Positive trial of ponsegromab may signal ‘start of a revolution’ for cancer cachexia
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Key takeaways:
- Patients with cancer cachexia assigned ponsegromab gained significantly more weight than those assigned placebo.
- Researchers observed improved appetite and higher physical activity in the ponsegromab group.
A randomized phase 2 trial of individuals with cancer cachexia showed those assigned ponsegromab gained significantly more weight than those assigned placebo.
Results also showed improved appetite and greater physical activity among individuals assigned ponsegromab (Pfizer).
“This is an exciting first step toward an intervention that may have profound implications on how we support patients as people going through their cancer treatment,” Eric Roeland, MD, FASCO, FAAHPM, medical oncologist, palliative care specialist and associate professor of medicine in the division of hematology/oncology at Oregon Health & Science University’s Knight Cancer Institute, told Healio. “I’m hopeful that this is the start of a revolution around scientific discovery and application for drug interventions for cancer cachexia.”
‘A huge unmet need’
Between 50% and 80% of individuals with cancer have cachexia.
The condition — per Fearon 2011 international consensus criteria for cancer cachexia — is defined as 5% or more weight loss over 6 months or at least 2% for patients with a certain BMI or sarcopenia.
Patients can have early, mid-phase or refractory-stage cachexia.
“Sadly, when you’re talking to clinicians about cachexia, what they’re thinking of is the severely emaciated person, and that’s refractory cachexia,” Roeland said. “Those of us in the field recognize that there’s weight loss, loss of appetite and loss of muscle that happens much earlier in the course of someone’s cancer — oftentimes just at presentation — and we haven’t done a great job of supporting the patient’s body as we’re also focusing our treatments on the cancer.”
There are no approved medications for cachexia in the United States or Europe.
Dexamethasone and megestrol acetate had previously been used to treat cachexia, but clinicians try to avoid them now due to potential adverse events.
“Patients feel like they’re failing because they’re not able to eat, which is compounded by caregivers watching their loved ones lose weight,” Roeland said. “This causes an immense amount of distress. Cachexia is a huge unmet need in up to 80% of people living with advanced cancers, most notably in lung and pancreatic cancer.”
Ponsegromab is a humanized monoclonal antibody that inhibits growth differentiation factor 15 (GDF-15).
The pathway GDF-15 uses “has emerged as a main modulator of anorexia and body-weight regulation and is implicated in the pathogenesis of cachexia,” researchers wrote.
Methods
Roeland and colleagues enrolled 187 patients (median age, 67 years; interquartile range, 60-74; 63% men; 62% white) with non-small cell lung cancer (40%), pancreatic cancer (32%) or colorectal cancer (29%) with cachexia.
Median baseline weight was 54.8 kg (interquartile range, 46-63.8).
Researchers randomly assigned patients in four equal groups to receive ponsegromab at one of three doses — 100 mg, 200 mg or 400 mg — or placebo every 4 weeks for three doses.
Body weight change at 12 weeks served as the primary endpoint. Secondary endpoints included safety, as well as changes in appetite, cachexia symptoms and physical activity.
‘They were enjoying food’
All ponsegromab cohorts gained weight compared with placebo, with median between-group differences as follows: 100 mg, 1.22 kg (95% CI, 0.37-2.25); 200 mg, 1.92 kg (95% CI, 0.92-2.97); and 400 mg, 2.81 kg (95% CI, 1.55-4.08).
In the 400-mg cohort, researchers reported consistent weight gain across subgroups, including those evaluated by cancer type, GDF-15 level, BMI, chemotherapy exposure and systemic inflammation.
“[Patients in] the 400-mg group were gaining over 6 pounds, which is incredibly challenging to achieve in that setting where you have this hypermetabolic weight loss syndrome,” Roeland said.
Both the 100-mg and 400-mg cohorts had significantly improved scores on the Functional Assessment of Anorexia Cachexia Therapy–Anorexia Cachexia Subscale and FAACT 5-Item Anorexia Symptom Scale compared with the placebo cohort.
A subset of patients assigned the 400-mg dose had 72 more minutes of nonsedentary physical activity per day compared with placebo. Their lumbar skeletal muscle index improved 2.04 cm2 per square meter, as well.
“We had 10 participants at our site and, early on in the study, I could tell there was something different happening,” Roeland said. “Patients were gaining weight, but, more importantly, they were enjoying food. I was hearing their caregivers state that [they were] enjoying being around the dinner table again or going out to eat. When food is no longer a struggle and more of a joy and an opportunity for social connection, that tells me we're on the right path.”
Researchers observed fewer any-cause adverse events in the ponsegromab groups (range, 67% to 74%) than the placebo group (80%).
Common adverse events associated with ponsegromab included diarrhea, cancer progression, anemia, hypokalemia, nausea, vomiting and pyrexia. The placebo cohort had higher rates of diarrhea, nausea and vomiting.
“There was no clear safety signal here, and maybe a suggestion that the patients receiving ponsegromab had fewer adverse events, which clearly needs to be explored further,” Roeland said.
Researchers are planning additional late-stage clinical trials. Eventually, Roeland would like future studies to evaluate ponsegromab for other cancer types.
“Here we have novel drug discovery in supportive care, and that’s not common to hear about,” Roeland said. “The last time we heard about exciting drug development like this happening [was] in the 1980s with the development of novel antiemetics to prevent chemotherapy-induced nausea and vomiting.
“It’s because of our colleagues across the gastrointestinal and thoracic oncology teams and, of course, the patients that we were able to get this study going and successfully accrued,” Roeland added. “Their voice is central to our ongoing efforts. I’m incredibly impressed by their engagement at a moment of absolute crisis. The patients continue to inspire us and keep us committed to this critical work.”
For more information:
Eric Roeland, MD, FASCO, FAAHPM, can be reached at roeland@ohsu.edu.
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