Ganetespib Aids Lung Cancer Survival

More than 200 human proteins are “clients” of the heat shock protein 90 (Hsp90) molecular chaperone, which is required to fold them into their active forms. The list includes oncogenic signaling proteins such as ALK and EGFR, and preclinical research has indicated that Hsp90 inhibition might preferentially kill tumor cells that are “addicted” to these oncogenic kinases. However, the first generation of geldanamycin-based inhibitors suffered from relatively low efficacy and high liver toxicity.

Now, interim analysis of a randomized phase II study has demonstrated that combining the second-generation Hsp90 inhibitor ganetespib (Synta Pharmaceuticals) with docetaxel can boost overall survival in patients with advanced lung adenocarcinoma.

“This is the first randomized trial to show that an Hsp90 inhibitor can benefit cancer patients,” said Suresh Ramalingam, MD, professor of medical oncology at the Winship Cancer Institute of Emory University in Atlanta, GA, who presented results on June 3 at the American Society of Clinical Oncology 2013 Annual Meeting in Chicago, IL.

In the GALAXY-1 trial, 252 patients with stage IV lung adenocarcinoma were assigned to receive either docetaxel or docetaxel plus ganetespib. Those who received the combination showed overall survival of 9.8 months versus 7.4 months for those in the control arm. That improvement did not reach statistical significance, but among 175 patients who started therapy more than six months after diagnosis, those who were given combined therapy demonstrated a 67% increase in survival over those treated with docetaxel alone. The follow-up phase III GALAXY-2 trial is now comparing the effects of combined treatment in that subset of patients, for whom the benefit is expected to be greatest.

Hsp90 inhibitors are expected to work best in combination with other therapies, Ramalingam noted. “In this trial, we're trying to exploit the synergy between Hsp90 and taxanes, particularly in inducing cell cycle arrest in G2-M phase, in which taxanes are most active,” he said. (Pre-clinical studies have shown that CDK1, PLK1, and other proteins involved in the G2-M phase are Hsp90 clients.) Ganetespib and other Hsp90 inhibitors are also thought to suppress resistance to taxanes by inhibiting AKT phosphorylation and HIF1-α expression.

Side effects for patients given the combination were manageable and similar to those seen in patients given only docetaxel. Ganetespib is hydrophobic, so it does not accumulate in the retina and cause eye disorders, an observed side effect of some other Hsp90 inhibitors, Ramalingam said.

About 90,000 people in the United States are diagnosed annually with lung adenocarcinoma, the most common type of lung cancer, and second-line treatments for the disease have not advanced much in recent years, Ramalingam said.

“If these preliminary results are confirmed in the phase III trial, ganetespib may have the ability to affect many patients with lung adenocarcinoma, and that also will pave the way for testing combinations of Hsp90 inhibitors with other chemotherapies or targeted agents for lung cancer,” he added.