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Published on: August 11, 2017
A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell
Mark A Socinski1, Jonathan Goldman, Iman El-Hariry
1University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15232, USA. socinskima@upmc.edu
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/m(2) 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.
Insights
Ganetespib showed clinical activity in advanced non-small cell lung cancer (NSCLC) patients, especially those with ALK gene rearrangements. The heat shock protein 90 (Hsp90) inhibitor demonstrated a manageable side effect profile in this heavily pretreated population.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Heat shock protein 90 (Hsp90) is a chaperone protein crucial for tumor growth and proliferation.
- Targeting Hsp90 is a strategy for cancer therapy.
- Ganetespib is a novel Hsp90 inhibitor.
Purpose of the Study:
- To evaluate the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC).
Main Methods:
- Phase II clinical study enrolling 99 patients with advanced NSCLC.
- Patients were assigned to cohorts based on EGFR, KRAS mutations, or neither.
- Treatment involved ganetespib 200 mg/m(2) weekly for 3 weeks, followed by 1 week rest, until disease progression.
Main Results:
- Progression-free survival (PFS) rates at 16 weeks were 13.3% (mutant EGFR), 5.9% (mutant KRAS), and 19.7% (no mutations).
- Four patients (4%) achieved partial response, all with ALK gene rearrangements.
- Serious adverse events occurred in 8.1% of patients, with diarrhea, fatigue, nausea, and anorexia being most common.
Conclusions:
- Ganetespib monotherapy demonstrated clinical activity in heavily pretreated advanced NSCLC patients.
- The drug exhibited a manageable side effect profile.
- Activity was particularly noted in patients with tumors harboring ALK gene rearrangement.
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