Zosia Chustecka

September 28, 2014

MADRID — "For the first time ever, we have seen a consistent benefit" from a drug in cancer cachexia, said David Currow, MD, from palliative and supportive services at Flinders University in Adelaide, Australia.

"We never thought that we would change this without changing the underlying cancer," he commented at a press briefing here at the European Society for Medical Oncology (ESMO) Congress 2014.

Cancer cachexia is a multifactorial problem, but it is typified by the loss of lean body mass, he said. Other symptoms of the wasting syndrome can include a loss of muscle, fatigue, weakness, and loss of appetite. It can be a limiting factor for treating patients as their cancer progresses, he noted.

Dr. David Currow

Dr. Currow was reporting results with an investigational agent, anamorelin (under development by Helsinn). This oral drug has a novel mechanism of action, acting as a mimetic of the so-called "hunger hormone" ghrelin, and resulting in the release of growth hormone.

Anamorelin significantly increased both lean body mass and body weight, and also improved appetite, in patients with advanced lung cancer and cachexia and anorexia in 2 clinical trials.

These results "will alter the way that we view the treatment of advanced cancer," he predicted, adding that they have potential to apply to patients right across the whole cancer spectrum.

ESMO spokesperson Roberto Labianca, MD, director of the Cancer Center, Ospedale Giovanni XXIII, in Bergamo, Italy, said: "This is really an important advance, as the study emphasizes the absolute need of establishing an approach of simultaneous palliative care in patients with advanced disease."

Significant Results in 2 Trials

The findings come from 2 phase 3 clinical trials, known as ROMANA 1 (n = 484) and ROMANA 2 (n = 495), presented at the meeting by Jennifer Temel, MD, from the Department of Medicine at the Massachusetts General Hospital in Boston. (Dr. Currow was the second author on the study.)

Both studies were conducted in patients with unresectable advanced non-small cell lung cancer (70% with stage IV disease) who had greater than 4 months' life expectancy and who had lost 5% or more body weight in the last 6 months or who had a body mass index below 20 kg/m². The average body weight was 68 kg in one trial and 63 kg in the other. Many of the patients (60% to 80%) were receiving chemotherapy or radiotherapy, or a combination of both.

Patients were randomized to anamorelin, given as 100 mg orally once daily, or placebo. The primary end point was lean body mass, assessed by dual-energy x-ray absorptiometry, as well as muscle strength, measured on a hand grip, and secondary end points were body weight and quality-of-life assessment.

Over the course of 12 weeks, patients on anamorelin significantly improved lean body mass, while the patients in the placebo control group continued to lose weight. The increase was already significant after 6 weeks, Dr. Temel noted.

In the ROMANA 1 study, the median increase in lean body mass was 1.10 kg with anamorelin, compared with a loss of 0.44 kg on placebo. In ROMANA 2, the increase was 0.75 kg, compared with a loss of 0.96 kg on placebo (P < .0001 for both studies).

In ROMANA 1, body weight increased by an average of 2.2 kg on anamorelin, compared with 0.14 kg on placebo. In ROMANA 2, body weight increased by an average of 0.95 kg, compared with a loss of 0.57 kg on placebo (P < .0001 for both studies).

In addition, patients were assessed on the Functional Assessment of Anorexia/Cachexia Therapy questionnaire. The total score did not change in one trial and showed a trend to improvement in the other, but a subdomain of the questionnaire that focused on anorexia/cachexia showed a significant improvement in scores, and these changes were clinically meaningful, especially in the ROMANA 1 trial, Dr. Temel said.

The hand-grip strength measurements did not show any difference between the 2 groups, and showed a decline in both study groups. However, Dr. Temel said that patients appeared to have had problems using this equipment.

Commenting on the results, Florian Strasser, MD, assistant professor from Cantonal Hospital St. Gallen in Switzerland, said this lack of effect of the drug on hand-grip strength requires further explanation. "Hand-grip strength measures only upper, but not lower, extremity strength, and it does not inform enough about physical function and daily living. The populations studied are relatively young and in a good performance status, without information on multimodal management, namely reversible secondary nutrition impact symptoms. Further data need, therefore, to show whether the improved symptoms and concerns are related to the known mechanism of the oral ghrelin agonist."

Patients are now being followed in an extension study, with a final assessment planned at 12 months. The manufacturer told Medscape Medical News that it is already starting interactions with the regulatory authorities in both Europe and the United States, but that they intend to wait for the 12-month data from the extension trial before the submission. "We believe that anamorelin is the only drug to have completed an important pivotal clinical program with a very large number of patients treated," the company said.

The drug was "incredibly well tolerated," Dr. Temel told the meeting. The most frequent drug-related adverse events in ROMANA 1 were hyperglycemia (5.3%) and nausea (3.8%), and in the ROMANA 2 study were hyperglycemia (4.2%) and diabetes (2.1%).

Hyperglycemia and diabetes can be expected as a result of the drug's mechanism of action, Dr. Temel told Medscape Medical News.

Anamorelin acts as a mimetic of ghrelin, which is secreted by the stomach and acts as a ligand for the growth hormone receptor. Anamorelin binds to this receptor, and the resultant release of growth hormone sets off a cascade of metabolic events affecting many different systems, including lean body mass, but also glucose metabolism, Dr. Temel explained. "So we anticipated that there may be some problems with glucose metabolism and breakdown with this drug, and I think we were happily surprised that the effects were quite mild, and no patients had problems tolerating the raised sugar levels."

Some patients did develop diabetes, and this is something that will need to be monitored, but the rate was low, she said. "This is manageable," she said, and noted that there are many cancer therapies that can lead to hyperglycemia, for instance steroids.

When asked if the drug would be likely to work in other cancer types, Dr. Temel said: "There is nothing about the positive results that are specific to non-small cell lung cancer.... If I had to bet a dollar, I would bet that it would also work in other types of cancer."

Responds to a Yet Unmet Frequent Need

The results are promising, commented Dr. Strasser, who is chair of the ESMO Palliative Care Working Group. "Anamorelin responds to a yet unmet frequent clinical need," he said in a statement.

This is the first anticachexia drug for which reports from 2 placebo-controlled double-blind phase 3 trials show a consistent effect on different components of the cancer anorexia–cachexia syndrome (CACS)," he noted.

"Do these trials already show a true clinical benefit, the clinical effectiveness, in a real-world population? Probably not yet," he said. But the data are promising, he emphasized, as the outcomes reported cover more than 1 relevant component of the CACS and are related to each other.

CACS is characterized by 4 interacting components: loss of muscle mass, decreased nutritional intake, metabolic and inflammatory alterations driven by active cancer disease, and decreased physical and psychosocial function, Dr. Strasser explained. Patients and their family members can become quite concerned by symptoms in each domain, such as weakness, loss of appetite, early satiety, taste problems, fatigue, or eating-related distress.

"Current management includes nutritional counseling, resistance training and increase of physical activity, psychosocial support, and multimodal symptom control. However, these interventions are limited in their effect, and no pharmacological treatment is available to address the relevant components of the syndrome," Dr. Strasser said. As well as affecting quality of life of patients and family members, this syndrome has an impact on anticancer treatment efficacy and toxicity, as well as overall survival.

In both the ROMANA trials, anamorelin showed an improvement of both muscle mass and patients' symptoms and concerns, with minimal and manageable adverse effects, Dr. Strasser said.

"Further data are needed to show whether the increase of muscle mass is accompanied by a gain of fat mass, which would confirm that patients can build reserves while having more appetite. This would be a novel finding: a drug stimulating appetite resulting in more muscle mass and increasing reserves," he added.

The studies were funded by Helsinn, the manufacturer or anamorelin. Dr. Temel and Dr. Currow have disclosed no relevant financial relationships. Several coauthors are company employees.

European Society for Medical Oncology (ESMO) Congress 2014: Abstract 1483O_PR. Presented September 27, 2104.


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