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ASCO 2013: Novel Heat Shock Protein Inhibitor Effective in Combination with Docetaxel as Second-line Therapy for Advanced Lung Cancer

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Key Points

  • A large randomized phase II study found that a novel heat shock protein (Hsp) 90 inhibitor, ganetespib, when combined with docetaxel in second-line therapy, leads to longer overall survival compared to standard second-line docetaxel alone in patients with advanced lung adenocarcinoma that progresses after initial therapy.
  • Patients with more than 6 months from time of diagnosis with advanced lung cancer derived the greatest benefit from the combination, experiencing a 67% improvement in overall survival.

A large randomized phase II study, GALAXY-1, found that a novel heat shock protein (Hsp) 90 inhibitor, ganetespib, when combined with docetaxel in second-line therapy, leads to longer overall survival compared to standard second-line docetaxel alone in patients with advanced lung adenocarcinoma that progresses after initial therapy. Patients with more than 6 months from time of diagnosis with advanced lung cancer derived the most benefit from the combination, experiencing a 67% improvement in overall survival.

“This is the first randomized study to demonstrate therapeutic benefit with a heat shock protein inhibitor in patients with cancer,” said lead study author Suresh S. Ramalingam, MD, Professor of Medical Oncology at the Winship Cancer Institute of Emory University in Atlanta. Dr. Ramalingam presented the findings at the 2013 ASCO Annual Meeting (Abstract CRA8007).

“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,” Dr. Ramalingam added. If the results are confirmed, this would be the first treatment to improve patient outcomes in this setting in a decade.

Molecular Chaperones

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.

Longer Overall Survival

All patients in this clinical trial had stage IV lung adenocarcinoma that progressed despite standard treatment with platinum-based chemotherapy. The current study reports on the primary enrollment stage of the trial, which was completed in November 2012. The 252 patients were randomly assigned to treatment with docetaxel alone, given at 75 mg/m2 on day 1 of a 3-week cycle, or docetaxel plus ganetespib at 150 mg/m2 on days 1 and 15. The median age of the patients was 60, about 60% were male, and 75% were current or former smokers.

Patients in the ganetespib arm had longer overall survival than those in the docetaxel alone arm (9.8 vs 7.4 months, respectively). “The adjusted hazard ratio was 0.73, reflecting a 27% reduction in the risk of death,” Dr. Ramalingam stated. For progression-free survival, “the median was 4.5 months for the combination and 3.2 months for treatment with docetaxel alone. The hazard ratio reflected an approximately 16% reduction in the risk of progression,” Dr. Ramalingam reported.

Deriving the Maximum Benefit

The researchers looked at the study’s prespecified stratification factors to determine which of those factors might help select the most sensitive patient population that would derive the maximum benefit from combination treatment. “That is where the greater than 6 month population came out as very significant,” Dr. Ramalingam stated. “For these patients, the progression-free survival is 5.4 months for the combination compared to 3.4 months, with a P value of .004, and the risk reduction was nearly 40%. When you look at overall survival, once again, the combination was associated with a favorable median survival—10.7 months compared to 6.4 months for the docetaxel therapy.” This represents a 67% improvement in median survival for patients with more than 6 months from time of diagnosis.

“Based on these promising results, we have initiated a phase III trial called GALAXY-2 that will have a similar design—but that will only include the patient population of those greater than 6 months from the time of diagnosis—for salvage therapy for lung adenocarcinoma,” Dr. Ramalingam announced.

Combination Well Tolerated

The combination of ganetespib and docetaxel was well tolerated. “The most common adverse event was mild to moderate diarrhea, which occurred within the first 2 or 3 days of getting this drug and can be easily managed with antidiarrheal agents,” Dr. Ramalingam reported. “Other common adverse events included some fatigue, nausea, and fever with neutropenia, which was seen in a slightly higher proportion in patients who got the combination,” he added.

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 research was supported by Synta Pharmaceuticals. Dr. Ramalingam reported a consultant or advisory role with Synta.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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