Sarcopenia and high NLR are associated with the development of hyperprogressive disease after second-line pembrolizumab in patients with non-small-cell lung cancer

Abstract

The aim of this multi-center retrospective study was to evaluate the incidence of hyperprogressive disease (HPD) after second-line treatment with pembrolizumab in patients (n = 167) with metastatic non-small-cell lung cancer (NSCLC) whose tumors expressed programmed cell death ligand 1 (PD-L1) in ≥ 1% and to search for hematological and imaging biomarkers associated with its development. Prior to chemotherapy, neutrophil : lymphocyte ratio (NLR1) and platelet : lymphocyte ratio (PLR1), and prior to immunotherapy, NLR2 and PLR2 were retrospectively analyzed. The psoas major muscle area (PMMA) was calculated at the L3 position on computed tomography before chemotherapy (PMMA1) and before immunotherapy (PMMA2) (n = 112). Patients with ∆PMMA (1-PMMA2/PMMA1) × 100 ≥ 10% were considered to have sarcopenia (low muscle mass). After treatment with pembrolizumab on the first computerized tomography (CT) scan evaluation, patients were subdivided as follows as: hyperprogressors (HPs), progressors (Ps), non-progressors (NPs) and pseudoprogressors (PPs). HPs had significantly higher ∆PMMA levels, NLR2 and PLR2 than the other patients. Moreover, in multinomial logistic regression analysis, higher levels of ∆PMMA were associated with a decreased likelihood of being a P [odds ratio (OR) = 0·81; 95% confidence interval (CI) = 0·65-0·99; P = 0·047] or an NP (OR = 0·76; 95% CI = 0·62-0·94; P = 0·012) versus an HP. Higher NLRs tended to decrease the likelihood of being a P versus an HP (OR = 0·66; 95% CI = 0·42-1·06; P = 0·09) and significantly decreased the likelihood of being an NP versus an HP (OR = 0·44; 95% CI = 0·28-0·69; P < 0·0001). Our data suggest that a high pre-immunotherapy NLR2 and the presence of sarcopenia are potential risk factors for the development of HPD.

Keywords: hyperprogressive disease; neutrophil : lymphocyte ratio; sarcopenia.

Fig. 1

Calculation of the rate of change of the psoas major muscle area (PMMA). The total PMMA was calculated as the sum of both right and left PMMA at the L3 position. In the case presented before chemotherapy, the left and right PMMA were 5·74 and 7·16 cm², respectively; before immunotherapy, the left and right PMMA were 4·98 and 6·12 cm², respectively. The change rate of PMMA was calculated as follows: (1 – 11·1/12·9) × 100 = 13·9%.

Fig. 2

Receiver operating curve (ROC) curve analysis using the neutrophil : lymphocyte ratio (NLR), the platelet : lymphocyte ratio (PLR) and psoas major muscle area (∆PMMA) to differentiate between patients with and without hyperprogressive disease. The diagnostic accuracy of biomarkers was determined by obtaining the largest possible area under the curve (AUC) in ROC analysis. (a) NLR2 AUC = 0·85; (b) PLR2 AUC = 0·79; (c) ∆PMMA AUC = 0·89.

Fig. 3

Kaplan–Meier estimates of overall survival (OS) in hyperprogressors (HPs), pseudoprogressors (PPs), progressors (Ps), non‐progressors (NPs) and patients with sarcopenia. (a) HPs had a significantly shorter mean OS [9·83 months; 95%, confidence interval (CI) = 8·44–11·22] than PPs (19·18 months; 95%, CI = 14·13–24·22) (log‐rank test P = 0·001), Ps (17·32 months; 95%, CI = 15·67–18·98) (log‐rank test P < 0·001) and NPs (29·79 months; 95%, CI = 26·87–32·71) (log‐rank test P < 0·001). (b) Patients with psoas major muscle area (∆PMMA) ≥ 10% had a significantly shorter mean OS (13·5 months, 95%, CI = 11·7–15·2) than patients with ∆PMMA < 10% (31·5 months, 95%, CI = 27·6–35·8) (log‐rank test P < 0·001).