Hsp90 Inhibitors May Soon Transition Into Clinic


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Suresh S. Ramalingam, MD

A number of key oncoprotein targets in lung cancer are activated in an Hsp90-dependent manner, and that’s why blocking Hsp90 is a rational therapeutic strategy.

— Suresh S. Ramalingam, MD

Inhibitors of heat shock protein 90 (Hsp90) look promising for the treatment of advanced non–small cell lung cancer (NSCLC) and have the advantage of not needing a specific mutation to target, said Suresh S. Ramalingam, MD, Professor and Chief of Medical Oncology at the Winship Cancer Institute of Emory University, Atlanta, during the 15th Annual International Lung Cancer Congress in Huntington Beach, California.

Underlying Mechanism

Hsp90s are important “chaperone proteins” to a number of oncoproteins. More than 200 Hsp90 “client proteins” have been described, many of which are relevant to NSCLC, such as the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR).

When Hsp90 binds to an inactive client protein, the protein then becomes activated and is able to perform its biologic functions.  Hsp90 inhibition prevents Hsp90 binding to the client, and the inactive client protein is instead degraded.

“Hsp90 inhibition is an indirect way of inhibiting oncoproteins, as compared to direct targeting,” Dr. Ramalingam noted. “A number of key targets in lung cancer are activated in an Hsp90-dependent manner, and that’s why blocking Hsp90 is a rational therapeutic strategy.”

Heat shock proteins have been recognized as cancer targets for decades, but only recently have inhibitors been developed that are safe and active. The first-generation Hsp90 inhibitors—which were 17-AAG derivatives—had issues with formulation, limited clinical activity, and undue toxicity, especially hepatotoxicity. The second-generation compounds, such as ganetespib, are structurally unrelated to 17-AAG, have higher potency, and are safer.

Indirect Targeting

According to Dr. Ramalingam, indirect targeting via Hsp90 inhibition may be preferable to direct molecular targeting in certain situations. For example, patients with ALK-positive tumors exposed to crizotinib (Xalkori) will develop resistance, often by mechanisms that are dependent on alterations to the receptor binding site. Since Hsp90 inhibition affects downstream proteins without binding to the receptors themselves, “no matter what the mechanism of resistance, ganetespib can inhibit the activation of the pathway,” he pointed out.

Dr. Ramalingam and his colleagues at Emory have also shown the drug’s effect on hypoxia-inducible factor-1 (HIF-1) alpha subunit, an important client protein that is involved in angiogenesis and that helps drive tumor aggressiveness. In rectal tumor biopsies, HIF-1 alpha was inhibited by ganetespib, leading to a reduction in VEGF.

“HIF-1 alpha can affect important pathways that are hallmarks of cancer,” he said. “This is another mechanism by which we can affect tumor growth and metastasis with Hsp90 inhibition.”

Clinical Data

As single agents, second-generation Hsp90 inhibitors such as ganetespib produce responses in 5% to 13% of unselected NSCLC populations, including ALK-positive and EGFR-mutated patients. This single-agent activity has been considered notable enough to explore combinations of Hsp90 inhibitors with other agents.

Synergy has been observed preclinically for the combination of ganetespib and docetaxel. The compounds have synergistic effects on the cell cycle, microtubules, and resistance pathways, and complementary effects on tumor biology. A phase I study proved the activity and tolerability of this duet, and led to the phase II GALAXY-1 trial, in which 241 patients with advanced adenocarcinoma and one prior regimen were randomly assigned to docetaxel alone (75 mg/m2 every 3 weeks) or with ganetespib (150 mg/m2 on days 1 and 15 every 3 weeks).1

One of the stratification factors was time since diagnosis of advanced disease (≤ 6 months vs > 6 months). Time > 6 months was suggestive of response to first-line therapy, and this constituted the chemosensitive subset.

“We found the regimen was tolerated well, and there was [essentially] no ocular toxicity, which we have seen with other second-generation compounds,” he reported. Two patients on the combination had grade 1 visual impairment.

The most common adverse events of all grades for the combination vs docetaxel alone were neutropenia (44% vs 45%), diarrhea (49% vs 16%), and fatigue (34% vs 24%). The most common grade 3 or 4 adverse events were neutropenia (38% vs 42%), febrile neutropenia (9% vs 4%), and anemia (8% vs 2%). The proportion of patients with adverse events leading to death were 15% vs 12%, and to treatment discontinuation were 7% vs 6% for the combination vs docetaxel, respectively.

Benefit in Chemosensitive Population

The best activity was observed in patients who were chemosensitive and in those with elevated lactate dehydrogenase (LDH), which may be a marker for upregulated HIF-1 alpha. Among patients with elevated LDH, median progression-free survival was 3.4 months with the combination vs 1.9 months with docetaxel alone, and median overall survival was 5.2 vs 4.3 months, respectively.

Somewhat surprisingly, patients with mutated KRAS derived no additional benefit from adding ganetespib, he reported.

Among the subset of 178 chemosensitive patients, the benefit was quite robust: median progression-free survival was 5.3 months with ganetespib/docetaxel vs 3.4 months with docetaxel (adjusted hazard ratio [HR] = 0.72; P = .030), and median overall survival was 10.7 vs 7.4 months, respectively (adjusted HR = 0.72; P = .040).

“Based on these findings, we are now conducting the phase III GALAXY-2 trial, evaluating this combination second-line in advanced adenocarcinoma patients who [had disease progression] more than 6 months from diagnosis [ie, are chemosensitive], with overall survival as the primary endpoint,” he said. This study is now enrolling.

Ganetespib is joined in the oncology pipeline by several other Hsp90 inhibitors. In ALK-positive NSCLC alone, there are six trials underway involving ganetespib, AUY922, and AT13387. Studies in breast cancer, prostate cancer, and other malignancies are also underway, he said. ■

Disclosure: Dr. Ramalingam has served on advisory boards for Amgen, Aveo, Ariad, AstraZeneca, Biodesix, Boehringer Ingelheim, Celgene, Lilly, Gilead, Genentech, and Novartis.

Reference

1. Ramalingam S, Shapiro G, Hirsh V, et al: GALAXY-1: Randomized phase II study of docetaxel with or without ganetespib in advanced lung adenocarcinoma: Results in biomarker sub-groups and all adenocarcinoma patients. World Conference on Lung Cancer. Abstract 003.01. Presented October 28, 2013.

 



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