Roxanne Nelson

June 03, 2013

CHICAGO — A novel agent has shown promise as a new second-line therapy for advanced lung cancer. When combined with docetaxel as second-line therapy, the novel heat shock protein 90 (Hsp90) inhibitor ganetespib (Synta Pharmaceuticals Corp.) improved outcomes in patients with advanced lung adenocarcinoma as compared with docetaxel alone.

The combination therapy improved overall survival, progression-free survival, and the overall response rate, as compared with docetaxel alone.

Overall survival was longer for those in the ganetespib arm (9.8 months) as compared with those taking docetaxel alone (7.4 months). For a prespecified subpopulation (175 patients, 69% of total accrual), whose time from diagnosis of metastatic disease to the beginning of therapy in the study was 6 months or longer, overall survival improved from 6.4 to 10.7 months.

The findings were presented here at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

The authors note that if these results are confirmed in an ongoing phase 3 trial (GALAXY-2), this would be the first treatment to improve patient outcomes in this setting in a decade.

"Ganetespib in combination with docetaxel was well tolerated with acceptable safety profile in patients with advanced lung cancer," said lead study author Suresh S. Ramalingam, MD, a professor of medical oncology at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

Dr. Suresh Ramalingam

"In this analysis, the combination of docetaxel plus ganetespib improved overall survival compared to docetaxel alone," he noted. "The median survival improved by 32% in all adenocarcinoma patients, and improved by 67% in the 6-month population."

The risk for death was reduced by 39% in this population, with significant P- value (P < .01), Dr. Ramalingam added. "Based on these promising results, we have initiated a phase 3 trial called GALAXY-2, that will have a similar design but that will only include the patient population greater than 6 months from diagnosis."

Molecular Chaperones: Completely New Strategy

Hsp90 belongs to a class of proteins known as molecular "chaperones," and is required for managing conformational development, stability, and function of proteins in the cellular environment. As a group, molecular chaperones play a pivotal role at the crossroads of multiple signaling pathways associated with cell proliferation and viability, and Hsp90 is an important hub in a variety of protein interaction networks associated with oncogenic pathways. The formation of many proteins that drive lung cancer growth, such as EGFR and ALK, requires Hsp90.

"It's very exciting to see a new class of agents," commented Andrew D. Seidman, MD, an oncologist at Memorial Sloan-Kettering Cancer Center in New York City. "It interrupts a very novel pathway and has great implications for a number of tumors."

Dr. Andrew D. Seidman

Blocking such chaperones is a completely new strategy in cancer therapy and is promising because it can disable many different cancer-fueling proteins at the same time. In addition, this strategy may still work in patients who develop mutations that make them resistant to traditional targeted drugs, because blocking the chaperone will inhibit the function of the mutated proteins, too.

"There has been a focus in breast tumors, and a number of pharmaceutical and biotech companies have been developing drugs in this area," said Dr. Seidman, who is an ASCO spokesperson and who also moderated a press briefing in which the study results were presented ahead of the session. "They are all different in terms of their toxicity profiles. This is a treatment that has a broad spectrum of activity and wouldn't necessarily be limited to 1 or 2 solid tumor types."

"So for me, that's also promising, as it goes beyond the potential of lung cancer," he added.

Dr. Ramalingam also pointed out that although there have been a number of trials with this agent, "they have not panned out, for a number of reasons." Early Hsp90 drugs did not succeed in clinical trials due to liver toxicity and insufficient efficacy.

This is the first randomized clinical trial of a second-generation Hsp90 inhibitor and the first time an agent in this class has been shown to be both safe and effective, he noted.

Study Details

Known as the GALAXY-1 study, this phase 2 trial was conducted on the basis of observations of synergistic preclinical interactions between docetaxel and ganetespib. In this study, Dr. Ramalingam and colleagues randomly assigned 252 patients with advanced lung adenocarcinoma (stage IIIB/IV) who had been treated with 1 prior systemic therapy and who were ECOG PS 0/1 to either docetaxel alone or to combination therapy with ganetespib.

Docetaxel was administered at 75 mg/m2 on day 1 of a 3-week cycle; in the experimental arm, docetaxel was given on day 1 and ganetespib at 150 mg/m2 on days 1 and 15.

The median progression-free survival was 4.5 months for all patients in the combination group and 3.2 months for those in the docetaxel alone group; that was reflected in a 16% reduction, explained Dr. Ramalingam.

For overall survival, there was a 27% reduction in the risk for death for the combination arm.

The majority of patients in the trial belonged in the group that was 6 months or longer from time of diagnosis to advanced-stage disease, he pointed out. The progression-free survival among these patients was 5.4 months for the combination therapy, compared with 3.4 months (P = .004). "This reduction was nearly 40%," Dr. Ramalingam said.

He also pointed out that the observed improvement in survival did not appear to be associated with EGFR or KRAS mutation status.

Marjorie Zauderer, MD, ASCO spokesperson and also a medical oncologist at Memorial Sloan-Kettering Cancer Center, noted that this "represents a potential advance in lung cancer, an area where we haven't had advances in a long time."

This research was supported by Synta Pharmaceuticals Corp. Dr. Ramalingam and several coauthors report financial relationships with Synta Pharmaceuticals.

2013 Annual Meeting of the American Society of Clinical Oncology. Abstract CRA8007. Presented June 3, 2013.


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