Phase I study of the recombinant humanized anti-HER2 monoclonal antibody–MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors

Abstract

Purpose RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer. Patients and methods This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48. Results Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20). Conclusion RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status. Clinical trial information NCT02881190.

From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression

“…According to literature, patients with HER2 IHC2+/FISH− account for about 40%–60% of GC ( Liu et al, 2016 ), which is expected to expand the targeted population of RC48-ADC. Actually, in a phase I study of RC48-ADC that we conducted in advanced solid tumors, patients with HER2 IHC2+/FISH- (ORR: 5/14, 35.7%) responded similarly to those with IHC2+/FISH+ (ORR: 2/10, 20%) and IHC3+ (ORR: 3/22, 13.6%) ( Xu et al, 2021 ). In addition, a phase II study of RC48-ADC also reported that eight urothelial carcinoma patients with IHC2+ and FISH-negative experienced PR (ORR: 40%) ( Sheng et al, 2021 ).…”

Novel ADCs and Strategies to Overcome Resistance to Anti-HER2 ADCs

“…In addition, promising results have been obtained in the preclinical setting using animal models, when combining this therapy with immune checkpoint inhibitors [ 66 ]. Based on these promising preclinical data, several clinical studies are verifying the beneficial effects of this ADC in different settings [ 67 , 68 ], including phase I/II and phase III trials and in advanced solid tumors, including breast cancer (NCT02881138, phase I; NCT02881190, phase I; NCT03052634, phase I/II; NCT04400695, phase III; and NCT03500380, phases II/III), non-small cell lung cancer (NCT04311034, phases I/II), gastric tumors (NCT04714190, phase III and NCT03556345, phase II), urothelic/bladder tumors (NTC05016973, phase II; NCT04879329, phase II; NCT04264936, phases I/II; NCT03809013, phase II; NCT03507166, phase II; and NCT04073602, phase II), gynecological tumors (NCT04965519, phase II), and biliary tract malignancies (NCT04329429, phase II). It is being tested as monotherapy or combined with other anti-HER2 therapies, conventional chemotherapeutic agents, or immune checkpoint inhibitors (NTC04280341 and NCT04264936).…”

Development of Marine-Derived Compounds for Cancer Therapy

“…In a phase I trial evaluating the effect of RC48 in HER2-overexpressing advanced or metastatic solid carcinoma patients (especially gastric cancer), RC48 was well tolerated and displayed encouraging antitumor activity in HER2-positive solid tumors with a 21.0% (12/57) objective response rate (ORR) and 49.1% (28/57) disease control rate (DCR). The most common TRAEs were hypoesthesia, leukopenia, neutropenia and increased conjugated blood bilirubin [57]. In its phase II study carried out in 43 locally advanced or metastatic HER2+ urothelial carcinoma patients, RC48 was promising in anti HER2+ cancer with a 51.2% ORR, a median 6.9 months of progression-free survival (PFS) and 13.9 months of overall survival (OS).…”