First Positive Trial of Heat Shock Protein 90 Inhibitor in Lung Cancer That Has Progressed after First-line Therapy 


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Ganetespib was well tolerated in combination with docetaxel, and overall survival was improved, especially in those patients who were at least 6 months from initial diagnosis of advanced cancer.

—Suresh S. Ramalingam, MD

The investigational heat shock protein (Hsp)90 inhibitor ganetespib plus docetaxel extended overall survival compared with docetaxel alone as second-line therapy in patients with advanced non–small cell adenocarcinoma of the lung that had progressed on first-line therapy in the randomized phase II GALAXY-1 trial, according to results presented at the ASCO Annual Meeting.1 If an ongoing phase III study of this combination confirms these findings and the FDA approves ganetespib, it would be the first new salvage therapy in this setting in a decade.

“Ganetespib was well tolerated in combination with docetaxel, and overall survival was improved, especially in those patients who were at least 6 months from initial diagnosis of advanced cancer,” said lead author Suresh S. Ramalingam, MD, Professor of Hematology and Medical Oncology and Director of Medical Oncology at the Winship Cancer Institute of Emory University, Atlanta. “GALAXY-2, the phase III trial just launched, will compare the combination vs docetaxel alone in patients who are at least 6 months from initial diagnosis of advanced cancer,” he noted.2

Role of Hsp90

Hsp90 is a “chaperone” protein that helps > 200 client proteins perform their biologic function. In fact, Hsp90 is required for many proteins that drive lung cancer growth, including EGFR and ALK. Blocking Hsp90 with an inhibitor such as ganetespib disables activation of these cancer-driving proteins.

Investigations of earlier-generation Hsp90 inhibitors were disappointing in terms of efficacy and safety. This is the first randomized trial of a second-generation Hsp90 inhibitor.

Study Design

The study enrolled 252 patients with advanced non–small cell lung cancer (stage IIIB/IV) that had progressed with one prior systemic therapy regimen  and randomly assigned them to docetaxel plus ganetespib vs docetaxel alone as salvage therapy.

Both groups were comparable at baseline. Median age was about 60 years, 56% were males, 75% were current or former smokers, 17% were from North America, and 83% were from Europe. Patients were stratified according to time from diagnosis (less than 6 months since diagnosis of advanced disease vs greater than 6 months), which was considered an indicator of sensitivity to prior therapy, Dr. Ramalingam said.

The combination was well tolerated, with safety findings similar to what is known about both ganetespib and docetaxel. Mild to moderate diarrhea was observed but was manageable with antidiarrheal medications. Grade 3/4 adverse events included neutropenia, fatigue, anemia, and febrile neutropenia, which occurred with a similar incidence in the two arms.

Survival Data

The combination of ganetespib plus docetaxel improved median overall survival in all patients in the study by 32% (9.8 vs 7.4 months) compared with docetaxel alone. Median overall survival improved by 67% (10.7 vs 6.4 months with docetaxel alone) in patients who were more than 6 months from initial diagnosis, a significant difference (P < .01).

The observed improvement in survival does not appear to be associated with EGFR or KRAS mutational status, Dr. Ramalingam commented.

Median progression-free survival was 4.5 months on the combination and 3.2 months with docetaxel alone, representing a 16% reduction in risk of progression. Dr. Ramalingam did not report on the study’s primary endpoint—the effect of the combination on progression-free survival in patients with a KRAS mutation—noting that these data are not mature. ■

Disclosure: Dr. Ramalingam has served in a consulting or advisory role with Synta, but has not received any financial compensation.

References

1. Ramalingam SR, Goss GD, Andric ZG, et al: 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). Abstract CRA8007. Presented June 3, 2013.

2. Fennell DA, Goss GD, Socinski MA, et al: GALAXY-2 trial: A randomized phase III study of ganetespib in combination with docetaxel versus docetaxel alone in patients with advanced non-small cell lung adenocarcinoma. 2013 ASCO Annual Meeting. Abstract TPS8126. Presented June 1, 2013.


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