Rathi Pillai, MD
Despite positive results in the phase II GALAXY-1 study, the addition of ganetespib to docetaxel in the phase III GALAXY-2 study did not improve overall survival or progression-free survival in patients with advanced non–small cell lung cancer (NSCLC), according to data presented by Rathi Pillai, MD, at the 2016 World Conference on Lung Cancer in Vienna.1
Ganetespib is a highly potent, novel second-generation heat shock protein 90 (Hsp90) inhibitor with single-agent activity in NSCLC, particularly in patients with anaplastic lymphoma kinase (ALK)-positive disease. In combination with docetaxel in the phase II GALAXY-1 study, ganetespib improved outcomes in overall survival (hazard ratio [HR] = 0.84) and progression-free survival (HR = 0.82) compared to docetaxel alone in the second-line treatment of patients with advanced adenocarcinoma of the lung.
“Hsp90 functions as a chaperone to stabilize several oncogenic proteins important for the proliferation and survival of NSCLC cells, and the inhibition of Hsp90 leads to impaired signaling and functioning of key oncogenic pathways,” said Dr. Pillai, who is Assistant Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, Atlanta.
In a preplanned subset analysis of GALAXY-1, the combination of ganetespib and docetaxel showed the most improvement in outcomes among patients with a diagnosis of advanced metastatic disease more than 6 months from the time of enrollment. Based on these findings, investigators conducted the GALAXY-2 trial, but the phase III study did not meet expectations. Dr. Pillai presented the results of the first planned interim analysis at 336 events, which occurred on October 5, 2015.
GALAXY-2 is a randomized (1:1), international, open-label study of docetaxel with or without ganetespib in patients with epidermal growth factor receptor (EGFR) and ALK wild-type advanced adenocarcinoma of the lung diagnosed more than 6 months prior to study entry and progressive disease after 1 prior line of therapy. Docetaxel was dosed at 75 mg/m2 every 21 days in both arms, and ganetespib was dosed at 150 mg/m2 on days 1 and 15. The primary endpoint of the study was overall survival.
A total of 1,200 patients were screened in order to identify 672 patients who were randomized and included in the intention-to-treat population. Baseline characteristics were well matched between the two arms, with over 80% smokers, 64% with an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, 70% with normal lactate dehydrogenase levels, and 60% female.
No Significant Improvement
The overall response rate of ganetespib and docetaxel was 13.7%, compared to 16% with docetaxel alone. The rate of stable disease was slightly higher in the combination arm (56%) compared to the docetaxel arm (50%), although this was not statistically significant, Dr. Pillai reported. Treatment delivery was equivalent in the two arms, with a median of five cycles of ganetespib and docetaxel administered, compared to four cycles of docetaxel alone.
Median overall survival was 10.9 months in the combination arm and 10.5 months in the docetaxel arm. The primary endpoint of overall survival at interim analysis met the rules for futility with a hazard ratio of 1.111 (95% confidence interval [CI] = 0.899–1.372). There was no improvement in progression-free survival in the intention-to-treat population. Median progression-free survival was 4.3 months in the docetaxel arm compared to 4.2 months in the combination arm, with a hazard ratio of 1.161 (95% CI = 0.961–1.403).
Secondary endpoints of overall survival and progression-free survival in patients with elevated lactate dehydrogenase also failed to show a significant difference with combination therapy, she added.
Subgroup analysis found no overall survival benefit for the combination in any subgroup. The combination also resulted in a higher rate of adverse events, with 65% grade 3 to 4 adverse events, compared to 54% in the docetaxel arm.
Based on these data, the researchers concluded that the addition of ganetespib to docetaxel did not result in improved efficacy for salvage therapy of patients with advanced-stage lung adenocarcinoma. “Further development of Hsp90 inhibitors should be limited to patients with driver mutations with relevant client proteins,” Dr. Pillai added. ■
Disclosure: Dr. Pillai reported no potential conflicts of interest.
1. Pillai RN, Fennell DA, Kovcin V, et al: Phase 3 study of ganetespib, a heat shock protein 90 inhibitor, with docetaxel versus docetaxel in advanced non-small cell lung cancer (GALAXY-2). 2016 World Conference on Lung Cancer. Abstract 5232. Presented December 6, 2016.
David R. Gandara, MD
“With the negative results of this phase III trial and the discontinuation of ganetespib development, is this the end for this once promising drug class in non–small cell lung cancer (NSCLC), or is there still an opportunity for heat shock protein (Hsp) inhibitors to...!-->!-->