The obesity survival paradox refers to the unexpected association of obesity with improved cancer survival outcomes. This phenomenon has been previously reported in IO treated solid tumor malignancies. We aimed to assess the impact of obesity on clinical outcomes in patients with advanced solid tumors treated with contemporary 1L IO based therapy.
Using the International Metastatic Renal Cell Carcinoma (RCC) Database Consortium and Alberta Immunotherapy Database, patients with advanced RCC, non-small cell lung cancer (NSCLC) or melanoma treated with 1L PD-(L)1 inhibition +/- tyrosine kinase inhibitor (RCC), chemotherapy (NSCLC) or CTLA-4 inhibitor (RCC/Melanoma) were included. As has been done in other analyses in the obesity paradox field, a comparison with obese (BMI ≥ 30.0 kg/m2) vs. normal weight (BMI 18.5-24.9 kg/m2) individuals was performed. Underweight (BMI < 18.5 kg/m2) patients (to avoid cachexia as a confounder) and overweight (BMI 25.0-29.9 kg/m2) patients (to not dilute the effect of obesity) were excluded. Objective response rate (ORR), time to treatment failure (TTF) and overall survival (OS) were calculated.
Of 1067 patients, 30% and 33% of patients were found to be obese and normal weight, respectively. There were more males in obese vs. normal weight patients (66% vs. 55%, p<0.01). In NSCLC, PDL-1 expression was not different (p=0.39); and in RCC, there were less IMDC intermediate/poor risk patients among obese vs. normal weight patients (81% vs. 87%, p <0.01). In melanoma, there was no difference in BRAF status (p=0.68), LDH level (p=0.32), or metastatic burden (p=0.81) between obese vs. overweight patients. Overall, obese patients experienced a superior OS compared to normal weight patients (Table). Changing the BMI threshold to compare BMI ≥ 25 kg/m2 vs. normal weight yielded a similar result (median OS of 31.6 vs. 21.8 mons, p <0.01, respectively). Subgroup analysis by tumor type showed that the observed benefit was primarily driven by NSCLC. We were unable to detect a significant difference in OS among obese vs. normal weight patients with RCC or melanoma. In the RCC subgroup, there was a higher response rate in obese patients compared to normal weight patients. Clinical outcomes of patients with obesity vs normal weight mTTF=median TTF, mOS=median OS
Clinical outcome Obesity Normal weight P-value Overall cohort (N=669) N=316 N=353 - ORR %, (n/n) 47% (125/265) 40% (107/271) 0.07 mTTF (mon) (95% CI) 6.0 (4.9-7.5) 4.8 (3.5-7.4) 0.41 mOS (mon) (95% CI) 32.2 (25.1-53.4) 21.8 (16.3-28.1)) 0.01 RCC (N=250) N=140 N=110 - ORR 47% (58/123) 31% (28/90) 0.02 mTTF 7.6 (6.0-11.0) 6.8 (3.0-9.6) 0.86 mOS 47.8 (29.6-57.8) 30.9 (20.0-41.4) 0.41 NSCLC (N=238) N=84 N=154 - ORR 35% (24/69) 34% (38/112) 0.90 mTTF 5.8 (3.6-11.3) 3.7 (2.7-4.9) 0.20 mOS 24.8 (18.5-28.3) 8.6 (6.4-20.4) 0.02 Melanoma (N=181) N=92 N=89 - ORR 59% (43/73) 59% (41/69) 0.95 mTTF 4.6 (3.2-5.7) 6.9 (2.9-10.8) 0.48 mOS 22.2 (13.0-NR) 26.9 (18.9-NR) 0.62
The obesity paradox exists in NSCLC. We are unable to demonstrate this finding in RCC, although the response rate was higher in obese patients. In melanoma, there was no difference in outcomes among obese vs. normal weight patients. The effect of obesity on treatment outcomes may be dependent on primary tumor type.
Daniel Y.C. Heng.
Has not received any funding.
J.C. Wells: Travel/Accommodation/Expenses: Pfizer. S.K. Pal: Advisory/Consultancy: Pfizer, Novartis, Aveo, Myriad Pharmaceuticals, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Ipsen, Eisai; Honoraria (self): Novartis, Medivation, Astellas Pharma; Research grant/Funding (institution): Medivation. F. Donskov: Research grant/Funding (institution): Pfizer, Ipsen. T.K. Choueiri: Advisory/Consultancy: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck, Bristol-Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Prometheus Laboratories, Alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aven; Leadership role: Dana Farber Cancer Hospital, NCCN, Kidney Cancer Association, KidneyCan, ASCO; Shareholder/Stockholder/Stock options: Pionyr, Tempest Therapeutics; Honoraria (institution): NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Cor; Research grant/Funding (institution): Pfizer, Novartis, Merck, Exelixis, Tracon Pharma, GlaxoSmithKline, Bristol Myers Squibb, AstraZeneca, Peleton Therapeutics, Roche/Genentech, Celldex, Agensys, Eisai, Takeda, Prometheus, Ipsen, Corvus Phaarmaceuticals, Cerulean Pharma, Seatlle Genetics/Ast; Speaker Bureau/Expert testimony: Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel. D.Y.C. Heng: Advisory/Consultancy: Pfizer, Novartis, Bristol-Myers Squibb, Janssen, Astellas Pharma, Ipsen, Eisai, Merck; Research grant/Funding (institution): Pfizer, Novartis, Exelixis, Bristol-Myers Squibb, Ipsen. All other authors have declared no conflicts of interest.