CHICAGO – A bispecific antibody-drug conjugate targeting EGFR and HER3 demonstrated promising antitumor activity in patients with various solid tumors, particularly those with EGFR-mutated non-small cell lung cancer, according to Phase I clinical trial data presented at the American Society of Clinical Oncology's annual meeting.
HER3 is overexpressed in many tumor types and contributes to EGFR inhibitor resistance in tumor cells by forming a heterodimer with EGFR. BL-B01D1, developed by Systimmune, a wholly owned subsidiary of Chengdu, China-based Baili Biopharmaceutical, is an EGFR/HER3 bispecific antibody linked to a topoisomerase I inhibitor payload by a cleavable linker. Li Zhang, an oncologist at Sun Yat-Sen University Cancer Center in Guangzhou, China, and a lead investigator of the study, said that because EGFR and HER3 are highly expressed in various epithelial tumors, his team hypothesized that targeting both receptors could lead to a "broad-spectrum and pan-tumor killing therapy."
In a preclinical study, BL-B01D1 was compared to single antigen-targeting ADCs in xenograft models of colorectal or pancreatic cancer cells. BL-B01D1 showed stronger anti-tumor activity than either the EGFR- or the HER3-targeted ADC.
In the first part of the Phase I clinical trial, dubbed BL-B01D1-101, researchers tested multiple doses of the drug and different dosing schedules in 195 patients with locally advanced or metastatic NSCLC or other solid tumors who had failed standard therapy or lacked treatment options. Then in the second part of the trial, they conducted a dose-expansion study in five patient cohorts. The main goal of the trial was to determine dose-limiting toxicities, maximum tolerated dose, and a recommended Phase II dose. A total of 195 patients participated at 12 sites in China. In addition, investigators tracked preliminary efficacy, pharmacokinetics, and immunogenicity of BL-B01D1.
Zhang and colleagues reported an overall response rate of 63.2 percent in EGFR-mutant NSCLC patients on BL-B01D1, which was notably higher than the responses seen in any other subgroup. For example, in patients with EGFR wild-type NSCLC tumors, the response rate was 44.9 percent. The overall response rate was 53.6 percent in patients with nasopharyngeal cancer, 14.3 percent in those with small cell lung cancer, and 6.7 percent among head and neck cancer patients. At a median follow-up of 4.1 months, the response rate among all patients in the study was 45.3 percent.
Zhang emphasized that the patients in the trial had received extensive prior treatments. Out of 41 patients with EGFR-mutant NSCLC, 89 percent had already received a third-generation EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy, while in the EGFR wild-type group, 90 percent had received anti-PD-1 or anti-PD-L1 therapy with platinum-based chemotherapy. A study of biomarkers associated with resistance showed there was no association between BL-B01D1 response and the resistance mechanisms of EGFR TKIs.
More than 90 percent of study participants had treatment-related adverse events, of which 57 percent were grade 3 or higher. There were five patients who discontinued treatment, one who died, and 48 who had their doses reduced. The most common treatment-related adverse events were leukopenia, anemia, neutropenia, and thrombocytopenia. "All of the hematological toxicities were manageable," Zhang said, adding that "EGFR/HER3-related toxicities such as mucositis, diarrhea, and rash were relatively low."
Zhang concluded that the first-in-human study of BL-B01D1 showed that the ADC has promising anti-tumor activity in multiple tumor types, particularly EGFR-mutant NSCLC. He added that the company is now preparing to conduct Phase III studies of BL-B01D1 in NSCLC and nasopharyngeal carcinoma.
In a discussion of these results, Kohei Shitara, an oncologist at the National Cancer Center Hospital East in Japan, said the response rates on BL-B01D1 were "impressive," especially in NSCLC patients regardless of EGFR mutation status and in nasopharyngeal carcinoma. "In contrast, the response rate was less impressive in patients with small cell lung cancer or squamous head and neck cancer," he said. "At this time, the exact reason for this difference remains unclear." While varying sensitivity of the particular cancer type to the ADC payload or differences in target expression could serve as explanations, Shitara noted that further studies will be needed to truly understand why some tumors appear to derive more benefit from the bispecific ADC than others.
Shitara highlighted that the response rate in small cell lung cancer was comparatively higher than what has been seen with other ADCs in that indication. "However, the difference is not large," he said. "Further enrichment by a biomarker or a combination with other treatment is needed before moving forward" in this setting.
In addition to BL-B01D1, Systimmune is developing a number of other clinical-stage bispecific and monospecific antibodies and ADCs in cancer indications. Those include a Phase I trial of an EGFR-HER3 bispecific antibody, SI-B001, in advanced or metastatic epithelial tumors and a Phase II trial of SI-B001 in EGFR wild-type, ALK wild-type NSCLC. Systimmune presented results from the latter trial in an ASCO poster discussion session, which showed an overall response rate of 31.3 percent.