First‐in‐Human Proof‐of‐Concept Study: Intralesional Administration of BQ788, an Endothelin Receptor B Antagonist, to Melanoma Skin Metastases

Lessons LearnedLocal tolerance of intralesional treatment of melanoma skin metastases with BQ788 is excellent. Hints of efficacy are observed, consisting of both direct effects (decreased expression of endothelin receptor B [EDNRB] and of survival factors, reduced proliferation) and indirect effects (enhanced immune cell infiltration and angiogenesis). Patients in future trials should be screened for EDNRB expression level prior to treatment because only patients with high EDNRB‐expressing melanomas (four of five) responded to BQ788. Future studies should be performed for at least 2 weeks because reduced lesion growth was observed in the only patient that was treated for longer than 1 week.Background. This first‐in‐human proof‐of‐concept study aimed to check whether safety and preclinical results obtained by intratumoral administration of BQ788, an endothelin receptor B (EDNRB) antagonist, can be repeated in human melanoma patients. Methods. Three patients received a single intralesional BQ788 application of 3 mg. After 3–7 days, the lesions were measured and removed for analysis. The administered dose was increased to a cumulative dosage of 8 mg in patient 4 (4 × 2.0 mg, days 0–3; lesion removed on day 4) and to 10 mg in patient 5 (3 × 3.3 mg, days 0, 3, and 10; lesion removed after 14 days). Control lesions were simultaneously treated with phosphate‐buffered saline (PBS). All samples were processed and analyzed without knowledge of the clinical findings. Results. No statistical evaluation was possible because of the number of patients ( n = 5) and the variability in the mode of administration. No adverse events were observed, regardless of administered dose. All observations were in accordance with results obtained in preclinical studies. Accordingly, no difference in degree of tumor necrosis was detected between BQ788‐ and PBS‐treated samples. In addition, both EDNRB and Ki67 showed decreased expression in patients 2 and 5 and, to a lesser extent, in patient 1. Similarly, decreased expression of EDNRB mRNA in patients 2 and 5 and of BCL2A1 and/or PARP3 in patients 2, 3, and 5 was found. Importantly, semiquantitatively scored immunohistochemistry for CD31 and CD3 revealed more blood vessels and lymphocytes, respectively, in BQ788‐treated tumors of patients 2 and 4. Also, in all patients, we observed inverse correlation in expression levels between EDNRB and HIF1A. Finally, in patient 5 (the only patient treated for longer than 1 week), we observed inhibition in lesion growth, as shown by size measurement. Conclusion. The intralesional applications of BQ788 were well tolerated and showed signs of directly and indirectly reducing the viability of melanoma cells.