David R. Gandara, MD

“With the negative results of this phase III trial and the discontinuation of ganetespib development, is this the end for this once promising drug class in non–small cell lung cancer (NSCLC), or is there still an opportunity for heat shock protein (Hsp) inhibitors to make a meaningful impact?” asked David R. Gandara, MD, Director of the Thoracic Oncology Program and Professor at the University of California, Davis, Comprehensive Cancer Center. As discussant for this presentation, he drew an analogy of ganetespib to “The Last of the Mohicans” for Hsp inhibitors.

He said Hsp90 is undoubtedly still an appropriate target for cancer therapy, as inhibitors have the potential to impact all six hallmarks of cancer, but measuring Hsp90 inhibition directly is difficult, and developing appropriate predictive biomarkers of patient outcomes from Hsp90 inhibition is a challenge. “In fact, we know that inhibition of the numerous client proteins for this class of agents can cause tumor growth inhibition and can induce apoptosis, so there’s a strong preclinical rationale,” he added. 

Synergy With Taxanes

Preclinical data support a broad-based approach to combining Hsp90 inhibitors with chemotherapy, but most of the Hsp90 inhibitors that were in development have been discontinued. “This agent showed particularly synergistic activity with taxanes; hence the trial with docetaxel,” he added. 

“In retrospect, it’s easy to say diagnosis > 6 months and lactate dehydrogenase level were not appropriate surrogates as predictive biomarkers for this Hsp90 inhibitor,” he said. “There is still an opportunity for this class of drugs to make a meaningful impact in NSCLC, but not with this broad-based approach and not with the surrogates used in the GALAXY-2 study.” ■

Disclosure: Dr. Gandara reported no potential conflicts of interest.