CHICAGO – A novel heat-shock protein inhibitor, ganetespib, showed glimmers of a survival benefit for lung cancer patients in a randomized phase II trial presented at the annual meeting of the American Society of Clinical Oncology.
Tested in combination with docetaxel, the experimental drug appeared to improve overall and progression-free survival, compared with docetaxel alone, as second-line therapy for patients with advanced non–small cell adenocarcinoma of the lung, Dr. Suresh Ramalingam reported.
Neither measure, however, was a primary end point of the study. Heat-shock protein 90 is a chaperone protein that activates other proteins binding to it so that they can perform their normal cellular function. Ganetespib binds to and inhibits Hsp90, causing oncoproteins to become inactivated and to degrade before they have had a chance to unfold into their functional configuration.
In the randomized phase II GALAXY-1 study, median progression-free survival reached 4.5 months among 125 patients assigned to ganetespib and docetaxel, compared with 3.2 months for 127 patients assigned to docetaxel and placebo (hazard ratio, 0.84; P = .038) in an unadjusted analysis.
However, after adjusting for sex, smoking status, lactate dehydrogenase (LDH), performance status, interval since diagnosis, and other common factors, the difference was no longer significant, said Dr. Ramalingam, chief of thoracic oncology and director of medical oncology, at Emory University in Atlanta.
Overall survival, in contrast, was not significantly different in an unadjusted analysis, at a median of 9.8 months for the combination and 7.4 months for docetaxel alone (HR, 0.82), but became significant after adjustment for potential confounders (adjusted HR, 0.73; P = .041).
"This is a first-in-class study showing the potential efficacy of this compound, and I think it presents a potential advance in an area of lung cancer where we haven’t had advances in a long time, and we’re all eagerly awaiting the outcome of the phase III trial," said Dr. Marjorie Zauderer, a medical oncologist and lung cancer specialist at Memorial Sloan-Kettering Cancer Center, New York.
Dr. Marjorie Zauderer
Dr. Zauderer was not involved in the study, but commented on it in a briefing held prior to the presentation of data later in the day.
Overall survival and progression-free survival were secondary end points in the trial. The co-primary end points were progression-free survival in patients with elevated LDH levels or tumors with mutations in KRAS, but these data were not reported. According to Synta Pharmaceuticals, maker of ganetespib, neither KRAS nor epidermal growth factor receptor (EGFR) mutations correlated with an overall survival benefit for the experimental arm of the trial.
When the investigators looked at only those patients who had been diagnosed more than 6 months before being enrolled in the trial (the "6-month population") they found that, in both unadjusted and adjusted analyses, the ganetespib and docetaxel combination was superior to docetaxel and placebo, with median overall survival of 10.7 vs. 6.4 months (unadjusted HR, 0.61; P = .0093; adjusted HR, 0.55; P = .0036), and median progression-free survival of 5.4 vs. 3.4 months (unadjusted HR, 0.61, P = .0041; adjusted HR, 0.62, P = .0075).
About 70% of the patients in the trial were included in the 6-month population. The follow-on GALAXY-2 phase III trial will enroll only those patients who have lived with an adenocarcinoma diagnosis for at least 6 months, the population that derived the greatest benefit in the current study.
The ganetespib and docetaxel combination was generally well tolerated, with manageable mild-to-moderate diarrhea being the most common adverse event.
The study was sponsored by Synta Pharmaceuticals. Dr. Ramalingam said that his institution receives research support from the company but that he had no personal financial disclosures. Dr. Zauderer reported having no conflicts of interest.