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Sunday, July 21, 2013
ONLINE FIRST: Lung Adenocarcinoma Salvage Therapy: Added Ganetespib, Heat Shock Protein Inhibitor, Shows Survival Extension in Phase II Study

BY PETER GOODWIN

 

CHICAGO – For patients with advanced adenocarcinoma of the lung not responding to first-line therapy, median overall survival improved from 7.4 to 9.8 months after use of the inhibitor of heat shock protein (Hsp)90 ganetespib, according to a report here at the American Society of Clinical Oncology’s Annual Meeting (Abstract CRA8007).

The Phase II GALAXY-1 study, reported by Suresh S. Ramalingam, MD, Chief of Thoracic Oncology at Winship Cancer Institute of Emory University, randomized 252 patients to treatment with docetaxel with or without ganetespib.

 

In an interview afterwards, he described Hsp90 as a molecular “chaperone” because it oversees several different molecular processes leading to cancer, such as those involving epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), which individually have therapeutic applications in cancer treatment. “Hsp90 is a unique target – by inhibiting it, you can actually get to a number of key oncoproteins that are critical for the cancer cell,” he said.

 

In the study, patients with stage IIIB/IV lung adenocarcinoma experienced “mild to moderate” gastrointestinal and other toxicities — described as manageable’ — with median progression-free survival (PFS) of 4.5 months in the docetaxel-plus-ganetespib arm compared with 3.2 months in the docetaxel arm. The unadjusted hazard ratio was 0.84 (p = 0.038), and the hazard ratio for overall survival was 0.82 (p = 0.082).

 

Patients who received the combination had an improved progression-free and overall survival,” Ramalingam said “Even more important and interesting, was the fact that patients who came in more than six months from the time of diagnosis had a hazard ratio of 0.6, for both PFS and overall survival with very significant p values [HR = 0.61, p = 0.0041 and HR = 0.61, p = 0.0093], and these were 70 percent of all patients enrolled to the trial -- suggesting that this group derived the maximal benefit from the combination therapy.”

 

He quoted improvements of 32 percent in median overall survival with the combination for the group as a whole and 67 percent gain for those diagnosed more than six months previously -- equivalent to a 39 percent reduced risk of death (p < 0.01) in this group.

 

“This is a large randomized Phase II trial, and these exciting observations have now prompted a Phase III trial, which will test the regimen against the same control arm,” he said. “We will enroll only patients who are more than six months from diagnosis.”

 

Andrew D. Seidman, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center and member of ASCO’s Cancer Communications Committee, was moderator of a news briefing covering the study. “It’s exciting to see a totally new class of agent that disrupts a novel pathway and has great implications for many different tumors,” he said.

 

Robert Pirker, MD, Professor of Medical Oncology and Program Director for Bronchial Carcinoma at the University of Vienna, was also impressed by the findings: “The data here are certainly promising. There’s no doubt about it,” he said in an interview. But he was cautious -- having reservations about reading too much into the findings among patients diagnosed more than six months before the treatment began.

 

Better Prognosis Selection

The time interval between diagnosis and treatment correlates with better outlook overall because it selects for patients who have a good prognosis, he explained. “And it might be easier to get a certain improvement in patients with a good prognosis compared with those who are rapidly progressing.”

 

Pirker said he agreed that the enhanced efficacy of Hsp90 inhibition in these patients would need to be established by further research, and said he thought the main value of the GALAXY 1 results was that they provide justification for conducting the Phase III research. “The take-home message is that you have a clear signal of efficacy at an acceptable toxicity in a randomized Phase II trial,” he said.

 

Still the heterogeneity of lung cancer is a hurdle to be overcome: “We need a randomized Phase III trial. This trial is ongoing, the trial is warranted, and this would then answer the question of whether the mechanism of inhibition of heat shock protein will result in improvement in outcomes.”

 

Changed Landscape

Ramalingam was adamant about the positive scene his group’s study had set: “If you look at the landscapes for lung cancer in the salvage therapy setting, for nearly 10 years there has not been a single drug approved. And we’ve reached a plateau for those patients. Having a combination or a drug that extends survival will be a breakthrough for these patients,” he said.

 

“We now have lung adenocarcinoma being viewed as distinct molecular subsets. You have EGF mutations that account for 15 percent, ALK translocations that account for five percent, and a slew of other abnormalities that are seen in one or less percent of patients. So for specific subgroups, if you can have a targeted agent, we treat them. But that’s only about 15 to 20 per cent of lung adenocarcinomas right now. So if we have a drug that broadly affects patients, it’s going to be very impactful for lung cancer.”