A Phase 1 Study Evaluating the Safety, Tolerability, and Efficacy of BL-B01D1 in Subjects With Metastatic or Unresectable Non-Small Cell Lung Cancer and Other Solid Tumors

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Overview

BL-B01D1 (international nonproprietary name: izalontamab brengitecan; also called Iza-bren; BMS-986507) is a first-in-class bispecific antibody–drug conjugate (ADC) that targets EGFR and HER3. It has entered multi-cohort phase 1/2 development across solid tumors, with the most mature data in non–small cell lung cancer (NSCLC). In May 2024, a peer‑reviewed first‑in‑human study in The Lancet Oncology reported antitumor activity across several tumor types. In August 2025, the FDA granted Breakthrough Therapy Designation for previously treated EGFR‑mutated NSCLC based on data from studies in China and a global program. Combination data with osimertinib in first‑line EGFR‑mutant NSCLC were presented at WCLC 2025. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

BL-B01D1 comprises an EGFR×HER3 bispecific antibody conjugated via a cleavable tetrapeptide linker to a novel topoisomerase I inhibitor payload. The construct is designed both to inhibit EGFR/HER3 signaling and to deliver a DNA‑damaging payload to receptor‑expressing tumor cells. (pubmed.ncbi.nlm.nih.gov)

Clinical development

• First‑in‑human, multi‑tumor phase 1 (NCT05194982; China): dose‑escalation/expansion across weekly and every‑3‑week schedules; recommended phase 2 dose selected as 2.5 mg/kg on days 1 and 8 every 3 weeks in Chinese patients. (pubmed.ncbi.nlm.nih.gov)
• Global phase 1 in NSCLC and other tumors (BL‑B01D1‑LUNG‑101): ongoing U.S./EU/Japan trial. (clinicalresearch.ucihealth.org)
• Phase 2 in NSCLC including combination with osimertinib (NCT05880706). (cdek.pharmacy.purdue.edu)
• Phase 2 in extensive‑stage SCLC evaluating monotherapy, SI‑B003 (PD‑1), and the combination (NCT05924841). (cdek.pharmacy.purdue.edu)

Efficacy

• Phase 1 (The Lancet Oncology; n=195 treated; 174 evaluable for activity): objective response rate (ORR) 34% (95% CI 27–42) across heavily pretreated solid tumors. Tumor‑type details were further elaborated in ASCO 2023 presentations and secondary reports. (pubmed.ncbi.nlm.nih.gov)
• Phase 1 (ASCO 2023 report; median follow‑up 4.1 months; n=139 efficacy‑evaluable):
• EGFR‑mutant NSCLC: ORR 63.2% (n=38).
• EGFR‑wild‑type NSCLC: ORR 44.9% (n=49).
• Nasopharyngeal carcinoma: ORR 53.6% (n=28).
• SCLC: ORR 14.3% (n=7).
• HNSCC: ORR 6.7% (n=15). (onclive.com)
• First‑line EGFR‑mutant NSCLC (phase 2; BL‑B01D1 + osimertinib):
• Across all treated patients, ORR 84.4% (confirmed ORR 80.5%); 12‑month PFS 86.5% and OS 95.9%.
• At the 2.5 mg/kg D1/D8 Q3W BL‑B01D1 dose, ORR 100% (confirmed ORR 95%); 12‑month PFS 92.1% and OS 94.8%. Data presented at WCLC 2025. (ascopost.com)

Safety

• Phase 1 (The Lancet Oncology; n=195): grade ≥3 treatment‑related adverse events (TRAEs) in 71%, most commonly neutropenia (47%), anemia (39%), leukopenia (39%), and thrombocytopenia (32%); dose reductions in 27% and discontinuations in 3% due to TRAEs. Treatment‑related deaths occurred in 3 patients (2%: pneumonia, septic shock, myelosuppression). One case of interstitial lung disease reported. Maximum tolerated doses were 3.0 mg/kg D1/D8 Q3W and 6.0 mg/kg D1 Q3W. (pubmed.ncbi.nlm.nih.gov)
• First‑line combination with osimertinib (phase 2): safety was manageable; hematologic TRAEs were common (anemia ~92%, neutropenia ~91%, leukopenia ~91%, thrombocytopenia ~76%). (ascopost.com)

Notes on regulatory status and naming

On August 18, 2025, the U.S. FDA granted Breakthrough Therapy Designation to izalontamab brengitecan for previously treated advanced EGFR‑mutated NSCLC after an EGFR TKI and platinum chemotherapy, based on data from BL‑B01D1‑101, BL‑B01D1‑203, and BL‑B01D1‑LUNG‑101. (news.bms.com)

Further reading

• The Lancet Oncology phase 1 publication (peer‑reviewed). (pubmed.ncbi.nlm.nih.gov)
• ASCO 2023 abstract (phase 1, multi‑tumor). (ascopubs.org)
• OncLive summary of ASCO 2023 cohort‑level ORRs. (onclive.com)
• WCLC 2025 reports on first‑line osimertinib combination (OncLive; The ASCO Post). (onclive.com)
• FDA Breakthrough Therapy Designation announcement (BMS). (news.bms.com)
• Trial listings: NCT05194982 (FIH), NCT05880706 (combo with osimertinib), NCT05924841 (SCLC). (npcf.us)

Disclaimer: Efficacy and safety data are from early-phase studies with ongoing follow‑up; dosing, response rates, and adverse event frequencies may evolve as datasets mature. (pubmed.ncbi.nlm.nih.gov)

Last updated: Oct 2025

Inclusion Criteria:

1. Sign informed consent

2. Expected survival \> or = 3months

3. Has histologically documented, incurable, locally advanced or metastatic epithelial origin malignant cancer, priority to include the following tumor types: Non-Small Cell Lung Cancer, HER2- breast cancer, esophageal cancer, Small Cell Lung Cancer, and Nasopharyngeal Cancer

4. Agree to provide a tumor sample

5. Has at least one measurable lesion based on RECIST 1.1

6. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) 0 to 1

7. Toxicity of previous antitumor therapy has returned to level ≤1 as defined by NCI-CTCAE V5.0 (except for asymptomatic laboratory abnormalities such as elevated ALP, hyperuricemia, elevated serum or plasma amylase/lipase, and elevated blood glucose; except for toxicity that the investigator determined to have no safety risk, such as alopecia, grade 2 peripheral neurotoxicity, hypothyroidism stabilized by hormone replacement therapy, etc.)

8. Has no serious cardiac dysfunction, left ventricular ejection fraction ≥50%.

9. Has adequate organ function before registration

10. Coagulation function: international normalized ratio (INR) ≤1.5×ULN, and activated partial thromboplastin time (APTT) ≤1.5 ULN

11. Urinary protein ≤2+ or ≤1000mg/24 hours

12. For premenopausal women with childbearing potential, a pregnancy test must be taken within 7 days prior to the start of treatment. Serum or urine pregnancy must be negative and must be non-lactating

13. Must agree to use adequate barrier contraceptive measures during the treatment and 6 months after the end of treatment for all subjects (regardless of gender)

Exclusion Criteria:

1. Chemotherapy, biological therapy, immunotherapy, radical radiotherapy, major surgery, targeted therapy and other anti-tumor therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to the first administration

2. Subjects with history of severe heart disease

3. Active autoimmune diseases and inflammatory diseases

4. Other malignant tumors were diagnosed within 5 years

5. Subjects with poorly controlled hypertension

6. Subjects have Grade 3 lung disease or a history of interstitial lung disease

7. Unstable thrombotic events such as deep vein thrombosis, arterial thrombosis, and pulmonary embolism requiring therapeutic intervention within the previous 6 months before screening

8. Symptoms of active central nervous system metastasis

9. Subjects who have a history of allergies to recombinant humanized antibodies or human mouse chimeric antibodies or any of the components of BL-B01D1

10. Subjects have a history of autologous or allogeneic stem cell transplantation

11. Known HIV, active tuberculosis, active Hepatitis B virus infection or active Hepatitis C virus infection

12. Subjects with active infections requiring systemic treatment

13. Participated in another clinical trial within 4 weeks prior to participating in the study

14. Other conditions that the investigator believes that it is not suitable for participating in this clinical trial

15. Subjects with prolonged QT interval (QTc \>470 msec), complete left bundle branch block, Grade 3 atrioventricular block

16. Has received treatment with anthracyclines with a cumulative dose exceeding 360 mg/m2