A multicenter Phase II study of ganetespib monotherapy in patients with genotypically-defined advanced non-small cell lung cancer
Mené sur 99 patients ayant reçu plusieurs lignes de traitement pour un cancer avancé du poumon non à petites cellules, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression à 16 semaines, et la toxicité du ganetespib, un inhibiteur de la protéine de choc thermique Hsp90, en fonction de la présence de réarrangements du gène ALK
Purpose:Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated non-small cell lung cancer (NSCLC) patients. Experimental Design:Patients were enrolled into Cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m2 ganetespib by intravenous infusion (IV) once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies. Results:Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; ninety-eight were assigned to Cohort A (n=15), B (n=17), or C (n=66), with progression-free survival rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n=1) or PCR-based assays (n=3), in crizotinib-naïve patients enrolled to Cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AEs); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia. Conclusions:Ganetespib monotherapy demonstrated a manageable side effect profile as well as clinical activity in heavily pre-treated patients with advanced NSCLC, particularly in patients with tumors harboring ALK gene rearrangement.