Synta’s Ganetespib Could Break The Hsp90i Curse
This article was originally published in Pharmaceutical Approvals Monthly
Executive Summary
If ganetespib succeeds in Phase III, it could become the first new treatment for advanced lung adenocarcinoma in a decade, but the heat shock protein class has yet to produce a winner.
Synta Pharmaceuticals Corp.’s second-generation heat shock protein 90 (Hsp 90) inhibitor ganetespib may provide the first successful proof of principle for the class and the first drug in a decade to improve outcomes in the salvage setting for advanced lung cancer.
Top-line results for the Phase II GALAXY-I trial in patients with stage IV adenocarcinoma of the lung were reported at the American Society of Clinical Oncology meeting June 3 by Suresh Ramalingam, Emory University’s Winship Cancer Institute, the lead investigator on the trial.
A Phase III trial is ongoing.
The trial enrolled 252 patients who had failed treatment with platinum-based chemotherapy and randomized them to either ganetespib in combination with docetaxel or docetaxel alone. Among the entire intent to treat population, patients who took ganetespib had a median overall survival of 9.8 months, compared to 7.4 months for docetaxel alone, and median progression-free survival for the combination was 4.5 months versus 3.2 months for docetaxel.
But for the 176 patients in a prespecified subgroup who had received the advanced disease diagnosis at least six months prior to enrollment – the population chosen for the ongoing pivotal Phase III GALAXY-II trial – the results were compelling. Patients taking ganetespib had a 67%, 4.3 month median overall survival advantage (10.7 months versus 6.4 months). Median progression-free survival in the ganetespib group was 5.4 months, compared with 3.4 months for docetaxel alone. Seventy percent of patients with advanced adenocarcinoma fit into this category, Ramalingam said.
The overall response rate was also better for the entire intent to treat population, with ORR improved from 9% to 14% in the combination arm. In the diagnosis greater than six months group, ORR improved from 9% to 15%. The program is continuing in order to confirm the findings in a fully powered pivotal trial.
GALAXY represents the first randomized clinical trial of a second-generation Hsp90 inhibitor and the first time an agent in the class has been shown to be safe and effective, according to ASCO (Also see "Patient Deaths Stop Infinity Pharma’s Phase III HSP90 Trial In Cancer" - Pink Sheet, 15 Apr, 2009.).
Adenocarcinoma is the most common type of lung cancer overall, accounting for about 45% of the 170,000 cases of non-small cell lung cancer cases reported each year in the U.S. “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,” ASCO said.
The ganetespib/docetaxel combination “shows promising early results in lung adenocarcinoma,” said Marjorie Zauderer, Memorial Sloan-Kettering Cancer Center, an ASCO spokesperson on lung cancer. “We’re hopeful about the outcome of the ongoing Phase III trial.”
Picking The Right Population
The GALAXY program is a two-stage Phase IIb/III adaptive design trial planned to first identify a patient population for the Phase III trial by biomarker or other clinical characteristic. Altogether five subpopulations were defined by enrollment stratifications and biomarker endpoints: mutant KRAS, elevated LDH, ECOG performance status, smoking status, and time since diagnosis of advanced disease (<6 months vs. >6 months). The co-primary endpoints were progression-free survival for patients with elevated LDH and mutant KRAS. Secondary endpoints included overall survival.
While the primary enrollment stage of the trial closed in November 2012, an extension that sought to complete enrollment of all subpopulations closed enrollment in May with an added 70 patients. Because of the late accrual of those patients, Ramalingam explained during a press briefing, the analysis of all of the data from biomarker-defined populations has not yet matured. So far, however, the advantage in overall survival between the two trial arms correlates with neither KRAS nor EGFR mutant status.
Tumor genetic markers were evaluated from 202 patients who had sufficient tissue available for testing for KRAS mutation; 63 of those (31%) tested positive. One hundred and fifty-four patients had sufficient remaining tissue for testing by a panel of 65 exploratory biomarkers and of those 20 (13%) tested positive for EGFR mutation. Additional biomarker analysis is ongoing. Not enough tumor tissue was available to test for ALK mutations, Ramalingam noted, adding that contributing tumor tissue for testing is mandatory in the Phase III trial.
The safety profile for patients taking the combination was generally similar to docetaxel alone and consistent with earlier studies of ganetespib. There were two reports of visual impairment, which Ramalingam referred to as “visual toxicity,” a signal that may be peculiar to the Hsp90 class. Both cases were transient and grade 1 or 2.
The Appeal Of Targeting Chaperones
Hsp 90 has been a target that we have known for a couple of decades, but attempts to target the “chaperone” protein have been elusive, Ramalingam said. Earlier molecules failed in the clinic because of toxicities, particularly to the liver, and insufficient efficacy. According to Synta, ganetespib is structurally unrelated to those first-generation, ansamycin-related Hsp90 inhibitors.
Heat shock proteins are molecular chaperones that control the folding and activation of a number of so-called “client” proteins that drive tumor development and progression. By inhibiting Hsp90, ganetespib is attacking the chaperone, not the client, so it is not specific to any of Hsp90’s client proteins.
What has tantalized drug developers is the potential to disrupt the formation of multiple classes of proteins that drive cancer growth, as well as their adaptive mutations. If ganetespib is successful, it could be used to thwart any of Hsp90’s clients, which could include ALK, HER2, mutant BRAF and EGFR, androgen receptor, estrogen receptor, and JAK2, as well as proteins involved in angiogenesis, such as VEGF (Also see "New Drugs Build On Personalized Medicine Momentum In Lung Cancer" - Pink Sheet, 8 Oct, 2012.).