Camtobell (belotecan)

Background: Sacituzumab Tirumotecan (SKB264/MK-2870)is a TROP2 ADC developed with novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor. SKB264 in combination with KL-A167 demonstrated promising efficacy results in treatment naive advanced NSCLC with manageable safety profile. SKB264 Q2W was recommended for further investigation. A Phase 3 study of SKB264 Q2W plus pembrolizumab vs pembrolizumab in 1L metastatic NSCLC with PD-L1 TPS ≥ 50% (NCT06170788) is ongoing.

The cytotoxic effect of belotecan was superior to that of topotecan in the six cell lines, and mRNA expressions of PD-L1, TNF, IL6 and TFGβ were increased in ES2, SKOV3, TOV21G and TOV112D cell lines. Moreover, the low concentration of decitabine did not show the additive cytotoxic effect when combined with belotecan, whereas decitabine increased apoptosis by belotecan synergically in the five human ovarian cancer cell lines. Even though PD-1 and CTLA4 were not increased in the allograft C57BL/6 mouse by ID8, CD3+CD8+T cells were increased after administration of belotecan and decitabine in the spleen and tumor cells.

SKB264 is a novel anti-TROP2 ADC developed using sulfonyl pyrimidine-CL2A-carbonate linker to conjugate its payload, a belotecan-derivative topoisomerase I inhibitor, to achieve an average Drug-to-antibody Ratio (DAR) of 7.4. Conclusions SKB264 at 5 mg/kg demonstrates a manageable safety profile and promising antitumor activity in pts with pre-treated HR+/HER2- mBC. Two phase 3 studies are currently planned in HR+/HER2- mBC, one in China for pts after at least one chemo for mBC and a second global for pts previously untreated with chemo for mBC, both comparing SKB264 vs investigator selected chemo.

SKB264 is a novel anti-TROP2 ADC developed using sulfonyl pyrimidine-CL2A-carbonate linker to conjugate its payload, a belotecan-derivative topoisomerase I inhibitor, to achieve an average Drug-to-antibody Ratio (DAR) of 7.4. SKB264 at 5 mg/kg Q2W demonstrated encouraging anti-tumor activity and manageable safety profile in pts with relapsed or refractory locally advanced/metastatic NSCLC. TRAEs were mainly hematologic. Phase 3 studies of SKB264 in pts with advanced NSCLC have been planned.

The aim of this study was to improve the intratumoral accumulation of an antibody-drug conjugate (ADC) and minimize its off-target toxicity, SKB264, a novel anti-trophoblast antigen 2 (TROP2) ADC that was developed using 2-methylsulfonyl pyrimidine as the linker to conjugate its payload (KL610023), a belotecan-derivative topoisomerase I inhibitor. At the same dose, SKB264's exposure in tumor tissue was 4.6-fold higher than that of IMMU-132. Compared with IMMU-132, the longer half-life of SKB264 had a stronger targeting effect and better antitumor activity, suggesting the better therapeutic potential of SKB264 for treating TROP2-positive tumors.

The combined administration of ATR inhibitor and belotecan proved to be synergistic in our preclinical model. This combination warrants further investigation in a clinical trial, with a particular aim of overcoming chemotherapy resistance in ovarian cancer.

SKB264 is being developed as a further optimized TROP2-targeting ADC with a proprietary cytotoxic, belotecan-derived payload and novel stable conjugation chemistry to achieve average DAR (Drug Antibody Ratio) of 7.4. The enrollment will began in Mar 2020 in USA sites. Research Funding: KLUS Pharm Inc.