ASCO: Heat Shock Protein 90 Inhibitor Shows Promise in NSCLC

Results from the GALAXY-1 trial showed that the novel second-generation heat shock protein 90 (HSP90) inhibitor ganetespib could potentially improve survival in patients with advanced-stage non–small-cell lung cancer (NSCLC).

Suresh S. Ramalingam, MD, of Emory University’s Winship Cancer Institute in Atlanta, presented results at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. He said that the HSP family of inhibitors are “important chaperone proteins for several key cellular oncogenic proteins.” Inhibiting HSP90 could inhibit proteins that are key to NSCLC’s development; in previous work, ganetespib has shown single agent activity and has been well tolerated as both monotherapy and in combination with docetaxel.

In the GALAXY-1 trial, 252 patients were randomized to either a combination of ganetespib and docetaxel or docetaxel alone. Initially, the trial included both adenocarcinoma and non-adenocarcinoma patients, but after 72 of the latter were enrolled, the investigators saw a signal for lack of efficacy and amended the trial to include only adenocarcinoma. The analysis presented at ASCO included 125 patients in the combination group and 127 in the docetaxel alone arm.

The median progression-free survival was 4.5 months in the combination group and 3.2 months in the monotherapy group, for a hazard ratio of 0.84 (90% CI, 0.65–1.07; P = .038). Overall survival was 9.8 months and 7.4 months for the two groups, respectively (HR = 0.82; 90% CI, 0.62–1.09; P = .082).

Patients were stratified by either less than or more than 6 months from diagnosis of advanced disease, and subgroup analysis suggested that those diagnosed more than 6 months prior to treatment were “deriving the robust benefit,” said Dr. Ramalingam. Progression-free survival in just those patients was 5.4 months for the combination group and 3.4 months for the monotherapy group (P = .0041), and overall survival was 10.7 months and 6.4 months, respectively (P = .0093).

“The observed improvement in survival at this point does not appear to be associated with EGFR or KRAS mutational status,” said Dr. Ramalingam. He noted that GALAXY-2, a phase III trial of the therapy in patients with diagnosis at least 6 months earlier, is ongoing.

Natasha B. Leighl, MD, of Princess Margaret Cancer Centre in Toronto, commented on the study and agreed that “HSP90 is a very interesting target in lung cancer.” She noted that it was somewhat surprising to see no treatment-related deaths in the study, and no increase in the number of patients that needed to stop therapy because of adverse events in the combination arm.

“I think we see an interesting survival signal in adenocarcinoma from this trial,” said Dr. Leighl. “The combination is more toxic, but dancing with docetaxel is always a bit dangerous.” There were more grade 3/4 adverse events with the combination, at 70% vs 56%.