A large randomized phase II study, GALAXY-1, finds that a novel heat shock protein 90 (Hsp90) inhibitor, ganetespib (STA-9090, Synta Pharmaceuticals) 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.The study results were presented at the 49th Annual Meeting of theAmerican Society of Clinical Oncology(ASCO), being held in Chicago, Il, May 31 – June 4, 2013.

If confirmed in an ongoing phase III trial, 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.” They are designed to 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.


Findings from a large phase II study point to a promising new second-line therapy for advanced lung cancer.

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?The goal of the GALAXY-1 trial was to select the patient population that would derive robust benefits with the novel combination,? said lead study author Suresh S. Ramalingam, MD, a professor of medical oncology at the Winship Cancer Institute of Emory University in Atlanta, Ga. ?The activity in patients with diagnosis of advanced disease greater than 6 months, together with the encouraging safety profile, suggest that ganetespib plus docetaxel has potential to be the first combination therapy for second-line treatment of adenocarcinoma of the lung.?

Unmet needs
?This is the first randomized study to demonstrate therapeutic benefit with a heat shock protein inhibitor in patients with cancer,? Ramalingam further noted. ?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.?

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 todocetaxel 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% 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.

?Ganetespib, in combination with docetaxel, shows promising early results in lung adenocarcinoma. We’re hopeful about the outcome of an ongoing phase III study, which could help more patients with this form of advanced lung cancer access this promising drug,? said Marjorie Zauderer, MD, ASCO spokesperson and lung cancer expert.

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.

Study design
The GALAXY-1 trial consists of two enrollment stages: a primary enrollment stage, which completed in November 2012 with 252 adenocarcinoma patients and an extension enrollment stage for those patients with certain biomarker disease characteristics, which completed enrollment in May 2013 with an additional 70 patients.

Interim analyses of overall survival from the primary adenocarcinoma enrollment stage were specified six and twelve months from the last patient enrolled. Data lock for the six-month follow-up analysis was May 15, 2013. As specified in the clinical trial protocol, analysis of the biomarker-defined patient populations will occur upon maturity of data from both the primary and extension enrollment stages, expected later this year.

Presented below are OS and PFS, in both the 252-patient all adenocarcinoma population (intent-to-treat; ITT) and the pre-specified patient population that was selected last year for evaluation in the ongoing GALAXY-2 Phase III trial: time since diagnosis of advanced disease greater than 6 months (?diagnosis > 6 months?). Patient baseline demographics, as well as post-study therapy, were generally well balanced between the two arms of the study for both populations.

Safety and efficacy results were reviewed by an independent data review committee consisting of a biostatician and four medical oncologists who did not participate in GALAXY-1. The study was further limited to patients with stage IV lung adenocarcinoma.

Significant survival improvement
Lung cancer is the leading cause of cancer-related death in the world, accounting for nearly 1.4 million deaths in 2008, according to the World Health Organization. The five-year survival rate for this disease is approximately 16%. Over half of people with lung cancer die within one year of being diagnosed. In the U.S., the American Cancer Society estimates that 228,000 cases of lung cancer will be diagnosed in 2013. Non-small cell adenocarcinoma, the most common type of lung cancer, accounts for about 45% of all NSCLC cases diagnosed lung cancers 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.

New lesion growth
A separate ASCO meeting abstract (e19097) reported preclinical results related to the ability of ganetespib to reduce cancer cell invasiveness and metastatic potential. These results are consistent with preclinical results from other groups on the role of Hsp90 in tumor invasiveness, angiogenesis, and metastasis [1-4].

In the GALAXY-1 trial, time to appearance of new lesions (TTNL) measured time from randomization until a new metastatic lesion was reported. In the diagnosis > 6 months population, TTNL increased from 6.9 months (D) to 11.3 months (G+D), with hazard ratio 0.5 (p=0.0053). This exploratory analysis suggests ganetespib may reduce the risk of emergence of new metastatic lesions by 50%
. TTNL has been specified as a secondary endpoint in the ongoing GALAXY-2 Phase III trial.

For more information:
Abstract #CRA8007: A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1).
Authors: Ramalingam SS, Goss GD, Andric ZG, Bondarenko I, Zaric B, Ceric T, Poddubskaya EV, et al.
Oral Abstract Sessions: Lung Cancer – Non-small Cell Metastatic
Date: Monday, June 3, 2013, 15:15 – 15:30 PM, CDT
Location: Room E Hall D2

References:
[1] Tsutsumi S, Beebe K, Neckers L. Impact of heat-shock protein 90 on cancer metastasis. Future Oncol. 2009 Jun;5(5):679-88.
[2] Staufer K, Stoeltzing O. Implication of heat shock protein 90 (HSP90) in tumor angiogenesis: a molecular target for anti-angiogenic therapy? Curr Cancer Drug Targets. 2010 Dec;10(8):890-7.
[3] Li W et al. Secreted Hsp90 is a novel regulator of the epithelial to mesenchymal transition (EMT) in prostate cancer. J Biol Chem. 2012 Nov 2;287(45):37732-44
[4] Wang J et al. High expression of heat shock protein 90 is associated with tumor aggressiveness and poor prognosis in patients with advanced gastric cancer. PLoS One. 2013 Apr 26;8(4):e62876

Clinical trials
NCT01348126 -Study of Ganetespib (STA-9090) + Docetaxel in Advanced Non Small Cell Lung Cancer (GALAXY)
NCT01798485 – A Phase 3 Study of Ganetespib in Combination With Docetaxel Versus Docetaxel Alone in Patients With Advanced NSCLC (Galaxy 2)

Photo:Suresh S. Ramalingam, MD, professor of medical oncology at the Winship Cancer Institute of Emory University in Atlanta, Ga. Photo Courtesy:Emory University in Atlanta, Ga.

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