Reference Detail

Ref Type

Journal Article

PMID

(32669375)

Authors

Fennell DA, Danson S, Woll PJ, Forster M, Talbot D, Child J, Farrelly L, Sharkey A, Busacca S, Ngai Y, Hackshaw A, Wheeler GM

Title

Ganetespib in Combination with Pemetrexed-Platinum Chemotherapy in Patients with Pleural Mesothelioma (MESO-02): A Phase Ib Trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	26	18	2020 Sep 15	4748-4755	Clin Cancer Res

URL

Abstract Text

Ganetespib, a highly potent, small-molecule Heatshock protein 90 inhibitor, has potential efficacy in malignant pleural mesothelioma (MPM) via activity on critical survival pathways and known synergies with antifolates and platinum chemotherapy. We conducted a dose-escalation study to identify the maximum tolerated dose (MTD) of ganetespib in patients with chemotherapy-naïve MPM.MESO-02 (ClinicalTrials.gov: NCT01590160) was a nonrandomized, multicenter, phase Ib trial of 3-weekly ganetespib (100 mg/m2, 150 mg/m2, 200 mg/m2; days 1 and 15) with pemetrexed (500 mg/m2; day 1) and cisplatin (75 mg/m2; day 1) or carboplatin (area under concentration-time curve 5; day 1) in patients with MPM. Dose escalation was performed using the 3 + 3 design (cisplatin) and accelerated titration design (carboplatin). Secondary endpoints included best response, progression-free survival (PFS), and pharmacogenomic analyses.Of 27 patients enrolled (cisplatin, n = 16; carboplatin, n = 11), 3 experienced dose-limiting toxicities: grade 3 nausea (cisplatin, n = 1; carboplatin, n = 1) and grade 2 infusion-related reaction (carboplatin, n = 1). Ganetespib's MTD was 200 mg/m2. Partial response was observed in 14 of 27 patients (52%; 61% in 23 response-evaluable patients) and 13 of 21 (62%) with epithelioid histology. At the MTD, 10 of 18 patients (56%) had partial response, 15 of 18 (83%) had disease control, and median PFS was 6.3 months (95% CI, 5.0-10.0). One responder exhibited disease control beyond 50 months. Global loss of heterozygosity was associated with shorter time to progression (HR 1.12; 95% CI, 1.02-1.24; P = 0.018).Ganetespib can be combined safely with pemetrexed and platinum chemotherapy to treat patients with MPM. This class of agent should be investigated in larger randomized studies.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References