Phase Ib study of berzosertib, carboplatin, gemcitabine, and pembrolizumab in patients with squamous non-small lung cancer (ETCTN 10313)
Mené sur 12 patients atteints d'un cancer épidermoïde du poumon non à petites cellules de stade avancé, cet essai de phase IB détermine la dose maximale tolérée du berzosertib (un inhibiteur d'ATR) en combinaison avec le carboplatine, la gemcitabine et le pembrolizumab, puis analyse ses caractéristiques pharmacocinétiques
Background: Berzosertib is a potent and selective inhibitor of ATR and potentiates cisplatin and gemcitabine in lung xenografts. We hypothesized that berzosertib plus carboplatin, gemcitabine and pembrolizumab is tolerable and active in newly diagnosed advanced squamous NSCLC.
Methods: This phase Ib clinical trial studied berzosertib 135 mg/m2 IV days 2 and 9 with carboplatin AUC 4 to 5 day 1, gemcitabine 800 mg/m2 days 1 and 8, and pembrolizumab 200 mg day 1, of a 3-week cycle. Primary endpoint was the recommended phase II dose (RP2D). Anti-tumor activity and pharmacokinetics were secondary endpoints.
Results: Twelve patients were enrolled and treated. Two of six patients at DL 1 (berzosertib 135 mg/m2, carboplatin AUC 5, gemcitabine 800 mg/m2 and pembrolizumab 200 mg) experienced a dose-limiting toxicity: grade 5 gastric hemorrhage upon intractable nausea and vomiting; grade 3 neutropenia resulting in treatment delay. None of 6 patients experienced a DLT at DL-1 (berzosertib 135 mg/m2, carboplatin AUC 4, gemcitabine 800 mg/m2 and pembrolizumab 200 mg). Most common grade ≥3 TRAEs were leukopenia (75%), neutropenia (67%), anemia (58%), thrombocytopenia (33%) and lymphopenia (33%). Berzosertib and gemcitabine exposure did not correlate with highest grade cycle 1 toxicity. Five of eleven evaluable patients (46%) experienced partial response.
Conclusion: In newly diagnosed advanced squamous NSCLC, berzosertib 135 mg/m2, carboplatin AUC 4, gemcitabine 800 mg/m2 and pembrolizumab 200 mg was the RP2D, which was both tolerable and associated with activity. This study did not proceed to phase II upon discontinuation of berzosertib development. Clinicaltrials.gov Identifier: NCT04216316.
The Oncologist , résumé, 2025