WX-0593 combined with an epithelial growth factor receptor (EGFR) monoclonal antibody in the treatment of xenograft tumors carrying triple mutations.

BACKGROUND

To evaluate the safety and therapeutic efficacy of WX-0593, a newly developed potent anaplastic lymphoma kinase (ALK) inhibitor, in combination with an epithelial growth factor receptor (EGFR) monoclonal antibody (QL1203 or Vectibix) for the treatment of xenograft tumors carrying mutant and osimertinib-resistant mutations (/T790M/C797S).

METHODS

The inhibition of tumor cell proliferation by WX-0593 and Vectibix alone or combined was evaluated in four EGFR triple-mutant cell lines: PC9 ( Del19/T790M/C797S), NCI-H1975 ( L858R/T790M/C797S), Ba/F3 ( L858R/T790M/C797S and Del19/T790M/C797S). The antitumor efficacy of WX-0593 alone or combined with QL1203 or Vectibix was evaluated in xenograft tumor models of BALB/c nude mice developed from H1975 (-Del19/T790M/C797S) and Ba/F3 (-L858R/T790M/C797S) cell lines. Mice were randomized into groups and treated with or without WX-0593, QL1203, Vectibix, or their combination. The tumor volume, mouse body weight, and therapeutic side effects were monitored routinely. Blood samples were obtained from all mice at different time points after the last dosage of treatment to evaluate the pharmacokinetic parameters of the drugs.

RESULTS

WX-0593 and Vectibix showed a strong synergistic inhibitory effect on the proliferation of two triple-mutant Ba/F3 cell lines ( L858R/T790M/C797S and Del19/T790M/C797S), but little synergistic inhibitory effect on the proliferation of NCI-H1975 ( L858R/T790M/C797S) and PC9 ( Del19/T790M/C797S). , WX-0593 (25 mg/kg) showed a modest therapeutic effect when combined with QL1203 or Vectibix, but had no effect on tumor growth as a monotherapy at this dosage. WX-0593 (75 mg/kg) exhibited modest antitumor efficacy that was further enhanced in combination with QL1203 or Vectibix in both tumor models (H1975 and Ba/F3). No significant body weight alteration, any other side effect, or deaths were observed during treatment. Pharmacokinetic analysis showed that the serum level of QL1203 or Vectibix was significantly increased and lasted longer when combined with WX-0593.

CONCLUSIONS

WX-0593 exhibited a synergetic effect with an monoclonal antibody on osimertinib-resistant EGFR-mutant non-small cell lung cancer (NSCLC) both and . Their combination showed potent antitumor efficacy and an acceptable safety profile, which may be a promising strategy for the treatment of patients with triple-mutant NSCLC resistant to osimertinib.