Novel Bispecific ADC Generates Early Efficacy Signals in Lung and Head and Neck Cancers


In Partnership With:

Pasi A. Jänne, MD, PhD, discusses the advantages of bispecific ADCs that target both HER3 and EGFR; preliminary efficacy and safety data seen with BL-B01D1 in patients with non–small cell lung cancer; and the activity of this agent in patients with head and neck squamous cell carcinoma, small cell lung cancer, and nasopharynx cancer.

Pasi A. Jänne, MD, PhD

Pasi A. Jänne, MD, PhD

The first-in-class HER3/EGFR-targeted antibody-drug conjugate (ADC) BL-B01D1 elicited antitumor activity with a tolerable safety profile in patients with locally advanced or metastatic solid tumors, including non–small cell lung cancer (NSCLC), regardless of EGFR mutation status, according to Pasi A. Jänne, MD, PhD.

A phase 1 trial (NCT05194982), findings from which were presented at the 2023 ASCO Annual Meeting, evaluated the efficacy and safety of BL-B01D1 in patients with locally advanced or metastatic NSCLC, small cell lung cancer (SCLC), head and neck squamous cell carcinoma (HNSCC), and nasopharynx cancer. All patients with EGFR-mutant NSCLC had received a prior EGFR TKI, and all patients with EGFR wild-type NSCLC had received prior platinum-based chemotherapy. At a median follow-up of 4.1 months, the overall response rate (ORR) in the entire study population was 45.3%. The respective ORRs in patients with EGFR-mutant NSCLC, EGFR wild-type NSCLC, SCLC, nasopharynx cancer, and HNSCC were 63.2%, 44.9%, 14.3%, 53.6%, and 6.7%.1

“These are high numbers, and for patients who have progressed on standard-of-care treatments, this represents a remarkable degree of clinical activity [with] this bispecific ADC,” Jänne said.

In an interview with OncLive®, Jänne discussed the advantages of bispecific ADCs that target both HER3 and EGFR; preliminary efficacy and safety data seen with BL-B01D1 in patients with NSCLC; and the activity of this agent in patients with HNSCC, SCLC, and nasopharynx cancer.

Jänne is the director of the Lowe Center for Thoracic Oncology, the director of the Belfer Center for Applied Cancer Science, the director of the Chen-Huang Center for EGFR Mutant Lung Cancers, and a senior physician at Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: What were the rationale and design for this phase 1 trial?

Jänne: This is a trial of a bispecific ADC. One arm [of the agent] binds to EGFR and the other arm binds to another EGFR family member, HER3. Previous studies investigating HER3-targeted [monoclonal] ADCs have shown clinical efficacy in patients with lung cancer whose cancers have EGFR mutations.

[The phase 1 trial investigators wanted to see whether a HER3-targeted ADC] would also have clinical activity in [patients with] lung cancer [with mutations] other than EGFR who had progressed on EGFR inhibitors and chemotherapy. [This] phase 1 study [included] dose-escalation and dose-expansion [parts, treating] multiple patients across different doses and with different treatment schedules. The trial included [patients with] cancers other than lung cancer, as well. [This trial], conducted in China, also included [patients with] nasopharynx cancer, and HNSCC, as well as SCLC: a plethora of aerodigestive [tract] cancers.

What efficacy findings from this trial were presented at the 2023 ASCO Annual Meeting?

Overall, across the patients, the [proportion] of patients whose tumors had an objective response was 45.3%. Excitingly, the response rate in the patients with EGFR-mutant [NSCLC] was even higher, at 63.2%. In the patients with no EGFR mutation in their [NSCLC, the response rate] was 44.9%. There was also activity in nasopharynx cancer, and, to a lesser degree, in SCLC and HNSCC.

What was also exciting in the EGFR-mutant [NSCLC] population, like what was previously seen [with a monoclonal] HER3-directed ADC, was that the activity of this agent was independent of the resistance mechanism to the EGFR inhibitor. That’s because HER3 is expressed on most EGFR-mutant cancers, as is, of course, EGFR itself when the cancer has an EGFR mutation. This bispecific antibody leverages the expression of those 2 proteins on EGFR-mutant cancers. HER3 is not a resistance mechanism to EGFR inhibitors or EGFR kinase inhibitors, such as osimertinib [Tagrisso]. It was nice to have that proof of concept that the agent works regardless of [the presence of] a resistance mechanism to a prior EGFR kinase inhibitor. We saw that in the correlative science analyses from this trial.

What is the safety profile of BL-B01D1?

In general, this agent was well tolerated. Since it’s an ADC and the conjugate is a type of chemotherapeutic agent, a type of topoisomerase inhibitor, many of the adverse effects [AEs] are chemotherapy-like AEs, mostly bone marrow toxicity, anemia, neutropenia, thrombocytopenia, some decreases in white cell count, a bit of the nausea that we see with chemotherapeutic agents, diarrhea, and rash. However, for the most part, the agent was well tolerated.

Importantly, in this study, at least so far, no cases of interstitial lung disease [ILD] have been observed, which has been a common toxicity amongst ADCs throughout the field. It’s encouraging not to see that here. Whether that’ll remain this way or we’ll start to see some [ILD] with additional patients being treated remains to be determined, but it’s certainly encouraging that across all the doses and schedules so far, none of that was observed.

What next steps are on the horizon for this research?

There is a plan to move this agent into further clinical development. The clinical trial presented at [the 2023 ASCO Annual Meeting] was conducted in China. There will be a clinical trial of this agent in the United States as well. There are plans for phase 3 clinical trials of this agent in lung cancer and nasopharynx cancer, given the degree of activity that was seen in this first-in-human trial.

What is your main message for colleagues based on this research?

We don’t have endless therapeutic options, especially for patients with EGFR-mutant [NSCLC] once they’ve exhausted EGFR inhibitors, such as osimertinib, as well as chemotherapy. Having this ADC as a new therapeutic option is wonderful and gives more options to patients after they’ve progressed on standard therapies. The hope is that maybe this agent will also be administered earlier, [rather] than after [patients progress] on EGFR inhibitors and chemotherapy. Those are some of the questions that will be addressed in future clinical studies.


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

Related Videos
Pasi A. Jänne, MD, PhD
Alessandro Di Federico, MD
Expert on SCLC
Dazhi Liu, PharmD, MS, BCOP
Stephen V. Liu, MD
Terufumi Kato, MD
Sanam Loghavi, MD
Experts on lung cancer
Luis Raez, MD, an expert on lung cancer
Melissa L. Johnson, MD
Related Content