Early Efficacy of BL-B01D1 in a Phase 1 Study Reflects Potential for ADCs in Lung Cancer and Beyond

The first-in-class, EGFR x HER3 bispecific antibody-drug conjugate (ADC) BL-B01D1 demonstrated preliminary antitumor activity with acceptable safety in heavily pretreated patients with advanced solid tumors, particularly those with EGFR-mutated and wild-type non–small cell lung cancer (NSCLC).¹ These results reflect the agent’s potential to expand options in later lines for certain subgroups, and contribute to the growing excitement surrounding the use of ADCs in lung cancer, according to Helena A. Yu, MD.

In a phase 1 study (NCT05194982) presented at the 2023 ASCO Annual Meeting, BL-B01D1 elicited an overall response rate of 45.3% in the overall patient population (n = 195), which included patients with NSCLC, small cell lung cancer (SCLC), nasopharyngeal carcinoma, head and neck squamous cell carcinoma, and other solid tumors.

When stratified by disease subtype, the response rate with BL-B01D1 was found to be highest in those with EGFR-mutant NSCLC (n = 38), at 63.2% (95% CI, 46.0%-78.2%). Moreover, the ORR achieved with the agent was 44.9% (95% CI, 30.7%-59.8%) in the EGFR wild-type subgroup (n = 49).

“After chemoimmunotherapy–which is our first-line therapy of choice for most of these patients—there are limited options, and certainly no targeted options,” said Yu, who is an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York. “For this [agent] to have reasonable efficacy…in that EGFR wild-type [subgroup] is exciting.”

In an interview with OncLive^®, Yu discussed the phase 1 investigation of BL-B01D1 in patients with advanced solid tumors, including the agent’s initial efficacy and safety, the potential significance of this research for those with EGFR-mutant and wild-type disease, and the expanding body of evidence supporting continued ADC development in NSCLC.

OncLive: What was the rationale for investigating the novel EGFRxHER3 ADC BL-B01D1 in locally advanced or metastatic solid tumors, particularly NSCLC?

Yu: ADCs are a new, exciting class of drugs within lung cancer; these are hybrid molecules that have a targeted antibody linked to a chemotherapy molecule. The idea is that they are targeting specific cancer cells and delivering the chemotherapy. BL-B01D1 is [one such] bispecific ADC being looked at in this phase 1 study in all advanced solid tumors, with a focus on NSCLC.

BL-B01D1 [consists of] a bispecific antibody against EGFR and HER3 linked to a chemotherapy molecule, which in this compound, is the topoisomerase chemotherapy inhibitor. EGFR and HER3 are both significantly expressed in lung cancers, particularly in EGFR-mutant lung cancer, which makes it a prime candidate to look at within NSCLC.

Could you describe the patient population included in this phase 1 study? Why were those with these tumor subtypes selected?

Phase 1 studies are always a bit broader in their eligibility. This study included various types of solid tumors. About half of the patients [on the study] had NSCLC. Of the NSCLC accruals, about half were patients with EGFR-mutant lung cancer. Sizable minorities had nasopharyngeal carcinoma, as well as head and neck squamous cell carcinoma. These specific subgroups of solid tumors were enrolled because EGFR signaling plays an important role in oncogenesis, for all these cancers.

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

[By] the data cutoff [date of March 13, 2023], 139 patients had [received] at least 1 tumor assessment. In those [patients], the ORR was 45.3%. For an early, phase 1 dose-escalation study, those are promising results. [The presenters] also broke [results] down into those different subgroups of enrolled subjects that we discussed. Among [these subgroups], the highest ORR of 63.2% was found in those who had EGFR-mutant lung cancer. That makes sense because both EGFR and HER3 are relevant in EGFR-mutant lung cancer.

Could you expand further on responses observed with BL-B01D1 in the NSCLC and SCLC subgroups?

Within NSCLC, they divided the groups into patients with EGFR mutations and those without EGFR mutations. The patients with EGFR-mutant lung cancer who were enrolled had all received prior EGFR TKIs. The majority had received third-generation EGFR TKIs like osimertinib [Tagrisso], and [about] three-fourths had [received] prior platinum-based chemotherapy. These heavily pretreated patients in the third-line setting [and beyond] had that response rate of 63.2% [with] this novel drug. [What we saw in those with] EGFR wild-type NSCLC is interesting, too. We’re looking to these ADCs to be relevant in that driver mutation–negative population.

In terms of SCLC, the data are quite limited; there were only [13] patients enrolled. One had a partial response, [so it’s still] early days in that setting.

What did the study reveal about the agent’s safety profile?

In terms of safety, it’s important to remember that these ADCs are chemotherapy. We do end up seeing some of the kind of standard toxicities we see with chemotherapy agents like decreased white blood cell count, anemia, and thrombocytopenia, as well as nausea, anorexia, or mouth sores. BL-B01D1 was relatively well tolerated [in this study]. Only 3% of patients discontinued the drug due to an adverse effect, which is quite low, and 25% required some degree of dose reduction.

What avenues exist for the continued investigation of BL-B01D1 in NSCLC, given the agent’s activity in patients with both EGFR-mutated and wild-type disease?

It is always hard to judge a new compound by these phase 1 dose-escalation studies, but I think the fact that there was a clear efficacy signal and minimal toxicity is exciting. We do need more of these chemotherapy and targeted therapy hybrid drugs within lung cancer. The area where I’m most interested to see this being moved forward is in EGFR-mutant lung cancer. After these third-generation EGFR TKIs, we really don’t have any targeted therapies available. Having an ADC that has good efficacy in the post-TKI, post-chemotherapy [space] is exciting, so I think there will be further study in that population. Of course, there will also be further study in patients with NSCLC at large.

Ultimately, we’ll have to see whether EGFR or HER3 expression is a good biomarker in terms of predicting the efficacy and activity of these agents. Those data will certainly be collected and analyzed post-hoc.

What is your take-home message for your colleagues regarding this research?

Over the past few years, there has been exciting initial data for these ADCs [in lung cancer]. We have been well trained to think about driver mutations and their effect on treatment choices for our patients with NSCLC. The next wave is understanding the right biomarkers to select patients for these different ADCs. We’ve now seen ADCs within lung cancer that target MET, TROP2, HER3, and EGFR. Understanding which patients would benefit from [any one of] these drugs is going to be the test to come. I am [also] excited for studies of this [particular] agent in the phase 2 [setting] and beyond, as it did show promising efficacy in this phase 1 trial.

Editor’s Note: Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

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