Eligibility requires locally advanced/metastatic NSCLC (RECIST v1.1 measurable lesions, ECOG 0-1). Dose escalation mandates EGFR TKI resistance (Jackman criteria), while expansion cohorts specify prior therapies (e.g., platinum-based regimens, KRAS-G12C inhibitors in Cohort 5). Exclusions include ILD, uncontrolled CVD, active infections, recent cytotoxic therapy, or contraindications like QT prolongation. Cohort-specific exclusions apply (e.g., EGFR mutations in Cohort 2, leptomeningeal disease in Cohort 4).

The study evaluates dose-limiting toxicities (DLTs) over 21 days in the dose-escalation phase and adverse event summaries over approximately 36 months. Efficacy measures include ORR (using RECIST v1.1 via BICR) during dose expansion. Pharmacokinetic endpoints-Cmax, AUCinf, and AUC (last)-for HER3-DXd, total anti-HER3, and MAAA-1181a are assessed across cycles with intensive blood sampling (pre-dose to Day 15).

Secondary outcomes include pharmacokinetics (Cmax, Tmax, AUC[0-21]) during dose escalation and efficacy metrics (ORR, DCR, DOR, TTR, PFS, OS) monitored over ~36 months. Dose expansion tracks similar endpoints over ~60 months, including NSCLC-SAQ symptom severity scores and PRO-CTCAE analyses to assess symptom progression. ADA status and PK parameters are also evaluated in specific cohorts.

Exclusion criteria include small cell or mixed histology NSCLC, active interstitial lung disease, uncontrolled respiratory conditions, symptomatic brain/spinal cord metastases, or inadequate washout periods (e.g., <14 days for chemo, <28 days for major surgery). Prior HER3 antibodies, topoisomerase I inhibitors, or ADCs containing such inhibitors are prohibited. Unresolved toxicities (>Grade 1), active secondary malignancies (except certain cured cancers), uncontrolled cardiovascular disease, or active HBV/HCV/HIV infections also exclude participation. Chronic systemic corticosteroids >10 mg prednisone/day or leptomeningeal disease are additional exclusions.

The primary objective is to assess Objective Response Rate (ORR) by BICR per RECIST v1.1, defined as the proportion of participants achieving confirmed CR (disappearance of all target lesions) or PR (≥30% decrease in sum of diameters) from screening until progression, death, or study discontinuation (up to ~21 months). Secondary endpoints include Duration of Response (time from first confirmed response to progression/death), Progression-Free Survival (time from treatment start to PD/death), ORR by investigator, Disease Control Rate (CR+PR+SD), Time to Tumor Response, and Best Percentage Change in Sum of Diameters of measurable tumors. Overall Survival will track from treatment start to death (up to ~45 months). Safety will be evaluated through Treatment-Emergent AEs, SAEs, and AESIs from baseline to Day 47 post-last dose.

Eligible participants must be ≥18 years with histologically confirmed advanced/metastatic NSCLC progressing after osimertinib and platinum-based chemotherapy, harboring EGFR exon 19 or L858R mutations, and having ≥1 measurable lesion per RECIST v1.1. Required tumor tissue includes fresh biopsy or archival specimen obtained within 3 months post-progression. ECOG 0-1 and adequate organ function (platelets ≥100K/mm ³, hemoglobin ≥9 g/dL, ANC ≥1500/mm ³, creatinine clearance ≥30 mL/min, and liver function within specified limits) are mandatory.

Eligible patients must have HER3-positive advanced/metastatic breast cancer, ECOG 0-1, LVEF &ge;50%, and measurable disease (RECIST 1.1). Dose expansion requires prior taxane therapy (except TNBC cohort), while TNBC patients need HR-/HER2- status and 1-2 prior lines. Exclusions include prior HER3/ADC treatment (e.g., exatecan-based), severe cardiac/pulmonary disease, or corrected QT prolongation (>450ms males, >470ms females).

In DE/DF, U3-1402 was administered intravenously (IV) Q2W or Q3W at doses ranging from 1.6 to 8.0 mg/kg. Patients had HER3-expressing advanced/unresectable disease refractory/intolerant to standard treatment or for which no standard treatment was available. In the expansion part, U3-1402 was administered IV Q3W to patients with HER3-high (4.8 or 6.4 mg/kg) or HER3-low (6.4 mg/kg) HR+/HER2- MBC or with HER3-high triple-negative breast cancer (TNBC; 6.4 mg/kg).

The primary safety and efficacy endpoints include the incidence of Treatment-emergent Adverse Events (TEAEs) up to 28 days post-last dose and Best Overall Response (CR, PR, or SD per RECIST 1.1) assessed via blinded independent review. ORR is defined as confirmed CR/PR, while SD indicates neither sufficient shrinkage nor progression (≥20% increase).

Clinical assessments span from baseline through treatment and follow-up, evaluating pathological, molecular (CelTIL/HER3/Ki67), and QoL outcomes. Safety monitoring includes AEs, lab abnormalities, and protocol compliance until 30 days post-surgery. The study emphasizes strict eligibility around treatment history and comorbidities to ensure patient suitability for neoadjuvant therapy and surgery.

The primary endpoint is pCRBL rate (ypT0/is ypN0) at surgery, indicating complete absence of invasive carcinoma in the breast and lymph nodes. Secondary endpoints include Residual Cancer Burden (RCB) categories, pCRB (breast-only response), tumor ORR per RECIST v1.1, iDFS at 3/5 years (covering recurrence types), CelTIL score changes, HER3/ERBB3 expression, Ki67 changes, Quality of Life via EORTC-BR45/QLQ-C30, and safety with AE monitoring per NCI CTCAE v5.0.

Inclusion criteria: Untreated, non-metastatic ER+/PgR+/HER2- breast adenocarcinoma with Ki67≥20% or high genomic risk, ECOG 0-1, chemotherapy/surgery eligibility, tumor sample availability, adequate organ function, and LVEF≥50%. Exclusion criteria: Metastatic/bilateral cancer, prior treatments (chemo/radiation/anti-HER3/topoisomerase inhibitors), excisional biopsy, cardiac/pulmonary diseases, other malignancies (exceptions apply), uncontrolled systemic conditions, infections (HIV/hepatitis), hypersensitivity to drug components, high anthracycline exposure, ILD history, unresolved toxicities (>grade 1), neuropathy, chronic steroids (>10mg prednisone), corneal disease, pregnancy, or hydroxychloroquine use within 14 days.

Eligible patients must have prior T-DXd progression, HER2+/HER2-low breast cancer, measurable lesions, and adequate organ function. Exclusions include ILD, uncontrolled systemic diseases, active brain metastases, unresolved toxicities, significant cardiovascular disorders, active HBV/HCV, pregnancy, or prior anti-HER3 therapy. Contraception and washout periods per protocol are mandatory.

Eligible participants must have HER2+ locally advanced or metastatic breast cancer, meet specific HIV/HBV/HCV and ECOG criteria, and have prior anti-HER2 therapy history (varying by study arm). Exclusion criteria include uncontrolled cardiovascular/pulmonary disease, active infections, prior HER2-targeted TKIs (Arm 3), and certain malignancies or neurological conditions.

Eligible participants have locally advanced TNBC/HR-low+/HER2- breast cancer (AJCC stages cT1c-T4/N0-N2), controlled HBV/HCV, ECOG 0-1, and LVEF &ge;50%/LLN. Exclusions include prior anti-PD-1/L1/HER3 therapy, active malignancies, CNS metastases, ILD, uncontrolled infections, or cardiovascular/corneal disease. Metastatic (M1) or cN3 disease is excluded.

An Open-label Randomized Phase 2 Study to Evaluate Safety and Efficacy of Patritumab Deruxtecan Plus Pembrolizumab Administered Either Before or After Carboplatin/Paclitaxel Plus Pembrolizumab Compared With Pembrolizumab in Combination With Chemotherapy Followed by Surgery and Adjuvant Pembrolizumab for High-Risk Early-Stage Triple-Negative or Hormone Receptor-Low Positive/Human Epidermal Growth Factor Receptor-2 Negative Breast Cancer (HERTHENA-Breast03)

Eligible patients are adults (&ge;18y) with untreated, non-metastatic HR+/HER2- or TNBC (ASCO-CAP criteria), measurable lesions (&ge;1cm), Ki67&ge;10%, LVEF&ge;50%, and adequate organ function. Exclusions include prior HER3/topoisomerase I inhibitor therapy, cardiac/pulmonary disorders, unresolved grade&ge;2 toxicity, QT prolongation, active infections, or concurrent malignancies (exceptions: cured cancers in past 3 years).

Eligible adults (&ge;18y) with HER2- (Parts A/B: 1-5 prior chemo lines, endocrine/CDK4/6i-refractory HR+) or HER2+ MBC (Part Z: &ge;2 anti-HER2 therapies including trastuzumab deruxtecan) must have measurable disease, ECOG 0-1, and adequate organ function. Key exclusions: prior HER3-targeted therapy, unresolved Grade>1 toxicity (except alopecia), active brain metastases/ILD, LVEF<50%, or severe cardiovascular/pulmonary conditions. HER2+ cohorts prohibit other exatecan ADCs (non-trastuzumab deruxtecan).

Exclusion criteria include curative-intent resectable disease, interstitial lung disease, uncontrolled systemic illnesses, active brain metastases, inadequate washout periods for prior therapies, cardiovascular risks (QT prolongation, LVEF <50%, recent MI), active HBV/HCV/HIV infections, pregnancy/breastfeeding, hypersensitivity to study drugs, and concurrent experimental treatments. Participants must not have unresolved grade &ge;2 toxicities (except alopecia) or other primary malignancies within 3 years (exceptions: cured non-melanoma skin cancer or in-situ lesions). Legal or psychological barriers to protocol compliance also disqualify.

The primary outcome is the investigator-assessed objective response rate (ORR), defined as the proportion of participants achieving complete response (CR) or partial response (PR), measured over an average of 8 months during treatment. Secondary outcomes include duration of response (DOR), progression-free survival (PFS), and clinical benefit ratio (CBR), all assessed by investigators and central review over up to 42 months. Safety endpoints cover adverse events, lab abnormalities, ECG changes, and quality of life measures via EORTC QLQ-C30 and ECOG performance status. Additional efficacy metrics include overall survival (OS) and central-review ORR.

Eligible participants are adults with histologically confirmed HER2-negative, hormone receptor-positive (HR+), unresectable locally advanced or metastatic breast cancer who progressed after CDK4/6 inhibitor therapy with endocrine treatment. Key requirements include accessible tumor biopsy sites, measurable lesions, ECOG PS 0-1, life expectancy ≥12 weeks, adequate organ function, and compliance with contraception protocols. Prior treatments may include anthracyclines, taxanes, PI3K/mTOR/AKT inhibitors, or PARP inhibitors, but only one line of chemotherapy for advanced disease is permitted.

Eligibility requires &ge;18y/o patients with advanced/metastatic disease progression after prior therapies (1-3 lines depending on tumor type), ECOG 0-1. Exclusions include HER2+ gastric cancer, active ILD, recent malignancies (except cured carcinomas), prior HER3/TOP1-ADC treatment, and metastatic irinotecan exposure. Tumor tissue confirmation and biomarker status (e.g., HPV, HER2) are mandated per protocol-specific thresholds.

This study evaluates HER3-DXd monotherapy efficacy in various cancer cohorts (excluding prostate cancer) with primary endpoints including confirmed objective response rate (ORR) per RECIST v1.1 and PSA reduction ≥50% (prostate cohort only), assessed over 27 months. ORR combines complete (CR) and partial response (PR) rates, while prostate-specific outcomes focus on biochemical markers.

Safety and efficacy assessments cover all cohorts, tracking treatment-emergent adverse events (graded via NCI-CTCAE v5.0), duration of response (DoR), clinical benefit rate (CR+PR+SD≥183d), and pharmacokinetics (Cmax, Tmax, AUC). The prostate cohort adds PCWG3-based radiographic PFS, time to first skeletal event, and subsequent therapy metrics over 27 months, with intensive PK sampling during cycles 1-8.

Eligible participants (&ge;18y/o, ECOG 0-1) must have progressed on &ge;2 prior lines including fluoropyrimidine/irinotecan/anti-EGFR/VEGF therapies, with measurable lesions and adequate organ function. Key exclusions: active ILD, uncontrolled cardiovascular disease, untreated CNS metastases, unresolved CTCAE Grade &ge;2 toxicities, prior HER3/exatecan-ADC exposure, or HIV/HBV/HCV viremia outside protocol-permitted thresholds. Tumor tissue requirements mandate pretreatment biopsy unless recent archival samples exist.

The study evaluates U3-1402 in advanced/metastatic colorectal cancer, assessing primary endpoints including blinded independent central review (BICR)-confirmed ORR (CR+PR per RECIST v1.1) and investigator-assessed efficacy outcomes (ORR, DoR, DCR) over 27 months, with tumor response metrics capturing both radiographic and clinical progression events.

Secondary objectives include safety profiling (TEAEs, lab abnormalities), pharmacokinetics (Cmax, Tmax, AUClast), and immunogenicity (ADA incidence), with intensive PK sampling during cycles 1-8. Disease control parameters (PFS by BICR/investigator, OS) and biomarker analyses (HER3 expression) are tracked alongside protocol-defined washout periods for prior therapies.

Key inclusion criteria involve unresectable/metastatic colorectal cancer, biliary tract cancer (BTC), or hepatocellular carcinoma (HCC), with prior therapy and recovery from treatment side effects. Exclusion criteria cover interstitial lung disease (ILD), severe respiratory compromise, leptomeningeal disease, corneal disease, uncontrolled cardiovascular/cerebrovascular conditions, or active systemic infections, ensuring patient safety in the study.

The primary endpoints include Dose-Limiting Toxicity (DLT) evaluated over 21 days in the dose-escalation phase, Adverse Events (AEs) monitored over approximately 45 months, and participants discontinuing treatment due to AEs. Additionally, Objective Response Rate (ORR) per RECIST 1.1 via Blinded Independent Central Review (BICR) will assess Complete Response (CR) or Partial Response (PR) rates. All endpoints aim to evaluate safety and efficacy.

Secondary endpoints include Duration of Response (DOR) and Progression-Free Survival (PFS) using RECIST 1.1 criteria (assessed by BICR), measuring time to progressive disease (PD) or death. Overall Survival (OS) tracks time from treatment initiation until death. Pharmacokinetic endpoints include maximum plasma concentration (Cmax) and trough concentration (Ctrough) of patritumab deruxtecan, measured at designated time points over ~45 months. These metrics evaluate treatment efficacy and drug exposure.

Eligibility requires untreated Stage IV NSCLC (squamous/nonsquamous) with archived tumor tissue. Exclusions include prior systemic therapy for metastatic disease, uncontrolled CNS metastases, active autoimmune/immunodeficiency conditions, recent major surgery/radiotherapy (>30Gy to lungs), live vaccines (excluding licensed COVID-19 vaccines), or severe irAEs from prior immunotherapy. GI/liver dysfunction affecting drug absorption and unresolved prior treatment toxicities (>CTCAE Grade 1) also preclude enrollment.

Exclusion criteria include small-cell histology, active ILD/pneumonitis, untreated brain metastases, unresolved Grade &ge;2 toxicities, uncontrolled cardiovascular disease (QTcF >450 ms, LVEF &le;45%, recent MI), strong CYP3A4 inducers, recent radiation/immunotherapy, prior malignancies (exceptions: non-melanoma skin cancer, curatively treated early-stage tumors), and poorly controlled HIV. Concomitant conditions jeopardizing protocol compliance also exclude participation.

The study evaluates dose-limiting toxicities (DLTs), treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events of special interest (AESIs) during dose escalation, classified per NCI-CTCAE v5.0. Objective response rate (ORR) is assessed in dose expansion phases, defined as confirmed CR or PR by RECIST v1.1 via blinded independent central review (BICR). Additional endpoints include duration of response (DoR), clinical benefit rate (CBR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS), immunogenicity (ADA assessment), and pharmacokinetic parameters (Cmax, Tmax, AUC).

Key inclusion criteria for dose escalation and second-line expansion include confirmed EGFR exon 19del/L858R mutations, prior osimertinib treatment (≥6 weeks) with progression. First-line expansion requires untreated EGFR-mutant NSCLC eligible for osimertinib. All participants must have measurable disease per RECIST v1.1, adequate organ function, and provide tumor tissue (pre-/on-treatment biopsies for certain cohorts).

Inclusion criteria require signed consent, age &ge;18, confirmed EGFRm NSCLC with progression post EGFR TKI (including osimertinib) and platinum-based chemotherapy, ECOG PS 0-1, adequate organ function, and contraception compliance. For resupply, continued treatment benefit and safety reporting are mandatory. Exclusion criteria include participation in Daiichi Sankyo ADC trials, small cell histology, active/past ILD, severe respiratory compromise, unresolved toxicities (Grade >1), uncontrolled cardiovascular disease, active HBV/HCV/HIV, HER3-DXd hypersensitivity, pregnancy, clinically significant infections, or corneal disease.

Eligible patients must have stage IV NSCLC (squamous/non-squamous), ECOG 0-1, available tumor tissue, and controlled HIV/HBV if applicable. Key exclusions include small cell histology, EGFR/ALK/ROS1 alterations (squamous), active CNS metastases, uncontrolled cardiovascular disease (recent MI, NYHA 3-4 CHF), prior topoisomerase I inhibitors/anti-HER3 ADCs, recent radiotherapy/vaccines, concurrent HBV/HCV, immunosuppressive therapy, or active autoimmune disease/infections requiring treatment. Washout periods for prior therapies and adequate recovery from major surgery are required.

Key exclusions include small cell/mixed histology, active ILD, uncontrolled respiratory conditions, symptomatic brain/spinal metastases, prior HER3 antibodies/topoisomerase I ADCs, other systemic therapies beyond EGFR TKIs in metastatic setting, active HBV/HCV/HIV, or secondary malignancies (excluding cured non-melanoma skin/cervical cancers). Chronic steroids >10 mg prednisone/day or leptomeningeal disease are excluded. Cardiovascular instability and clinically significant corneal disease also preclude participation.

The primary endpoint is Progression-Free Survival (PFS) per BICR, measured from randomization to first documented disease progression or death (up to ~49 months). Secondary efficacy outcomes include Overall Survival (OS), PFS by investigator/local practice, Objective Response Rate (CR+PR), Duration of Response (time from first response to progression/death), and Clinical/Disease Control Rates (CR+PR±SD). Intracranial PFS will be assessed by BICR per CNS-RECIST in patients with baseline CNS lesions. Patient-reported outcomes include NSCLC symptom burden (NSCLC-SAQ), QoL (EORTC-QLQ-C30, EQ-5D-5L), and treatment tolerability (PGI scales). Safety will evaluate TEAEs (CTCAE v5.0) and immunogenicity (ADA incidence).

Eligible patients must be ≥18 years with confirmed metastatic/locally advanced non-squamous EGFR-mutant NSCLC (exon 19del/L858R) progressing after 1-2 prior EGFR TKIs (including 3rd-gen TKI). Prior neoadjuvant/adjuvant therapy is allowed if recurrence occurred >12 months post-treatment. Patients must have ≥1 measurable lesion per RECIST v1.1, ECOG 0-1, and adequate organ function (platelets ≥100K/mm ³, ANC ≥1500/mm ³, Hb ≥9 g/dL, CrCl ≥45 mL/min, liver enzymes ≤3×ULN). Archival/fresh tumor tissue is required.

Eligible participants include adults (&ge;18) with locally advanced/metastatic NRG1 fusion-positive solid tumors, measurable lesions per RECIST v1.1, ECOG PS 0-1, and adequate organ function. Key exclusions involve interstitial lung disease, uncontrolled cardiovascular conditions, active hepatitis B/C, unresolved prior toxicities, certain recent treatments, and other active malignancies.

In dose escalation phase, pts with metastatic or unresectable non-small cell lung cancer (NSCLC) with EGFR activating mutation after disease progression during/after EGFR TKI therapy; In Dose Expansion phase, pts with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC with disease progression during/after systemic treatment for locally advanced or metastatic disease.