High BMI Linked to Better Immunotherapy Outcomes in NSCLC

Ganessan Kichenadasse, MBBS, FRACP

A high body mass index (BMI) at baseline may be independently associated with improved survival outcomes in patients with non—small cell lung cancer (NSCLC) who receive immune checkpoint inhibitor therapy, according to study results published recently in JAMA Oncology.¹

The findings add to the growing evidence of an “obesity paradox” in patients with cancer in which a high BMI is linked to an increased incidence of some malignancies but may offer protection from others, investigators noted.

“This is an interesting outcome, and it raises the potential to investigate further with other cancers and other anticancer drugs,” lead investigator Ganessan Kichenadasse, MBBS, FRACP, a medical oncology researcher at the Flinders Centre for Innovation in Cancer in Adelaide, Australia, said in a statement.² “We need to do further studies into the possible link between BMI and related inflammation, which might help [us] to understand the mechanisms behind paradoxical response to this form of cancer treatment.”

Kichenadasse and colleagues noted that findings in other studies have suggested that high BMI correlates with improved survival rates in patients with advanced cancers and melanoma.

“Previous studies have explored a concept called an ‘obesity paradox’ where obesity is associated with increased risks for developing certain cancers and, counterintuitively, may protect and give greater survival benef its in certain individuals,” Kichenadasse said. “Our study provides new evidence to support the hypothesis that high BMI and obesity may be associated with response to immunotherapy.”

To examine the relationship between body weight and outcomes, investigators analyzed patient-level data from 4 clinical trials in which participants with NSCLC were treated with atezolizumab (Tecentriq), a PD-L1 inhibitor, or docetaxel. The post hoc analysis comprised data from 1434 patients who received atezolizumab and 890 treated with docetaxel during the OAK (NCT02008227), POPLAR (NCT01903993), BIRCH (NCT02031458), and FIR (NCT01846416) trials.

Among the evaluable patients, 49% were normal weight, 34% were overweight, and 7% were obese. BMI, calculated by weight in kilograms divided by height in meters squared, was categorized by the World Health Organization criteria: underweight (<18.5 kg/m²); normal weight (18.5 kg/m²-24.9 kg/ m²); overweight (25 kg/m²-29.9 kg/ m²); and obese (≥30 kg/m²). If the patient’s height or weight information for the calculation of BMI was missing, or if they fell into the underweight category, they were excluded from the analysis.

Many of the patients who were obese, compared with those who were not obese, were white, male, previous smokers, had a neutrophil-to-lymphocyte ratio <3, and lower C-reactive protein concentrations. Overall, the median age was 64 years (range, 57-70) and 62% were men.

Patients who were considered normal weight, overweight, and obese had significant differences in overall survival (OS) when treated with atezolizumab (P <.001). Patients who were obese and overweight had an improved OS (HR, 0.64; 95% CI, 0.51-0.81 and HR, 0.81; 95% CI, 0.68-0.95; respectively), compared with patients who had a normal BMI.

Additionally, there was a significant difference between PD-L1—positive and PD-L1–negative tumors (P value for interaction = .02).Patients considered overweight or obese had a larger survival advantage associated with PD-L1—positive tumors (overweight: HR, 0.73; 95% CI, 0.58-0.91 vs obese: HR, 0.48; 95% CI, 0.34-0.66) when compared with PD-L1–negative tumors.

Patients who were obese and had high PD-L1 expression (≥50% of tumor cells or ≥10% of tumor-infiltrating immune cells) had an OS HR of 0.36 (95% CI, 0.21-0.62) and for patients who were overweight, the HR was 0.69 (95% CI, 0.48-0.98).

Of note, those in the obese and overweight BMI groups of these trials did not have a statistically significant progression-free survival (PFS) when analyzed separately (overweight: HR, 0.89; 95% CI, 0.78-1.01 vs obese: HR, 0.86; 95% CI, 0.73-1.01; P = .09) but demonstrated an improved PFS together over patients with a normal BMI (HR, 0.88; 95% CI, 0.780.99; P = .03).

Similar to OS, those with high PD-L1 expression had the best PFS HR (obese: HR, 0.68; 95% CI, 0.49-0.94; overweight: HR, 0.72; 95% CI, 0.56-0.92) of the patients with PD-L1—positive tumors.

The incidence of treatment-related adverse events did not differ significantly between the BMI groups, with all-grade events at 65% for the normal BMI group, 64% for overweight BMI, and 65% for those in the obese BMI group (P = .92). Grade 3 through 5 events were 12%, 14%, and 12%, respectively (P = .66).

In patients treated with docetaxel in the OAK and POPLAR trials, no significant associates were observed between BMI and OS and PFS, and the OS for PD-L1—positive and –negative tumors did not significantly differ between the groups.

OAK, a phase III trial, and POPLAR, a phase II trial, randomized patients with advanced disease who failed prior platinum therapy to 1200 mg of atezolizumab or 75 mg/m2 of docetaxel administered intravenously every 3 weeks. BIRCH and FIR were both phase II trials of patients with PD-L1—positive tumors who were receiving atezolizumab as first line or later lines of treatment. PD-L1 positivity was defined as PD-L1 expression on ≥5% of the tumor or tumor-infiltrating cells based on the Ventana SP142 immunohistochemistry assay.

Investigators emphasized that the results are exploratory and need to be confirmed by future clinical trials. They also pointed out the limitation of BMI as a measurement of obesity because it is unable to differentiate fat from lean muscle mass and cannot be used to diagnose sarcopenia. BMI is also not reflective of body fat distribution.

References

1. Kichenadasse G, Miners JO, Mangoni AA, Rowland A, Hopkins AM, Sorich, MJ. Association between body mass index and overall survival with immune checkpoint inhibitor therapy for advanced non—small cell lung cancer [published online December 26, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.5241.
2. High BMI may improve cancer survival [news release]. EurekAlert! website. eurekalert.org/pub_releases/2019-12/fu-hbm122219.php. Published December 26, 2019. Accessed January 31, 2020.