A Multicenter Phase II Study of Ganetespib Monotherapy in Patients with Genotypically Defined Advanced Non–Small Cell Lung Cancer

Abstract

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 patients with non–small cell lung cancer (NSCLC). 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 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; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS 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 (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia. Conclusions Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement.

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

“…34,35), and mutant BRAF in melanoma (36). In particular, inhibition of HSP90 has been shown to have potent antitumor activity in mutant KRAS NSCLC models in vivo (37,38). Moreover, we have demonstrated that activation of Bim though ER stress plays an essential role in AUY922-induced apoptosis of mutant KRAS colon cancer cells ( Supplementary Fig.…”

“…This suggests that clinical evaluation of the efficacy of AUY922 in patients with metastatic colon cancers carrying activating mutations of KRAS is warranted, and that agents that potentiate the apoptosis-inducing effect of Bim, such as inhibitors of the prosurvival Bcl-2 family proteins, may be considered for combination with AUY922 in the treatment colon cancer (50). As a precedent, although the HSP90 inhibitor ganetespib showed only modest clinical activity in patients with mutant KRAS NSCLC, combinations of the inhibitor and other agents have been proposed (37,38).…”

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

“…HSP90 is an actively pursued target in oncology; however, no selective agents have yet been approved for human therapeutic use. HSP90 inhibitors, including ganetespib, have shown encouraging single-agent efficacy in early-stage clinical trials, most commonly in molecularly defined subgroups of tumors that are oncogenically "addicted" to specific client proteins, for example, ALK-rearranged NSCLC and HERamplified breast cancer (5,31,32). More typically, however, the results obtained for HSP90-directed monotherapy in unselected patient populations have proven less definitive (33).…”

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

“…Another possibility to overcome resistance to ALK inhibitors includes the combination with HSP90 inhibitors such as retaspimycin hydrochloride (IPI-504) and ganetespib (STA-9090) that have demonstrated clinical activity in ALK+ NSCLC patients [60][61][62]. Several clinical trials are evaluating HSP90 inhibitors in combination with ALK inhibitors.…”