People have an image of stage III or IV lung cancer patients getting chemotherapy or chemoradiation, and they look terrible; they are losing weight. The fact is, when they respond, they can gain weight,” according to Philip Bonomi, MD, MS. He is the lead author of a phase III study showing that the investigational agent anamorelin hydrochloride significantly increased weight and lean body mass and improved anorexia-cachexia symptoms among patients with unresectable stage III/IV non–small cell lung cancer (NSCLC).

The patients were underweight or had lost more than 5% of body weight at the time of diagnosis. More than 50% had not received prior treatment. During the trial, most of the patients were being treated with chemotherapy or radiation, and some were treated with both.

Dr. Bonomi presented the results of ROMANA 1, an international double-blind randomized trial,¹ at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology and expanded on the clinical implications in an interview with The ASCO Post. Dr. Bonomi is Director of the Division of Hematology-Oncology at Rush and Alice Pirie Wirtz Professor of Medicine at Rush University Medical Center.

‘Would You Prescribe That for Your Patients?’

Following Dr. Bonomi’s presentation, the discussant, Jeffrey Crawford, MD,
Chief of the Medical Oncology and Transplantation Division and Associate Director of Clinical Research at Duke University Comprehensive Cancer Center, Durham, North Carolina, commented on the clinical benefit of anamorelin, as shown in the ROMANA 1 trial.

“If we ask ourselves this question: If you had a drug today that improved appetite with the resultant improvement in body weight and lean body mass, with minimal toxicity, would you prescribe that for your patients with cancer cachexia? For the patients we deal with on a daily basis in our clinic and their family members, I think the overwhelming answer to that is yes.” According to Dr. Crawford, “The pathway to regulatory approval of anamorelin would be a major step forward in the management of patients with cancer cachexia.”

Calling ROMAMA 1 “a very important trial,” Dr. Crawford lauded the inclusion of supportive care issues in the symposium agenda. Supportive care issues have continued to be in the news, as their value in quality of life and survivorship have gained more widespread recognition.

A Common and Debilitating Condition

The cancer anorexia-cachexia syndrome is a common and debilitating condition among patients with advanced NSCLC and is characterized by loss of appetite and decreased body weight, mainly through the loss of lean body mass (skeletal muscle), Dr. Bonomi explained. Cachexia “is associated with poor overall survival and worse quality of life,” he added. “All of us who have treated these patients have tried many things, with very limited success. So we definitely have an unmet need.”

Cachexia is seen even in patients with early-stage disease. “When you see weight loss in somebody who has stage I or II lung cancer, that is a bad prognostic factor. It usually means there is disease out there; you just can’t find it. As the disease progresses, these patients continue to lose weight.”

Patients can, however, gain weight during the course of their treatment. He cited a study “looking across 2,300 patients entered on three different phase III trials, and no matter what the regimen was, about 18% of patients or more gained about 5% of their starting body weight, and those patients had a significantly longer survival.” The patients had stage IV lung cancer, and not all of them had been losing weight at the time of their diagnosis. He noted that an abstract of the study was included at the World Lung Conference in Sydney, Australia, in 2013, and a manuscript is in preparation but has not yet been submitted.

Concomitant Cancer Therapy

Anamorelin is a novel, orally active, selective ghrelin receptor agonist with appetite-enhancing and anabolic activity. Released by the stomach, gherlin stimulates multiple pathways that regulate body weight, lean body mass, appetite, and metabolism. Anamorelin is being developed by Helsinn Therapeutics, which supported the study.

Patients were randomized 2:1 to take a 100-mg pill daily for 12 weeks or placebo. They could not be taking prescription medications intended to increase appetite or treat weight loss. Most patients were 61 to 62 years old, and 16% to 20% had a performance status score of 2. More than 75% of participants were male, and close to 99% were Caucasian. The patients were from Eastern and Western Europe, the United States, and Canada. Dr. Bonomi conjectured that the predominance of Caucasian patients was probably related to the patient population of the participating centers.

At the time of enrollment, 52.6% of the patients in the anamorelin group and 54.7% of those in the placebo group had not received prior treatment for NSCLC. During the trial, at the discretion of the treating physician, 89.2% of patients taking anamorelin were receiving concomitant chemotherapy and 11.5% were receiving radiation therapy. Among those in the placebo group, 86.3% were receiving concomitant chemotherapy, and 11.2 % were receiving radiation therapy.

Significant Benefits

Patients receiving anamorelin had a median increase of 1.10 kg in lean body mass, one of the study’s two coprimary endpoints, and 2.20 kg in body weight vs a 0.44-kg median decrease in lean body weight and a 0.14-kg median weight increase among those receiving placebo (P < .001).

In the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) questionnaire, where patients could register concerns about appetite, looking too thin, vomiting, and stomach pain, scores significantly improved for patients receiving anamorelin. FAACT scores at week 12 were 4.12 ± 0.8 vs 1.92 ± 0.8 for patients receiving placebo (P = .004).

The significant benefits in lean body mass, body weight, and FAACT scores were also observed in the identically designed ROMANA 2 study, “highlighting the consistency between these two independent trials,” Dr. Bonomi noted. (Combined results from ­ROMANA 1 and 2 were summarized at the European Society for Medical Oncology [ESMO] 2014 Congress in Madrid and reported in the November 1 issue of The ASCO Post.²) Survival data are expected in 2015.

“Patients’ symptoms and concerns about fatigue appeared to improve slightly or stabilize among patients receiving anamorelin and worsen among those receiving placebo, according to their responses to the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT–F) 2 questionnaire. Differences in scores attained statistical significance at week 9 (0.33 ± 0.9 in the anamorelin group vs −1.50 ± 1.0 in the placebo group, P = .331) and at week 12 (0.48 ± 1.0 vs −2.10 ± 1.0,
P = .0244).

Not Strong on Strength

Handgrip strength, the other coprimary endpoint, actually decreased in both groups: -1.00 kg in the anamorelin group and -2.69 in the placebo group.

“Training is another important variable. If you put muscle mass on and don’t have some associated training, are you going to see a change in grip or strength? My suspicion is you are not going to see it unless you train. And these patients did not do any training,” at least as part of the study, Dr. Bonomi noted.

“The handgrip not only didn’t correlate with gaining any muscle mass, it didn’t correlate with how the patients felt. The FAACT, which is a highly validated instrument, showed patients had significant improvements in cancer cachexia/anorexia. The scores went up by 3 or 4 points. Those are considered clinically meaningful by gurus in that area.”

Little Toxicity

“Anamorelin was well tolerated when administered daily over 12 weeks,” Dr. Bonomi reported. The most common drug-related adverse events were hyperglycemia, occurring in 5.3% of patients, and nausea, occurring in 3.8%. Treatment-emergent adverse events of any kind occurred in 14.4% of patients receiving anamorelin vs 9.3% of patients receiving placebo. Grade 3/4 drug-related adverse events occurred in < 1.5% of patients in both groups.

Among the 979 total patients in both ROMANA 1 and 2, about 55% continued on to the ROMANA 3 trial. That trial is looking at the effects of anamorelin and its tolerability in patients who take it for an additional 3 months. Although uncertain when the ROMANA 3 investigators will release results, Dr. Bonomi said, “I expect that results of ROMANA 3 will be described in an abstract submitted to ASCO for the 2015 Annual Meeting.”

Additional Studies

An ongoing study at Rush University Medical Center is looking at skeletal muscle mass index, as determined by serial CT scans of lean body masses of patients being treated with chemotherapy or chemoradiation, and correlating that with their response to therapy and survival. “We have already seen that increased weight correlates with longer survival. Now what we would like to see is, does increased weight, including increased lean body mass, correlate with regression of the tumor? Our clinical impression is yes, but we are going to do all the measurements,” Dr. Bonomi reported.

Noting that the investigators do not have a direct intervention for muscle mass, Dr. Bonomi commented, “Since anamorelin increases muscle mass, if we interfere with the muscle breakdown—and I realize I may be getting carried away, but I am the eternal optimist—might this anabolic effect have a positive impact on survival? I look forward to seeing the survival data from the ROMANA studies. If anamorelin doesn’t affect survival, its  effects on appetite and energy level are big positives  for lung cancer patients.” ■

Disclosure: Dr. Bonomi received honoraria from Helsinn for participation in advirosry boards. Dr. Crawford reported no potential conflicts of interest.

References

1. Bonomi P, Temel J, Currow D, et al: Anamorelin for the treatment of cancer anorexia-cachexia in advanced NSCLC: Results from ROMANA 1, a pivotal phase 3 study. 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract 5. Presented October 31, 2014.

2. Goodman A: Novel oral agent treats cachexia in patients with non-small cell lung cancer. The ASCO Post November 1, 2014.