CAN016, a HER2-targeted dual-payload ADC, phase 1 clinical development

HER2 amplification, mutation and overexpression have been reported in various types of cancers. Based on those findings, targeted monoclonal antibodies (such as Herceptin) and ADC (such as Enhertu) have been approved, expending the landscape of cancer therapy. However, resistance to such targeted therapies, especially to Enhertu, remains a critical clinical challenge. CAN016 is developed as the first HER2 targeting ADC coupling with two distinct MOA payloads-Exatecan and MMAE, via CanWell's proprietary StarLinker™ technology. This dual-payload strategy features in enhancing antitumoral potency, overcoming tumor heterogenicity, and reversing the resistance. Preclinically, CAN016 exhibited similar binding and internalization profiles as trastuzumab in vitro and demonstrated robust dose-dependent anti-tumor activities in vivo. These effects were superior over Enhertu in HER2-high, HER2-low and even Enhertu-resistant CDX and PDX models. Compared to each of respective single-payload HER2ADCs, CAN016 showed greater efficacies than analog ADCs in monotherapy or in combination (concurrent/sequential schedules). DMPK and GLP NHP studies confirmed a favorable PK and safety profile with the HNSTD of 20 mg/kg. Study population: Eligible patients ≥ 18 years old, patients must have failed to HER2-targeted ADC;life expectancy ≥ 3 months with ECOG performance score 0 or 1; measurable lesion as per RECIST version 1.1. Clinical trail design: his phase I/II FIH study consists of two parts. Dose escalation, with a starting dose of 0.75mg/kg by accelerated titration. If ≥ grade 2 AEs were observed then switch to the 3+3 design for further assessing the MTD and/or RP2D. Once the MTD/RP2D was determined, further patients will be recruited to evaluate the preliminary efficacy of CAN016 in different advanced solid tumors including breast cancer, NSCLC, gastric cancer etc. The primary endpoint for phase I is to assess the safety and tolerability of CAN016 and determine the MTD/RP2D; for phase II is to evaluate the preliminary clinical efficacy. Conclusion: CAN016 represents a promising therapeutic for HER2-positive/mutant solid tumors in preclinical study, particularly in the post-ADC setting. IND applications have been submitted to the US FDA and China CDE.