Luminespib plus pemetrexed in patients with non-squamous non-small cell lung cancer. (September 2019)

• Record Type: Journal Article
• Authors: Noor, Zorawar S.; Goldman, Jonathan W.; Lawler, William E.; Telivala, Bijoy; Braiteh, Fadi; DiCarlo, Brian A.; Kennedy, Kathleen; Adams, Brad; Wang, Xiaoyan; Jones, Benjamin; Slamon, Dennis J.; Garon, Edward B.
• Is Part Of: Lung cancer. Volume 135(2019)
• Page Start: 104
• Page End: 109
• Publication Date: 2019-09
• Subjects: Luminespib (AUY922) -- Heat Shock Protein 90 (HSP90) Inhibitor -- Non-small cell lung cancer (NSCLC) -- Dihydrofolate Reductase (DHFR) -- Targeted therapy -- Pemetrexed; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2019.05.022
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: The maximum tolerated dose of luminespib is 55 mg/m 2 when given in combination with pemetrexed at 500 mg/m 2 . The objective response rate was 14% amongst patients treated at the maximum tolerated dose. Tolerability of luminespib plus pemetrexed is limited by ocular toxicity. Abstract: 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/m 2, 55 mg/m 2, or 70 mg/m 2 according to a standard 3 + 3 dose-escalation design along with pemetrexed at 500 mg/m 2 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/m 2 . 69% (N = 9) of patients experienced ophthalmologic toxicity related to luminespib. Maximum serum concentration (C max ) 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/m 2 per week. The combination of luminespib and pemetrexed demonstrated clinical activity. Tolerability of luminespib with pemetrexed is limited by ocular toxicity.