rhythm.

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I had a heart attack in the last 6 months.

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I have heart issues like failure, recent unstable angina, or arrhythmia needing treatment.

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I have or might have a lung condition called interstitial lung disease.

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I have a serious eye condition affecting my cornea.

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I haven't taken any cancer drugs or been in a trial recently.

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I have spinal cord compression or brain metastases needing steroids or seizure meds.

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I have a condition where cancer has spread to the lining of my brain and spinal cord.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ approximately within 36 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~approximately within 36 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and approximately within 36 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) Committee during dose expansion (Cohorts 1, 2, 3a, 3b, and 5)

Secondary study objectives

Mean Change from Baseline in the NSCLC-SAQ Total Score (Cohort 5)

Overall response rate (ORR) by Investigator during dose expansion (Cohorts 1-5)

Overall response rate (ORR) during dose escalation

Trial Design

10Treatment groups

Experimental Treatment

Group I: Dose Expansion: Cohort 5, KRAS-G12C mutant NSCLCExperimental Treatment1 Intervention

Participants with locally advanced or metastatic NSCLC harboring a KRAS-G12C mutation after progression on the most recent line of therapy will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks.

Group II: Dose Expansion: Cohort 4, EGFR mutantExperimental Treatment1 Intervention

Participants with NSCLC (including any histology other than small-cell or combined small-cell and non-small cell) with an EGFR-activating mutation will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks.

Group III: Dose Expansion: Cohort 3b, EGFR mutantExperimental Treatment1 Intervention

Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3b will receive HER3-DXd IV once every three weeks following an up-titration regimen (Cycle 1, Day 1: 57% of RDE or aRDE; Cycle 2, Day 1: 86% of RDE or, if applicable aRDE; Cycle 3 and subsequent cycles, Day 1: 114% of RDE or aRDE).

Group IV: Dose Expansion: Cohort 3a, EGFR mutantExperimental Treatment1 Intervention

Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3a will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE) or, if applicable, adjusted RDE (aRDE).

Group V: Dose Expansion: Cohort 2, EGFR wild-typeExperimental Treatment1 Intervention

Participants with squamous or non-squamous NSCLC without EGFR-activating mutations in the Dose Expansion Cohort 2 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE).

Group VI: Dose Expansion: Cohort 1, EGFR mutantExperimental Treatment1 Intervention

Participants with adenocarcinoma NSCLC with EGFR mutations in the Dose Expansion Cohort 1 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE).

Group VII: Dose Escalation: Cohort 4, 6.4 mg/kgExperimental Treatment1 Intervention

Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 6.4 mg/kg.

Group VIII: Dose Escalation: Cohort 3, 5.6 mg/kgExperimental Treatment1 Intervention

Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 5.6 mg/kg.

Group IX: Dose Escalation: Cohort 2, 4.8 mg/kgExperimental Treatment1 Intervention

Participants in Dose Escalation Cohort 2 will receive HER3-DXd intravenously (IV) once every three weeks at 4.8 mg/kg.

Group X: Dose Escalation: Cohort 1, 3.2 mg/kgExperimental Treatment1 Intervention

Participants in the Dose Escalation Cohort 1 will receive HER3-DXd intravenously (IV) once every three weeks at 3.2 mg/kg.

0 / 21Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Non-Small Cell Lung Cancer (NSCLC) include targeted therapies like antibody-drug conjugates (ADCs). ADCs, such as HER3-DXd, work by combining monoclonal antibodies that specifically target proteins overexpressed on cancer cells (e.g., HER3) with potent cytotoxic agents. This targeted delivery allows for direct attack on the tumor cells while sparing healthy tissues, which can enhance treatment effectiveness and reduce side effects. This approach is particularly important for NSCLC patients, as it offers a more precise and potentially less toxic treatment option compared to conventional chemotherapy.

High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas.