MADRID—Cancer-related cachexia—the wasting of lean body mass in advanced cancer patients—appears to be controlled and even reversed with the investigative drug anamorelin, researchers reported here at the European Society for Medical Oncology Congress.
In the so-called ROMANA I study, lean body mass increased 1.70 kg among patients on anamorelin compared with a 0.10 kg gain among patients with advanced non-small-cell lung cancer on placebo (p<0.0001), said David Currow, BMed, MPH, FRACP, Professor of Palliative and Supportive services at Flinders University in Adelaide, Australia.
In the companion trial, ROMANA II, patients treated with anamorelin gained 1.4 kg while those on placebo lost 0.6 kg (p<0.0001), he reported in an ESMO-sponsored news briefing.
“Not only was there an improvement in the patients on anamorelin, but the patients in the control group continued to decline. This is a drug that has the potential ability to influence cancer therapy.”
There was a similar pattern, he said, when the researchers looked at changes in overall body weight: In ROMANA I, body weight increased 2.5 kg among patients treated with anamorelin while placebo patients lost about 0.3 kg; In ROMANA II, patients on anamorelin gained about 1 kg, while placebo patients lost about 1 kg during the 12 week period. The differences were highly significant, he said, at the p<0.0001 level.
“What we have for the first time in more than a decade is a novel agent, and for the first time ever an agent that shows consistent response for people in advanced non-small-cell lung cancer in terms of lean body mass, in terms of body weight, and in terms of quality of life related to anorexia and cachexia, Currow said. “This has been a major problem in treating patients with advanced cancer.
“For the first time we see something that demonstrates essential change—with safety and toxicity profiles that are incredibly positive across two studies over 12 weeks.”
He suggested that treatment with the new drug will be practice-changing, and the moderator of the news conference, Giuseppe Curigliano, MD, Director of Experimental Therapeutics at the European Institute of Oncology in Milan, agreed: “This is a real breakthrough, I think, for our patients,” he said. “It will be useful in many patients when it becomes available. It is a very interesting drug.”
Trial will be Extended to 74 Months
Currow presented the pooled results of the ROMANA trials, but noted that the results of each trial held up separately, with significant results for one of the primary endpoints: lean body mass increase.
The second primary endpoint—handgrip strength—did not improve versus placebo in the 12-week trial. However, he said, the 12-week length of the trial might not have been long enough to demonstrate improvements in handgrip strength.
Also, he noted in an interview, there was no survival benefit seen in the 12-week trial. “However, the extension of this trial will go out to 74 months, and we will be able to determine if there is a survival benefit when those results come in.”
Curigliano said he expected anamorelin will be beneficial to many late-stage cancer patients: “We have a lot of patients—maybe 70 percent of our cancer patients with advanced disease—who will die from cachexia,” he said. “They will not eat; they will lose weight; they will die. So that we have a new drug that can increase the body weight and that can improve the quality of life for our patients is impressive.”
‘Interesting Mechanism of Action’
“What is very interesting is the mechanism of action,” he continued. “Anamorelin will bind with ghrelin in the gastric mucosa, and that increases production of growth hormone. Previous treatment with this condition is with dexamethasone, a steroid, which has its own side effects.”
FAACT QOL Questionnaire
The researchers administered the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire to patients to assess how treatment with anamorelin would affect quality of life.
At every three-month time point when the quality-of-life questionnaire was filled out, there was a significant difference in favor of treatment with the new drug in both trials: The FAACT subdomain scores in the ROMANA I study improved 4.3 points from baseline among the anamorelin patients, compared with an improvement of about 1.50 points in the placebo patients (P=0.0012); and in ROMANA II, the patients assigned to anamorelin improved about 3.1 points compared with 0.9 points among patients on placebo (P=0.0150).
To conduct the two international double-blind Phase III trials, patients diagnosed with unresectable Stage III or Stage IV non-small cell lung cancer and cachexia—defined as at least a five percent weight loss within six months or a body mass index of less than 20 kg/m2—were randomly assigned to treatment with placebo or anamorelin at 100 mg daily for 12 weeks.
The researchers assigned 603 patients to treatment with anamorelin and 297 patients to placebo arms of the trials. Currow said there were no within-study population differences between the trials. The ROMANA I trial recruited 484 patients; the ROMANA II trial enrolled 495 patients.
In the anamorelin patients, the most frequent drug-related adverse events were hyperglycemia (5.3%) and nausea (3.8%) for the ROMANA I trial. In ROMANA II, hyperglycemia (4.2%) and diabetes (2.1%) were the most frequent drug-related adverse events.
Currow explained that anamorelin, an orally active ghrelin receptor agonist, works by augmenting levels of ghrelin, an endogenous peptide secreted by the stomach. Upon binding to its receptor, ghrelin stimulates multiple pathways in the positive regulation of body weight, lean body mass, appetite, and metabolism, he said.
The study was sponsored by the company developing anamorelin, the Helsinn Group of Lugano, Switzerland.