Luminespib plus pemetrexed in patients with non-squamous non-small cell lung cancer
Mené sur des patients atteints d'un cancer du poumon non épidermoïde non à petites cellules, cet essai randomisé analyse les caractéristiques pharmacocinétiques et l'efficacité, du point de vue du taux de réponse, du luminespib (un inhibiteur de HSP90) en combinaison avec le pémétrexed, et évalue la dose maximale tolérée
Background : Luminespib (AUY922) is a second-generation heat shock protein 90 (HSP90) inhibitor with demonstrated activity in non-small cell lung cancer (NSCLC). Since luminespib reduces levels of dihydrofolate reductase (DHFR), a key enzymatic target of pemetrexed, we assessed the safety and tolerability of luminespib in combination with pemetrexed in patients with previously treated metastatic non-squamous non-small cell lung cancer (NSCLC). We also sought to study the pharmacokinetics and correlate tumor dihydrofolate reductase (DHFR) expression with clinical response. Methods : Patients received weekly luminespib at either 40 mg/m2, 55 mg/m2, or 70 mg/m2 according to a standard 3 + 3 dose-escalation design along with pemetrexed at 500 mg/m2 followed by an expansion at the maximum tolerated dose (MTD). Results : Two-dose limiting toxicities (DLTs) were experienced in the 70 mg/m2 cohort, therefore the MTD was determined to be 55 mg/m2. 69% (N = 9) of patients experienced ophthalmologic toxicity related to luminespib. Maximum serum concentration (Cmax) of luminespib was associated with increased grade 2 drug related adverse events (DRAEs) (rs = 0.74, P < 0.01), with volume of distribution (VD) inversely associated with the number of DRAEs (rs = -0.81, P = 0.004) and ophthalmologic related DRAEs (rs = -0.65, P = 0.04). The best response was partial response in one patient for 20 months, prior to expiration of all luminespib. Amongst patients treated at the MTD, the objective response rate was 14%. Conclusion : In patients with previously treated metastatic NSCLC, the MTD of luminespib in combination with pemetrexed was 55 mg/m2 per week. The combination of luminespib and pemetrexed demonstrated clinical activity. Tolerability of luminespib with pemetrexed is limited by ocular toxicity.