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 is a first-in-class bispecific antibody-drug conjugate (ADC) targeting both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). It is designed to deliver cytotoxic agents directly to tumor cells expressing these receptors, thereby enhancing antitumor efficacy while minimizing off-target effects.

Mechanism of Action

BL-B01D1 combines a bispecific antibody that simultaneously targets EGFR and HER3 with a cytotoxic payload. This dual targeting facilitates precise delivery of the cytotoxic agent to cancer cells expressing these receptors, leading to enhanced tumor cell death.

Efficacy

Non–Small Cell Lung Cancer (NSCLC):

In a phase 1 study involving 195 patients with advanced solid tumors, BL-B01D1 demonstrated promising antitumor activity, particularly in NSCLC:

• EGFR-Mutant NSCLC (n = 38): Overall response rate (ORR) of 63.2% (95% CI, 46.0%-78.2%).
• EGFR Wild-Type NSCLC (n = 49): ORR of 44.9% (95% CI, 30.7%-59.8%).

The disease control rates (DCR) were 89.5% and 91.8% for EGFR-mutant and wild-type NSCLC, respectively. (onclive.com)

Nasopharyngeal Carcinoma:

Among 28 patients with nasopharyngeal carcinoma, BL-B01D1 achieved an ORR of 53.6% (95% CI, 33.9%-72.5%) and a DCR of 100%. (targetedonc.com)

Urothelial Carcinoma:

In a phase 2 study focusing on urothelial carcinoma, the confirmed ORR was 33.3% (95% CI, 16.5%-54.0%) among 27 patients. Notably, patients who had received one prior line of chemotherapy exhibited an ORR of 75.0% (95% CI, 42.8%-94.5%). (onclive.com)

Safety

BL-B01D1 has been generally well tolerated across studies. In the phase 1 trial, 92% of patients experienced treatment-related adverse events (TRAEs), with 57% reporting grade 3 or higher TRAEs. Common adverse events included neutropenia (47%), anemia (39%), leukopenia (39%), and thrombocytopenia (32%). Serious TRAEs occurred in 29% of patients, leading to treatment discontinuation in 3% of cases. (pubmed.ncbi.nlm.nih.gov)

In the urothelial carcinoma study, no treatment-related deaths or instances of interstitial lung disease were reported. The most common TRAEs were hematologic toxicities. (onclive.com)

Further Reading

• Early Efficacy of BL-B01D1 in a Phase 1 Study Reflects Potential for ADCs in Lung Cancer and Beyond
• BL-B01D1 Generates Antitumor Activity in Solid Tumors, Including EGFR+ NSCLC
• BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study

Last updated: Apr 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