Novel Hsp Inhibitor May Offer NSCLC Salvage Option

Jason M. Broderick @jasoncology
Published: Friday, Jun 07, 2013

Dr. Suresh S. Ramalingam

Suresh S. Ramalingam, MD

Salvage therapy combining the novel heat shock protein 90 (Hsp90) inhibitor ganetespib with docetaxel significantly improved overall survival (OS) in some patients with non—small cell lung cancer (NSCLC) in the phase IIb/III GALAXY-1 trial. The results were presented at a press conference at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO).    

“This is the first randomized trial to document improvement in efficacy of an Hsp90 inhibitor in patients with cancer,” said Suresh Ramalingam, MD, professor of Hematology and Medical Oncology, and director of the Division of Medical Oncology at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

In GALAXY-1, ganetespib was administered following progression on first-line chemotherapy in advanced NSCLC. If approved, the drug would become the first newly available option in this setting in more than a decade. However, the data, while promising, came with some reservations.

While a significant survival benefit was observed in a prespecified group of patients whose time since diagnosis of advanced disease was >6 months, the survival improvement for the overall study population was not statistically significant. Even within the >6 month subgroup, the data were less robust than interim results reported last September at the 2012 Congress of the European Society for Medical Oncology. Further, it had been hoped that mutational analysis in GALAXY-1 would reveal a potential biomarker for ganetespib, and this has not yet happened.

Still, hope remains that a phase III study will support use of ganetespib in the salvage setting. “This research unto itself isn’t practice changing, but I think it does merit further investigation in this prespecified subgroup [of patients >6 months postdiagnosis]” said Marjorie G. Zauderer, MD, an ASCO spokesperson who participated in the press briefing.  

Heat shock proteins have long been an enticing target for cancer researchers. The proteins are called “chaperones” because newly formed proteins require their assistance to become structurally active and perform their biologic function. In lung cancer, proteins such as EGFR and ALK, which stimulate tumor growth, depend on Hsp90 for activation. The promise with ganetespib is that by inhibiting Hsp90, multiple oncoproteins that fuel lung cancer would be inhibited at the same time.

The phase II open-label GALAXY-1 trial randomized 252 patients with stage III/IV lung adenocarcinoma 1:1 to docetaxel alone (75 mg/m2 on day 1 of a 3-week cycle; n = 127) or the same dose of docetaxel plus ganetespib (150 mg/m2 on days 1 and 15; n = 125). The median patient age was 60 years, 56% were male, and 75% were current or former smokers. The median number of cycles administered was five for the combination arm versus four for docetaxel alone.

In the overall study population, a nonstatistically significant 2.4-month OS advantage was observed in the ganetespib arm versus the control arm (9.8 vs 7.4 months; hazard ratio [HR] = 0.82; P = .082). Progression-free survival (PFS) was also slightly higher in the treatment arm (4.5 vs 3.2 months), but the benefit was also not statistically significant (HR = 0.84; P = .038).

In patients enrolled in the trial >6 months postdiagnosis (n = 176), however, there was a statistically significant 4.3-month OS advantage with ganetespib (10.7 vs 6.4 months; HR = 0.61; P = .0093). PFS was also significantly improved in the treatment arm (5.4 vs 3.4 months; HR = 0.61; P = .0041).

The ganetespib combination was well tolerated with a toxicity profile similar to docetaxel monotherapy and consistent with safety outcomes in previous ganetespib studies. In the treatment arm, the most common adverse event across all grades was diarrhea (48%), which was usually manageable through over-the-counter treatments. The most frequently reported grade 3 or 4 adverse events in the ganetespib versus the control arm were neutropenia (37% vs 38%), febrile neutropenia (11% vs 2%), and anemia (8% vs 2%).

The acceptable toxicity profile for ganetespib is critical because safety issues have derailed promising Hsp inhibitors in the past. “The first-generation of Hsp inhibitors had a lot of toxicities and formulation issues, and that’s why we didn’t see them deliver on their promise,” said Ramalingam.




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