Prediction of Early Response to Immune Checkpoint Inhibition Using FDG-PET/CT in Melanoma Patients

Abstract

We aimed to investigate, whether ¹⁸F-2-fluoro-2-desoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans performed at baseline (time point 0; TP 0) and three months after initiation of immunotherapy (time point 1; TP 1) can be used on a metastasis- and patient-level to predict the response to immune-checkpoint inhibition using FDG-PET/CT six months after treatment start (time point 2; TP 2) in metastatic melanoma patients. This single-center retrospective study considered metastatic melanoma patients treated with immune checkpoint inhibition from TP 0 to TP 2. An analysis on a metastasis- and patient-level was carried out. Tumor volume, standardized uptake values SUV (mean, maximum, and peak), metabolic tumor volume MTV and total lesion glycolysis TLG of each included metastasis were recorded at each time point, respectively TP 0, TP 1 and TP 2. Total tumor volume, total metabolic tumor volume and total lesion glycolysis per patient were also calculated at TP 0, TP 1 and TP 2. Treatment response was assessed at metastasis- and patient-level based on FDG-PET/CT scans at TP 2. 612 melanoma metastases in 111 patients were included. The analysis on a metastasis-level showed that metastatic SUVpeak at TP 1 and volume variation between TP 0 and TP 1 were the strongest negative predictive biomarkers for response. However, at TP 0, metastatic SUVmean and SUVpeak indicated a low negative prediction power, whereas initial metastatic volume was not a predictive biomarker. Also, melanoma metastases located in bone structures had a negative influence on the outcome at TP 2, particularly in women. The analysis on a patient-level showed, that total tumor volume, total metastatic tumor volume and total lesion glycolysis of all metastases three months after treatment initiation were strong negative predictive biomarkers for response to immunotherapy six months after initiation. Age and female sex were also found to be negative predictive biomarkers with lower predictive power. Interestingly, total tumor volume at TP 0 and number of metastases at TP 0 as well as the occurrence of early immune-related adverse events between TP 0 and TP 2 did not have any predictive value for early treatment response. FDG-PET/CT performed for treatment response assessment three months after initiation of immune checkpoint inhibition in metastatic melanoma patients can also be used to predict early response to treatment. On a metastasis-level SUV peak and volume variation of metastases are strong outcome predictive biomarkers. On a patient-level total tumor volume and semiquantitative parameters such as total metabolic tumor volume MTV and total lesion glycolysis TLG of all metastases are promising outcome predictive biomarkers. Also, early complete response on a metastasis- and patient-level seems to be predictive for lasting complete response.

Keywords: biomarkers; immunotherapy; melanoma; outcome prediction; positron emission tomography computed tomography.

Figure 1

Exclusion criteria. In order to optimize the accuracy and also the reproducibility of the measurements using a manual 3D-contouring tool in accordance with the aim of the investigation 92 melanoma metastases were excluded. In total, 612 melanoma metastases fulfilled our criteria.

Figure 2

Boxplot of metastatic volume per time point. In green (1) non progressive melanoma metastasis with clinical benefit six months after treatment. In red (0) progressive melanoma metastasis six months after treatment. First column from left: Metastatic volume at baseline TP 0. Column in the middle: Metastatic volume three months after initiation of immunotherapy TP 1. First column from right: Metastatic volume six months after initiation of immunotherapy TP 2.

Figure 3

Boxplot of standardized uptake value per time point SUVmean (first column from left), SUVmax (column in the middle) and SUVpeak (first column from right). In green non progressive melanoma metastasis with clinical benefit six months after treatment. In red progressive melanoma metastasis six months after treatment. First raw from the top: at baseline TP 0. Second raw: three months after initiation of immunotherapy TP 1. First raw from the bottom: six months after initiation of immunotherapy TP 2.

Figure 4

Sankey plot of treatment response over time from TP 0 to TP 2 per metastasis. In total, 612 melanoma metastases were included at TP 0. From the top to the bottom: Treatment response per metastasis. Progressive Disease PD in red; Stable Disease SD in orange; Partial Response PR in lime-green; Complete Response CR in green. From left to right: Time point baseline TP 0; three months after initiating immunotherapy TP 1; six months after initiation immunotherapy TP 2.

Figure 5

Predicted probability of clinical benefit at TP 2 based on volume ratio TP1 to TP 0 (in ml). On the x-axis: Volume ratio TP 1 to TP 0 (in ml). On the y-axis: Probability of clinical benefit at TP 2.

Figure 6

Sankey plot of treatment response over time from TP 0 to TP 2 per patient. In total 111 metastatic melanoma patients were included at TP 0. From the top to the bottom: Treatment response per patient. Progressive Disease PD in red; Stable Disease SD in orange; Partial Response PR in lime-green; Complete Response CR in green. From left to right: Time point baseline TP 0; three months after initiating immunotherapy TP 1; six months after initiation immunotherapy TP 2.

Figure 7

Receiver operating characteristic ROC of our backward regression model for outcome prediction in metastatic melanoma patients six months after initiation of immunotherapy.