BL-B01D1 Demonstrates Antitumor Activity in EGFR+ NSCLC and Other Solid Tumors

The first-in-class EGFR x HER3 bispecific antibody-drug conjugate BL-B01D1 generated antitumor activity and safety in patients with advanced solid tumors, particularly EGFR-mutated and wild-type non–small cell lung cancer (NSCLC) and nasopharyngeal carcinoma, according to data from a phase 1 study (NCT05194982) presented at the 2023 ASCO Annual Meeting.

At a median follow-up of 4.1 months, the overall response rate (ORR) across all patients (n = 139) treated with BL-B01D1 was 45.3%. In terms of specific tumor types, the ORR was 63.2% (95% CI, 46.0%-78.2%) for EGFR-mutant NSCLC (n = 38), 44.9% (95% CI, 30.7%-59.8%) for EGFR wild-type NSCLC (n = 49), 53.6% (95% CI, 33.9%-72.5%) for nasopharyngeal carcinoma (n = 28), 14.3% (95% CI, 0.36%-57.9%) for small cell lung cancer (SCLC; n = 7), 6.7% (95% CI, 0.19%-36.03%) for head and neck squamous cell carcinoma (HNSCC; n = 15), and 0% for other (n = 2).

The disease control rate (DCR) was 89.5% (95% CI, 75.2%-97.1%) in patients with EGFR-mutant NSCLC, 91.8% (95% CI, 80.4%-97.7%) in those with EGFR wild-type NSCLC, 100% in patients with nasopharyngeal carcinoma, 85.7% (95% CI, 42.1%-99.6%) in patients with SCLC, 80% (95% CI, 46.19%-94.96%) in those with HNSCC, and 100% in patients with other tumor types.

In all patients evaluable for safety (n = 195), 92% experienced any-grade treatment-related adverse effects (TRAEs). Fifty-seven percent of patients had grade 3 or higher TRAEs, and 29% experienced serious TRAEs. Three percent of patients discontinued treatment due to TRAEs, 25% needed dose reduction, and TRAEs were associated with death in 1% of patients.

The recommended phase 2 dose (RP2D) was established at 2.5 mg/kg on days 1 and 8 every 3 weeks.

“BL-B01D1 demonstrated promising antitumor activity in this heavily treated population, and tumor shrinkage was observed in nearly 80% of patients,” lead study author Li Zhang, MD, of State Key Laboratory of Oncology in South China, University Cancer Center in Guangzhou, China, said in a presentation of the data. “BL-B01D1 has promising antitumor activity in multiple tumor types, especially in EGFR-mutant and wild-type NSCLC, and nasopharyngeal carcinoma.”

The study enrolled patients with locally advanced or metastatic NSCLC and other solid tumors who had an ECOG performance status of 0 or 1 and measurable disease per RECIST v1.1 criteria. Additionally, patients were eligible for the trial if they had progressed on standard therapy or did not have any additional feasible treatment options.

In the dose-escalation portion of the trial, treatment included 0.27 mg/kg of intravenous BL-B01D1 once weekly (n = 1), 1.5 mg/kg once weekly (n = 1), and 3.0 mg/kg once weekly (n =4). Zhang said 2 dose-limiting toxicities (DLTs) were observed 3.0 mg/kg, prompting investigators to continue the dose escalation on 2 different schedules: day 1 and day 8 every 3 weeks, and day 1 every 3 weeks. Zhang noted that 2 additional DLTs were observed at a dose of 3.5 mg/kg given on day 1 and day 8 every 3 weeks, prompting the end of dose escalation.

Patients received 3.5 mg/kg of BL-B01D1 on days 1 and 8 every 3 weeks (n = 5 in dose escalation), 3.0 mg/kg intravenously on days 1 and 8 every 3 weeks (n = 4 in dose escalation; n = 3 in dose expansion), 2.5 mg/kg on days 1 and 8 every 3 weeks (n = 4 in dose escalation; n = 102 in dose expansion), 4.5 mg/kg on day 1 every 3 weeks (n = 35 in dose expansion), 5.0 mg/kg on day 1 every 3 weeks (n = 3 in dose escalation; n = 21 in dose expansion); or 6.0 mg/kg on day 1 every 3 weeks (n = 3 in dose escalation; n = 9 in dose expansion).

The primary end points of the study were to assess DLTs, as well as establish the maximum tolerated dose and the RP2D of BL-B01D1. Secondary end points included pharmacokinetics, anti-drug antibodies, ORR, DCR, and duration of response. Exploratory end points consisted of progression-free survival, overall survival, biomarkers, and neutralizing antibody assays.

Across all 195 patients enrolled onto the study, the median age of patients was 56.0 years and 68% were male. Moreover, 55% of patients were never smokers, 43% were smokers, 3% had an unknown smoking history. Furthermore, 8% of patients had an ECOG performance status of 0 and 92% had a performance status of 1. Additionally, 18% had brain metastasis at baseline. The median number of organs with metastases was 3 (range, 1-7). Additionally, patients received 1 (20%), 2 (30%), or 3 or more (50%) prior lines of treatment.

At a data cutoff of March 13, 2023, 47.2% of patients had discontinued the treatment. Reasons for treatment discontinuation included progressive disease (21.0%), AEs (1.5%), death (6.2%), loss of follow-up (10.3%), and other (8.2%).

All patients with EGFR-mutant NSCLC received a prior treatment with an EGFR TKI, 89% received a previous third-generation EGFR TKI, and 74% had prior platinum-based chemotherapy. All patients with EGFR wild-type NSCLC received previous platinum-based chemotherapy, and 90% received a prior anti–PD-1/PD-L1 therapy and platinum-based chemotherapy. Notably, investigators emphasized that there was no association of response to BL-B01D1 and the resistance mechanism of EGFR TKIs.

In patients treated at the RP2D (n = 64), the ORR was 45.3% (95% CI, 32.8%-58.3%), with all 29 responders achieving a partial response. Thirty patients had stable disease, and 5 patients had progressive disease. The DCR was 92.2% (95% CI, 82.7%-97.4%).

Notable TRAEs included leukopenia (any-grade, 61%; grade ≥3, 30%), anemia (58%; 25%), neutropenia (53%; 34%), and thrombocytopenia (all grade 50%; grade 3 or higher, 24%). Notably, no interstitial lung disease was observed. No instances of interstitial lung disease were reported.

Reference

Zhang, L, Ma Y, Zhao Y, et al. BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study. J Clin Oncol. 2023;41(suppl 16):3001. doi:10.1200/JCO.2023.41.16_suppl.3001