Preclinical tolerance evaluation of the addition of a cisplatin-based dry powder for inhalation to the conventional carboplatin-paclitaxel doublet for treatment of non-small cell lung cancer

Abstract

Despite the advances in targeted therapies and immunotherapy for non-small cell lung cancer (NSCLC) patients, the intravenous administration of carboplatin (CARB) and paclitaxel (PTX) in well-spaced cycles is widely indicated for the treatment of NSCLC from stage II to stage IV. Our strategy was to add a controlled-release cisplatin-based dry-powder for inhalation (CIS-DPI-ET) to the conventional CARB-PTX-IV doublet, administered during the treatment off-cycles to intensify the therapeutic response while avoiding the impairment of pulmonary, renal and haematological tolerance of these combinations. The co-administration of CIS-DPI-ET (0.5 mg/kg) and CARB-PTX-IV (17–10 mg/kg) the same day showed a higher proportion of neutrophils in BALF (35 ± 7% vs 1.3 ± 0.8%), with earlier regenerative anaemia than with CARB-PTX-IV alone. A first strategy of CARB-PTX-IV dose reduction by 25% also induced neutrophil recruitment, but in a lower proportion than with the first combination (20 ± 6% vs 0.3 ± 0.3%) and avoiding regenerative anaemia. A second strategy of delaying CIS-DPI-ET and CARB-PTX-IV administrations by 24 h avoided both the recruitment of neutrophils in BALF and regenerative anaemia. Moreover, all these groups showed higher cytotoxicity (LDH activity, protein content) with no higher renal toxicities. These two strategies seem interesting to be assessed in terms of antitumor efficacy in mice.

Keywords

• Regenerative anaemia
• Thrombocytopenia
• Acute kidney injury
• Cytotoxicity
• Therapeutic intensification
• Dry powder for inhalation