The primary endpoint was the incidence of DLTs occurring during the first two cycles (4 weeks) of study drug administration. DLTs (reversible grade 3 microcystic keratopathy) occurred in three of eight patients treated with tusamitamab ravtansine 12.00 mg/m² and in two of three patients treated with 15.00 mg/m². The maximum tolerated dose was identified as 10.00 mg/m².

Three patients (9.68%) had objective responses [all confirmed partial responses (PRs) with durations of 2.60, 6.10, and 4.00 months]; 11 patients (35.48%) had stable disease, and 13 patients (41.94%) had progressive disease. Objective responses were achieved in two of six patients (33.33%) at a DL of 10.0 mg/m², and in one of nine patients (11.11%) at 12.0 mg/m² with maximum reduction in RECIST target lesions of 32.30%-51.20%.

Key inclusion criteria: metastatic NSQ NSCLC patients (post-platinum/IO) with moderate/negative CEACAM5 expression (IHC 2+ in 1-50% or 1+ tumors) plus CEA ≥100 ng/mL, measurable lesions, ECOG 0-1. Major exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved grade ≥2 toxicity (except alopecia/vitiligo), corneal disorders, contact lens use, or poor organ function. Reproductive-age participants require contraception.

The study assesses efficacy through Objective Response Rate (ORR), defined as the percentage of participants achieving confirmed complete response (CR, disappearance of all target lesions and lymph nodes <10mm) or partial response (PR, ≥30% reduction in target lesion sum) per RECIST v1.1, evaluated at baseline and every 8 weeks (±7 days) over approximately 46 weeks.

Safety analyses include treatment-emergent adverse events (TEAEs/SAEs) recorded from first dose until primary completion (~21 months). Secondary efficacy endpoints - Progression-Free Survival (PFS), Disease Control Rate (DCR), and Duration of Response (DOR) - all follow RECIST v1.1 criteria, with PD requiring ≥20% (minimum 5mm absolute) increase in target lesions or new lesions, assessed every 8 weeks over 46 weeks.

Key inclusion criteria: metastatic NSQ NSCLC patients (post-platinum/IO) with moderate/negative CEACAM5 expression (IHC 2+ in 1-50% or 1+ tumors) plus CEA &ge;100 ng/mL, measurable lesions, ECOG 0-1. Major exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved grade &ge;2 toxicity (except alopecia/vitiligo), corneal disorders, contact lens use, or poor organ function. Reproductive-age participants require contraception.

The study assesses efficacy through Objective Response Rate (ORR), defined as the percentage of participants achieving confirmed complete response (CR, disappearance of all target lesions and lymph nodes <10mm) or partial response (PR, ≥30% reduction in target lesion sum) per RECIST v1.1, evaluated at baseline and every 8 weeks (±7 days) over approximately 46 weeks.

Safety analyses include treatment-emergent adverse events (TEAEs/SAEs) recorded from first dose until primary completion (~21 months). Secondary efficacy endpoints - Progression-Free Survival (PFS), Disease Control Rate (DCR), and Duration of Response (DOR) - all follow RECIST v1.1 criteria, with PD requiring ≥20% (minimum 5mm absolute) increase in target lesions or new lesions, assessed every 8 weeks over 46 weeks.

Key inclusion criteria: metastatic NSQ NSCLC patients (post-platinum/IO) with moderate/negative CEACAM5 expression (IHC 2+ in 1-50% or 1+ tumors) plus CEA &ge;100 ng/mL, measurable lesions, ECOG 0-1. Major exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved grade &ge;2 toxicity (except alopecia/vitiligo), corneal disorders, contact lens use, or poor organ function. Reproductive-age participants require contraception.

The study assesses efficacy through Objective Response Rate (ORR), defined as the percentage of participants achieving confirmed complete response (CR, disappearance of all target lesions and lymph nodes <10mm) or partial response (PR, ≥30% reduction in target lesion sum) per RECIST v1.1, evaluated at baseline and every 8 weeks (±7 days) over approximately 46 weeks.

Safety analyses include treatment-emergent adverse events (TEAEs/SAEs) recorded from first dose until primary completion (~21 months). Secondary efficacy endpoints - Progression-Free Survival (PFS), Disease Control Rate (DCR), and Duration of Response (DOR) - all follow RECIST v1.1 criteria, with PD requiring ≥20% (minimum 5mm absolute) increase in target lesions or new lesions, assessed every 8 weeks over 46 weeks.

Eligibility required metastatic disease progression post-platinum chemotherapy and PD-1/PD-L1 inhibitors, CEACAM5 expression &ge;2+, measurable lesions (RECIST v1.1), and ECOG 0-1. Exclusion criteria included untreated brain metastases, major comorbidities, active infections, uncontrolled hypertension, prior treatments targeting CEACAM5 or maytansinoids, and severe organ dysfunction. Specific Triplet Cohort exclusions included autoimmune diseases, transplant history, interstitial lung disease, or recent live vaccines.

Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Tusamitamab Ravtansine (SAR408701) Used in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Metastatic, Non-squamous, Non Small-cell Lung Cancer (NSQ NSCLC) Patients With CEACAM5-positive Tumors, Previously Treated With Platinum-based Chemotherapy and an Immune Checkpoint Inhibitor

The study involves evaluating dose-limiting toxicities (DLTs) in both Doublet (Part 1 and 2) and Triplet Cohorts, including grade 4 neutropenia, thrombocytopenia, non-hematologic AEs, keratopathy, and refractory hypertension. Key efficacy measures include objective response rate (ORR) in the Doublet Cohort (Part 2) and Triplet Cohort, calculated per RECIST v1.1 criteria for solid tumors.

Safety assessments covered treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and clinically significant abnormalities in lab parameters, ECG, and urinalysis. Efficacy endpoints in the Doublet Cohort included duration of response (DOR), progression-free survival (PFS), and disease control rate (DCR). Pharmacokinetic parameters such as Cmax, AUC0-14d, and Ctrough were analyzed for tusamitamab ravtansine and ramucirumab. Immunogenicity was assessed via anti-therapeutic antibodies (ATAs).

Participants had advanced CEACAM5+ cancers (CRC/NSCLC/gastric favored; CEA >5ng/mL accepted). Mandatory criteria: measurable disease (expansion phase), archived tumor tissue, and biopsy consent (CRC/gastric cohorts). Exclusions included active CNS metastases, unresolved ocular/cardiac disorders (LVEF<50%), prior CEACAM5/DM1/DM4 therapy, strong CYP3A inhibitor use, or contraindications to ophthalmic medications (glaucoma/hypertension/allergies). Reproductive-age patients required contraception for &ge;3 months post-treatment.

In cohort Q2W-LD, 38 patients were screened for eligibility and 28 patients were enrolled and treated with tusamitamab ravtansine across four LD-DLs ranging from 120 to 170 mg/m2 between March 13, 2017, and February 17, 2020, at study sites in Canada, France, Republic of Korea, and Spain (Table 1). In cohort Q3W, 21 patients were screened for eligibility and 15 patients were enrolled and initiated treatment with tusamitamab ravtansine across four DLs ranging from 120 to 190 mg/m2 between July 15, 2019, and October 20, 2020, at study sites in Canada, France, and Spain (Table 1).

Eligible participants had advanced/metastatic NSQ NSCLC (no EGFR/BRAF/ALK/ROS mutations), CEACAM5 expression &ge;2+, measurable disease (RECIST 1.1), and ECOG 0-1. Exclusions included uncontrolled brain metastases, active infections, autoimmune diseases, prior anti-PD-1/PD-L1 therapy, recent live vaccines, significant allergies, or unresolved toxicities (&ge;Grade 2). Prior chemotherapy for metastatic disease or CEACAM5-targeted treatments was prohibited.

Across all cohorts, dose-limiting toxicities (DLTs) included severe hematologic (grade 4 neutropenia, febrile neutropenia, thrombocytopenia) and non-hematologic events (grade 4 AEs, keratopathy) observed during Cycle 1. Efficacy endpoints assessed in Doublet and Quadruplet Cohorts included objective response rate (ORR), defined per RECIST v1.1 as confirmed complete (CR) or partial response (PR), with CR requiring disappearance of target lesions and PR a ≥30% reduction in lesion sum diameters.

Safety assessments covered treatment-emergent adverse events (TEAEs) and serious AEs (TESAEs). Key efficacy measures included progression-free survival (PFS), disease control rate (DCR), and duration of response (DOR) across cohorts, evaluated via RECIST v1.1 criteria. Pharmacokinetic parameters (Ctrough, Ceoi) were measured for tusamitamab ravtansine, pembrolizumab, pemetrexed, cisplatin, and carboplatin. Immunogenicity was assessed via anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine.

Key inclusion criteria: metastatic NSQ NSCLC patients (post-platinum/IO) with moderate/negative CEACAM5 expression (IHC 2+ in 1-50% or 1+ tumors) plus CEA &ge;100 ng/mL, measurable lesions, ECOG 0-1. Major exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved grade &ge;2 toxicity (except alopecia/vitiligo), corneal disorders, contact lens use, or poor organ function. Reproductive-age participants require contraception.

The study assesses efficacy through Objective Response Rate (ORR), defined as the percentage of participants achieving confirmed complete response (CR, disappearance of all target lesions and lymph nodes <10mm) or partial response (PR, ≥30% reduction in target lesion sum) per RECIST v1.1, evaluated at baseline and every 8 weeks (±7 days) over approximately 46 weeks.

Safety analyses include treatment-emergent adverse events (TEAEs/SAEs) recorded from first dose until primary completion (~21 months). Secondary efficacy endpoints - Progression-Free Survival (PFS), Disease Control Rate (DCR), and Duration of Response (DOR) - all follow RECIST v1.1 criteria, with PD requiring ≥20% (minimum 5mm absolute) increase in target lesions or new lesions, assessed every 8 weeks over 46 weeks.

Eligibility required metastatic disease progression post-platinum chemotherapy and PD-1/PD-L1 inhibitors, CEACAM5 expression &ge;2+, measurable lesions (RECIST v1.1), and ECOG 0-1. Exclusion criteria included untreated brain metastases, major comorbidities, active infections, uncontrolled hypertension, prior treatments targeting CEACAM5 or maytansinoids, and severe organ dysfunction. Specific Triplet Cohort exclusions included autoimmune diseases, transplant history, interstitial lung disease, or recent live vaccines.

Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Tusamitamab Ravtansine (SAR408701) Used in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Metastatic, Non-squamous, Non Small-cell Lung Cancer (NSQ NSCLC) Patients With CEACAM5-positive Tumors, Previously Treated With Platinum-based Chemotherapy and an Immune Checkpoint Inhibitor

The study involves evaluating dose-limiting toxicities (DLTs) in both Doublet (Part 1 and 2) and Triplet Cohorts, including grade 4 neutropenia, thrombocytopenia, non-hematologic AEs, keratopathy, and refractory hypertension. Key efficacy measures include objective response rate (ORR) in the Doublet Cohort (Part 2) and Triplet Cohort, calculated per RECIST v1.1 criteria for solid tumors.

Safety assessments covered treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and clinically significant abnormalities in lab parameters, ECG, and urinalysis. Efficacy endpoints in the Doublet Cohort included duration of response (DOR), progression-free survival (PFS), and disease control rate (DCR). Pharmacokinetic parameters such as Cmax, AUC0-14d, and Ctrough were analyzed for tusamitamab ravtansine and ramucirumab. Immunogenicity was assessed via anti-therapeutic antibodies (ATAs).

Eligible participants had advanced/metastatic NSQ NSCLC (no EGFR/BRAF/ALK/ROS mutations), CEACAM5 expression &ge;2+, measurable disease (RECIST 1.1), and ECOG 0-1. Exclusions included uncontrolled brain metastases, active infections, autoimmune diseases, prior anti-PD-1/PD-L1 therapy, recent live vaccines, significant allergies, or unresolved toxicities (&ge;Grade 2). Prior chemotherapy for metastatic disease or CEACAM5-targeted treatments was prohibited.

Across all cohorts, dose-limiting toxicities (DLTs) included severe hematologic (grade 4 neutropenia, febrile neutropenia, thrombocytopenia) and non-hematologic events (grade 4 AEs, keratopathy) observed during Cycle 1. Efficacy endpoints assessed in Doublet and Quadruplet Cohorts included objective response rate (ORR), defined per RECIST v1.1 as confirmed complete (CR) or partial response (PR), with CR requiring disappearance of target lesions and PR a ≥30% reduction in lesion sum diameters.

Safety assessments covered treatment-emergent adverse events (TEAEs) and serious AEs (TESAEs). Key efficacy measures included progression-free survival (PFS), disease control rate (DCR), and duration of response (DOR) across cohorts, evaluated via RECIST v1.1 criteria. Pharmacokinetic parameters (Ctrough, Ceoi) were measured for tusamitamab ravtansine, pembrolizumab, pemetrexed, cisplatin, and carboplatin. Immunogenicity was assessed via anti-therapeutic antibodies (ATAs) against tusamitamab ravtansine.

Eligible participants required &ge;18 years, measurable lesions (RECIST v1.1), ECOG 0-1, CEACAM5+ tumors, and metastatic disease. Cohort-specific criteria: mBC (Cohort A) needed 2-4 prior chemotherapy lines; mPAC (Cohorts B/C) required progression after gemcitabine/5-FU regimens (B) or 1st-line fluoropyrimidine (C). Key exclusions: active infections (HIV/hepatitis), untreated brain metastases, unresolved Grade &ge;2 toxicities, corneal disorders, prior CEACAM5/DM4 therapy, major surgery <2 weeks, or inadequate organ function. Cohort C additionally excluded prior taxane/gemcitabine exposure.

The primary focus was evaluating Objective Response Rate (ORR) across cohorts (A:26.1w, B:51.6w, C:43.3w), defined as confirmed CR (complete lesion disappearance) or PR (≥30% target lesion reduction) per RECIST v1.1. Dose-limiting toxicities (DLTs) in Cohort C included Grade 4 neutropenia ≥7 days, Grade 3-4 neutropenia with infection, ≥Grade 3 thrombocytopenia with bleeding, Grade 4 non-hematologic AEs, or Grade ≥3 keratopathy during Cycle 1 (28 days).

Secondary outcomes included TEAEs/TESAEs (up to 150 weeks), lab abnormalities (hematology/chemistry per NCI CTCAE v5.0), PFS (time to progression/death), DCR (CR+PR+SD), DOR (response duration), ATAs against tusamitamab ravtansine, and PK parameters (Cmax, AUC0-14d, CL for tusamitamab/gemcitabine/dFdU in Cohort C during Cycle 1). Assessments spanned treatment exposure periods specific to each cohort.

Eligible patients had CEACAM5+ advanced solid tumors (archival tissue required) with no standard alternatives. Exclusions: ECOG &ge;2, active CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved corneal disorders, strong CYP3A inhibitor use (unless discontinued &ge;2 weeks pre-dose), or inadequate contraception. Reproductive-age participants required contraception for 6 months post-treatment.

Eligible participants had CEACAM5-high metastatic/unresectable gastric/GEJ adenocarcinoma (measurable lesions, ECOG 0-1). Key exclusions: untreated CNS metastases, prior CEACAM5/DM1/DM4 therapy, unresolved corneal disorders, recent thrombotic/hemorrhagic events (within 2-6 months), uncontrolled hypertension, or CYP3A inhibitor use. Reproductive-age participants required contraception (7 months post-treatment for females, 4 for males).

Participants received ramucirumab 8 milligram/kilogram (mg/kg) via intravenous (IV) infusion followed by tusamitamab ravtansine loading dose at 170 mg/meter square (m^2) via IV infusion on Cycle 1 Day 1 (each cycle was 2 weeks); and then ramucirumab 8 mg/kg via IV infusion followed by tusamitamab ravtansine 100 mg/m^2 via IV infusion at Cycle 2 and every 2 weeks (Q2W) in all subsequent cycles until disease progression, unacceptable adverse event (AE), death, initiation of a new anticancer therapy, or the participant's or investigator's decision to stop the treatment.

The study assessed dose-limiting toxicities (DLTs) during the first 28 days, defined as grade 4 neutropenia ≥7 days, febrile neutropenia, significant thrombocytopenia with bleeding, grade 4 non-hematologic AEs, or grade ≥3 keratopathy. Objective response rate (ORR) was evaluated per RECIST v1.1 as the percentage of participants achieving complete or partial response based on tumor assessments every 6 weeks.

Safety outcomes included treatment-emergent AEs (TEAEs/TESAEs) up to 30 days post-treatment (~92 weeks). Efficacy endpoints comprised duration of response (DOR), progression-free survival (PFS), and disease control rate (DCR) assessed via RECIST v1.1. Pharmacokinetic analysis measured Ctrough for tusamitamab ravtansine and ramucirumab, alongside antitherapeutic antibody (ATA) detection against tusamitamab ravtansine.

Eligible patients (&ge;18y, ECOG 0-1) have CEACAM5+ (&ge;2+ in 50% cells) metastatic NSCLC (post-chemo/IO), ER+ breast cancer (hormone-refractory), or gastric cancer (exhausted SOC). Key exclusions: untreated brain metastases, recent thromboembolism (<6mo), CYP3A modulator use, unresolved grade &ge;2 toxicity (except alopecia), prior CEACAM5/DM4 therapy, corneal disorders, or contact lens use. Required organ function: ANC &ge;1.5x109/L, platelets &ge;100x109/L, eGFR &ge;50mL/min, and serum albumin &ge;25g/L. Reproductive-age participants must use contraception (females: 7 months post-treatment; males: 4 months).

The study measures intratumoral DM4 and tusamitamab ravtansine concentrations via PK assay on Cycle 2 Day 3 (~5 weeks). Additional pharmacodynamic assessments include CEACAM5 expression changes (IHC), RNA sequencing (DESeq2), tumor microenvironment analysis (quanTIseq/TIL signatures), somatic genomic profiling (WGS), and circulating CEA levels tracked every 8 weeks for up to 2 years. PK parameters (AUCinf, Cmax, Tmax) are evaluated through serial plasma sampling across cycles.

Safety monitoring records CTCAE v5.0 grade 3-4 AEs during treatment (≤2 years), while efficacy is assessed per RECIST v1.1 for PD/SD/PR/CR every 8 weeks. Systemic PK analysis quantifies tusamitamab ravtansine (clearance, volume), DM4 metabolites (Lys-SPDB-DM4, Me-DM4), and calculates Thalf (ln (2)/Lambda z) using trapezoidal AUC methods from baseline through Cycle 4.

Eligible participants were &ge;18 years with metastatic non-squamous NSCLC progressing after platinum/immunotherapy, CEACAM5 expression &ge;2+ in &ge;50% tumor cells, measurable lesions, and ECOG 0-1. Exclusions included active brain metastases, other malignancies within 3 years, unresolved toxicities &ge;Grade 2, HIV/hepatitis, corneal disorders, prior docetaxel/CEACAM5-targeted therapy, corticosteroid contraindications, or hypersensitivity to study drugs.

The study assessed Progression-free Survival (PFS) as the time from randomization to first documented disease progression (PD) or death per RECIST 1.1 criteria, with PD defined as 20% increase in target lesions (minimum 5mm absolute increase) or new lesions. Overall Survival (OS) was measured from randomization to death from any cause up to 189 weeks.

Objective Response Rate (ORR) measured the percentage of participants achieving complete (CR) or partial response (PR) per RECIST 1.1, where CR required lesion disappearance and PR required ≥30% decrease in target lesions. Time to Deterioration (TTD) in symptoms and functions was evaluated using EORTC QLQ-LC13/C30 scales, with deterioration defined as ≥10-point worsening. Safety endpoints included treatment-emergent adverse events (TEAEs/TESAEs), lab abnormalities, and Duration of Response (DOR) from first CR/PR to PD/death.

Human patient-derived gastric tumors were induced on the right flank by a subcutaneous injection. When tumor volume reached approximately 200 mm3 in size, mice were randomized into 5 groups with 8, 9, and 9 animals in vehicle, BGA7650, and BGA9962 groups on Day 0, respectively. After ensuring all cohorts hadapproximately equal average tumor volumes to start, animals were intravenously administered vehicle, BGA7650 (4 mg/kg) on treatment Day 1. Animal body weight and tumor volume were measured twice weekly.