Could Weight-Based Immunotherapy Dosing Improve Outcomes for Some?

Patients with cancer who were overweight or obese appeared to have better outcomes when they underwent immune checkpoint inhibitor (ICI) therapy administered with a weight-based dosing strategy, according to a single-center study.

With weight-based dosing, overweight cancer patients (BMI ≥25) had better survival than lighter patients, while both groups had similar outcomes with fixed dosing, reported David E. Gerber. MD, of the Harold C. Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center in Dallas, and colleagues, in the Journal for Immunotherapy of Cancer.

“What we are seeing is a big difference between heavier patients and lighter patients when you use weight-based dosing,” Gerber told MedPage Today. “When everyone gets a fixed dose, you don’t see the difference.”

Studies have shown that in melanoma, lung cancer, and kidney cancer, overweight and/or obese patients receiving immunotherapy have superior outcomes compared with individuals with lower BMI. And this “obesity paradox” has been unexpected, Gerber pointed out, “since when we think about obesity and cancer, we think about worse outcomes.”

Gerber noted that nivolumab (Opdivo) and pembrolizumab (Keytruda) were originally dosed by weight. However, in 2016 the FDA modified the dosage regimen for nivolumab to a flat dose of 240 mg, and also approved a flat dose of 200 mg of pembrolizumab for the treatment of non-small cell lung cancer (NSCLC). In 2020, the FDA approved a new pembrolizumab dosing regimen of 400 mg every 6 weeks, in addition the 200 mg every 3 weeks.

An examination of studies illustrating this obesity paradox shows that many were published in the era of weight-based immunotherapy dosing, Gerber pointed out. “And knowing that years back we had switched from weight-based immunotherapy to fixed-dose immunotherapy, I thought it was important to ask whether overweight patients still do better than underweight patients.”

Gerber and colleagues enrolled 297 patients (40% female; 59% with a BMI ≥25). Of these patients, most (53%) had NSCLC, while other cancer types included melanoma, renal cell carcinoma, head and neck squamous cell carcinoma, and small cell lung cancer. More than two-thirds (69%) of patients received fixed ICI dosing, while the remaining received weight-based dosing.

In general, patients with a higher BMI had improved outcomes with ICI therapy. For example, patients with a BMI ≥25 had a median progression-free survival (PFS) of 305 days, as compared to 160 days for the BMI <25 group (HR 0.69, 95% CI 0.51-0.94). A trend for improved overall survival (OS) was also seen, with a median OS of 503 days versus 414 days, respectively (HR 0.77, 95% CI 0.57-1.04).

Overweight patients whose treatment was weight-based had significantly improved PFS and OS compared with patients with a BMI <25:

• Median PFS: 406 vs 81 days (HR 0.53, 95% CI 0.3-0.96)
• Median OS: 742 vs 158 days (HR 0.56, 95% CI 0.33-0.95)

However, there was no difference in outcomes according to BMI with fixed dosing for either PFS (HR 0.79, 95% CI 0.54-1.14) or OS (HR 0.89, 95% CI 0.62-1.29).

“While BMI had a significant or near-significant association with PFS and OS in univariable analysis, there was no association with either endpoint in multivariable analysis,” Gerber’s group wrote. “However, the interaction of BMI and weight-based dosing had a near-significant trend toward association with PFS and was significantly associated with OS.”

They also reported that when outlying groups, such as patients with melanoma, or patients receiving anti-CTLA-4 therapy, were removed from the analysis, it still didn’t change their findings.

For example, they noted that anti-CTLA-4 therapies are most commonly used for melanoma treatment and are only administered by weight-based dosing. But the removal of patients receiving anti-CTLA-4 ICI alone, or in combination, created a cohort of 258 patients with results that didn’t differ meaningfully from the overall study population.

“Because the prevalence of overweight and obesity is increasing in the USA and globally, and the most commonly used ICIs now employ fixed-dosing approaches, further research into the interplay between patient characteristics, ICI dosing strategy, and treatment efficacy are warranted,” Gerber and colleagues concluded.