A large randomized phase II study, GALAXY-1, finds that a novel heat shock protein (Hsp) 90 inhibitor, ganetespib, when combined with docetaxel in second-line (salvage) therapy, leads to longer overall survival compared to standard second-line docetaxel alone in patients with advanced lung adenocarcinoma that progresses after initial therapy. If confirmed in an ongoing phase III trial, this would be the first treatment to improve patient outcomes in this setting in a decade.
Suresh S. Ramalingam, MD, associate professor and chief of medical oncology at Winship Cancer Institute of Emory University, presented the results this week at the American Society for Clinical Oncology meeting in Chicago. Physicians and patients from Canada, Serbia, Ukraine, Spain, Germany and the United Kingdom also participated in the study.
"This is the first randomized study to demonstrate therapeutic benefit with a heat shock protein inhibitor in patients with cancer," Ramalingam says. "We hope that the ongoing phase III study will confirm our findings, as patients with this common form and stage of lung cancer urgently need more effective treatments."
Hsp90 belongs to a class of proteins known as molecular "chaperones." Chaperones help newly formed proteins assume the proper shape needed to perform their specific biologic function. Formation of many proteins that drive lung cancer growth, such as EGFR and ALK, requires Hsp90. Blocking such chaperones is a completely new strategy in cancer therapy, and is promising because it can disable many different cancer-fueling proteins at the same time. In addition, this strategy may still work in patients who develop mutations that make them resistant to traditional targeted drugs, because blocking the chaperone will inhibit the function of the mutated proteins, too.
All patients in this clinical trial had disease that progressed despite standard treatment with platinum-based chemotherapy. The current study reports on the primary enrollment stage of the trial, which completed in November 2012. The 252 patients were randomly assigned to treatment with docetaxel plus ganetespib or docetaxel alone. Those in the ganetespib arm had longer overall survival (9.8 vs. 7.4 months) compared to docetaxel alone.
The combination was particularly interesting in patients who were at least six months from initial diagnosis of advanced lung cancer as that group of patients experienced a 67 percent improvement in overall survival with the combination of ganetespib and docetaxel (median overall survival 10.7 months vs. 6.4 months). This group of patients is being studied in a recently launched phase III trial, GALAXY-2, that is comparing docetaxel plus ganetespib to docetaxel alone.
Early Hsp90 drugs did not succeed in clinical trials due to liver toxicity and insufficient efficacy. This is the first randomized clinical trial of a second-generation Hsp90 inhibitor and the first time an agent in this class has been shown to be both safe and effective.
This study was limited to patients with stage IV lung adenocarcinoma. Adenocarcinoma is the most common type of lung cancer overall, and accounts for about 45 percent of the 170,000 non-small cell lung cancer (NSCLC) cases diagnosed in the U.S. each year. Progress in second-line therapy for NSCLC has plateaued in the past decade, so the survival improvement seen with the addition of ganetespib is significant.
Researchers are planning to separately assess outcomes in subsets of patients defined by genetic markers in the tumor or markers in blood. In the present study to date, the observed improvements in progression-free survival and overall survival did not appear to be associated with EGFR mutations status, KRAS mutations status, or baseline level of LDH in blood.