A novel bispecific antibody-drug conjugate, BL-B01D1, targeting both EGFR and HER3, has shown promising early results in patients with advanced urothelial cancer. The agent demonstrated a 40% response rate in previously treated patients, offering a potential new avenue for treatment in this challenging disease. These findings were presented at ESMO 2024, highlighting the expanding pipeline of therapeutics in genitourinary cancers.
Targeting EGFR and HER3 in Urothelial Cancer
BL-B01D1 is derived from cetuximab, a high-affinity antibody for EGFR, and conjugated to two HER3 single-chain fragments (scFv's). This bispecific design allows the drug to bind to either EGFR or HER3, or both, potentially enhancing its efficacy. The cytotoxic payload, Ed-04, is a highly potent topoisomerase inhibitor with a high drug-to-antibody ratio of eight. Preclinical studies suggest that this ADC is more active than either EGFR or HER3 ADCs alone.
Jonathan Rosenberg, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center, explained that EGFR and HER3 are in the same family and can heterodimerize or homodimerize. "Most of the signaling and most of the internalization is probably from EGFR, but certainly HER3 is modulating this," he noted.
Clinical Trial Results
The initial phase I study of BL-B01D1, primarily in lung cancer, showed a high rate of activity. At ESMO, results were reported for 34 urothelial cancer patients treated at a slightly lower dose. Most patients had received prior checkpoint inhibitors and chemotherapy, but few had prior antibody-drug conjugates. In this heavily pretreated population, a 40% response rate was observed at the dose level being taken forward. Notably, in a subset of 12 patients in the second-line setting, three-quarters achieved objective responses. While these sample sizes are small, the data are encouraging.
According to Dr. Rosenberg, IHC staining did not seem to correlate with intensity, and most tumors expressed EGFR or HER3. The progression-free survival (PFS) data appear promising, but longer follow-up is needed. Interestingly, the skin toxicity typically associated with cetuximab was not observed at high grade or frequency, with hematologic toxicity being the primary adverse event.
Implications for Urothelial Cancer Treatment
With the recent lack of success of Sacituzumab, the exploration of different ADCs is crucial. BL-B01D1 opens up a new set of targets in advanced urothelial cancer. The agent's unique dual-targeting mechanism and manageable toxicity profile make it a promising candidate for further development.
NKT2152: A HIF2a Inhibitor in Renal Cell Carcinoma
In addition to the urothelial cancer data, Dr. Rosenberg discussed NKT2152, a HIF2a inhibitor being investigated for renal cell carcinoma. HIF2a is a transcription factor that regulates genes involved in RCC growth and metastasis. Belzutifan is currently approved for previously treated renal cell carcinoma in the United States.
NKT2152 is similar in biological function to belzutifan, inhibiting the same target genes. A dose escalation and expansion study was conducted to determine the recommended phase II dose. The study used a loading and maintenance strategy and assessed pharmacodynamic and pharmacokinetic markers. Erythropoietin suppression was observed, as expected. However, the drug has a very long half-life of 38 days, compared to belzutifan's 16 hours, which could lead to potential issues with hypoxia.
The response rate in the phase I study was 20%, increasing to 26% with longer follow-up. The median PFS was 9.2 months. While belzutifan has an established role in advanced renal cell carcinoma, the different PK properties of NKT2152 might allow it to be used after belzutifan failure. However, the long half-life and potential for hypoxia pose challenges. Further evaluation is needed to determine the optimal placement of NKT2152 in the kidney cancer treatment landscape.
