A lack of association between BMI and chemoimmunotherapy efficacy in advanced non-small cell lung cancer: Secondary analysis of the IMpower150 and IMpower130 clinical trials.

BACKGROUND: Multiple studies have indicated that patients with high body mass index (BMI) may have favourable survival outcomes following treatment with an immune checkpoint inhibitor (ICI). However, this evidence is limited by several factors, notably the minimal evidence from randomised controlled trials (RCTs), the use of categorised BMI with inconsistent cut point definitions, and minimal investigation of contemporary combination ICI therapy. Moreover, whether overweight and obese patients gain a larger benefit from contemporary frontline chemoimmunotherapy in non-small cell lung cancer (NSCLC) is unclear. METHODS: This secondary analysis pooled individual patient data from the intention-to-treat population of the IMpower130 and IMpower150 RCTs comparing chemoimmunotherapy versus chemotherapy. Co-primary outcomes were overall survival (OS) and progression-free survival (PFS). The potentially non-linear relationship between BMI and chemoimmunotherapy treatment effect was evaluated using Multivariable Fractional Polynomial Interaction (MFPI). As a sensitivity analysis, chemoimmunotherapy treatment effect (chemoimmunotherapy versus chemotherapy) on survival was also estimated for each BMI subgroup defined by World Health Organisation classification. Exploratory analyses in the respective chemoimmunotherapy and chemotherapy cohort were undertaken to examine the survival outcomes among BMI subgroups. RESULTS: A total of 1282 patients were included. From the MFPI analysis, BMI was not significantly associated with chemoimmunotherapy treatment effect with respect to either OS (p = 0.71) or PFS (p = 0.35). This was supported by the sensitivity analyses that demonstrated no significant treatment effect improvement in OS/PFS among overweight or obese patients compared to normal weight patients (OS: normal BMI HR = 0.74 95% CI 0.59-0.93, overweight HR = 0.78 95% CI 0.61-1.01, obese HR = 0.84 95% CI 0.59-1.20). Exploratory analyses further highlighted that survival outcomes were not significantly different across BMI subgroups in either the chemoimmunotherapy therapy cohort (Median OS: normal BMI 19.9 months, overweight 17.9 months, and obese 19.5 months, p = 0.7) or the chemotherapy cohort (Median OS: normal 14.1 months, overweight 15.9 months, and obese 16.7 months, p = 0.7). CONCLUSION: There was no association between high BMI (overweight or obese individuals) and enhanced chemoimmunotherapy treatment benefit in front-line treatment of advanced non-squamous NSCLC. This contrasts with previous publications that showed a superior treatment benefit in overweight and obese patients treated with immunotherapy given without chemotherapy.

Low Risk of Hyperprogression with First-Line Chemoimmunotherapy for Advanced Non-Small Cell Lung Cancer: Pooled Analysis of 7 Clinical Trials.

BACKGROUND: Monotherapy immune checkpoint inhibitor (ICI) used in second- or later-line settings has been reported to induce hyperprogression. This study evaluated hyperprogression risk with ICI (atezolizumab) in the first-, second-, or later-line treatment of advanced non-small cell lung cancer (NSCLC), and provides insights into hyperprogression risk with contemporary first-line ICI treatment. METHODS: Hyperprogression was identified using Response Evaluation Criteria in Solid Tumours (RECIST)-based criteria in a dataset of pooled individual-participant level data from BIRCH, FIR, IMpower130, IMpower131, IMpower150, OAK, and POPLAR trials. Odds ratios were computed to compare hyperprogression risks between groups. Landmark Cox proportional-hazard regression was used to evaluate the association between hyperprogression and progression-free survival/overall survival. Secondarily, putative risk factors for hyperprogression among second- or later-line atezolizumab-treated patients were evaluated using univariate logistic regression models. RESULTS: Of the included 4644 patients, 119 of the atezolizumab-treated patients (n = 3129) experienced hyperprogression. Hyperprogression risk was markedly lower with first-line atezolizumab-either chemoimmunotherapy or monotherapy-compared to second/later-line atezolizumab monotherapy (0.7% vs. 8.8%, OR = 0.07, 95% CI, 0.04-0.13). Further, there was no statistically significant difference in hyperprogression risk with first-line atezolizumab-chemoimmunotherapy versus chemotherapy alone (0.6% vs. 1.0%, OR = 0.55, 95% CI, 0.22-1.36). Sensitivity analyses using an extended RECIST-based criteria including early death supported these findings. Hyperprogression was associated with worsened overall survival (HR = 3.4, 95% CI, 2.7-4.2, P < .001); elevated neutrophil-to-lymphocyte ratio was the strongest risk factor for hyperprogression (C-statistic = 0.62, P < .001). CONCLUSIONS: This study presents first evidence for a markedly lower hyperprogression risk in advanced NSCLC patients treated with first-line ICI, particularly with chemoimmunotherapy, as compared to second- or later-line ICI treatment.