Quantitative imaging biomarkers of immune-related adverse events in immune-checkpoint blockade-treated metastatic melanoma patients: a pilot study

Abstract

Purpose: To develop quantitative molecular imaging biomarkers of immune-related adverse event (irAE) development in malignant melanoma (MM) patients receiving immune-checkpoint inhibitors (ICI) imaged with 18F-FDG PET/CT.

Methods: 18F-FDG PET/CT images of 58 MM patients treated with anti-PD-1 or anti-CTLA-4 ICI were retrospectively analyzed for indication of irAE. Three target organs, most commonly affected by irAE, were considered: bowel, lung, and thyroid. Patient charts were reviewed to identify which patients experienced irAE, irAE grade, and time to irAE diagnosis. Target organs were segmented using a convolutional neural network (CNN), and novel quantitative imaging biomarkers - SUV percentiles (SUVX%) of 18F-FDG uptake within the target organs - were correlated with the clinical irAE status. Area under the receiver-operating characteristic curve (AUROC) was used to quantify irAE detection performance. Patients who did not experience irAE were used to establish normal ranges for target organ 18F-FDG uptake.

Results: A total of 31% (18/58) patients experienced irAE in the three target organs: bowel (n=6), lung (n=5), and thyroid (n=9). Optimal percentiles for identifying irAE were bowel (SUV95%, AUROC=0.79), lung (SUV95%, AUROC=0.98), and thyroid (SUV75%, AUROC=0.88). Optimal cut-offs for irAE detection were bowel (SUV95%>2.7 g/mL), lung (SUV95%>1.7 g/mL), and thyroid (SUV75%>2.1 g/mL). Normal ranges (95% confidence interval) for the SUV percentiles in patients without irAE were bowel [1.74, 2.86 g/mL], lung [0.73, 1.46 g/mL], and thyroid [0.86, 1.99 g/mL].

Conclusions: Increased 18F-FDG uptake within irAE-affected organs provides predictive information about the development of irAE in MM patients receiving ICI and represents a potential quantitative imaging biomarker for irAE. Some irAE can be detected on 18F-FDG PET/CT well before clinical symptoms appear.

Keywords: 18F-FDG PET/CT; Immune-checkpoint inhibitors; Immune-related adverse effects; Quantitative imaging biomarkers.

Conflict of interest statement

Robert Jeraj is a co-founder and CSO of AIQ Solutions, Madison, WI, USA. No potential conflicts of interest were disclosed for other co-authors.

© 2021. The Author(s).

Figures

Fig. 1

AUROC as a function of organ SUV histogram percentile. The optimal SUV percentile (SUVOPT%) is defined as the percentile which maximized the AUROC

Fig. 2

ROC curves for the optimal SUV percentile (SUVOPT%) for predicting irAE status in the three target organs. The optimal cutoff (TOPT) was defined as the threshold which maximized the Youden’s index (sensitivity+specificity-1). The operating point corresponding to this threshold is marked on the ROC curve

Fig. 3

Patient maximum SUVOPT% dichotomized by irAE status (normal control NC versus adverse event AE). The maximum SUVOPT% value is taken for each patient from the set of all on-treatment PET scans. p-value from Wilcoxon rank-sum test

Fig. 4

Longitudinal SUVOPT% for patients who experienced irAE in bowel, lung, and thyroid. Dashed vertical lines indicate dates of clinical irAE identification, when available. The grey band indicates the 95% confidence interval for organ SUVOPT% of patients who did not experience irAE

Fig. 5

A 67-year-old patient with metastatic BRAF V600E-mutated melanoma with metastases to soft tissue, adrenal gland, and bone receiving pembrolizumab treatment in the first-line setting. Serial 18F-FDG PET maximum intensity projections were obtained before and during ICI therapy (a). After 8 months of immunotherapy (day 245), a follow-up 18F-FDG PET/CT scan showed a partial metabolic response in all metastatic lesions and diffusely elevated 18F-FDG uptake in multiple lung lobes. Axial slices at the lung base of the day 245 imaging study on CT (b), PET (c), and fused PET/CT (d). The patient reported only mild dyspnea and no other symptoms at his next oncology follow-up visit. Additional workup included a high-resolution CT scan and bronchoscopy. Immune-related pneumonitis was histologically proven on day 275, and the patient started treatment with systemic glucocorticoids (0.5 mg/kg/day methylprednisolone p.o.). Pneumonitis improved significantly after 3 months of corticosteroid treatment (day 371). 18F-FDG PET/CT follow-up performed 8 months later (day 614) shows complete response and normal 18F-FDG uptake within the lungs and lymph nodes. In this case, increased 18F-FDG uptake in the lungs was detected before the clinical presentation of irPneumonitis and 18F-FDG uptake gradually decreased as the symptoms improved on systemic corticosteroid therapy (e)

Fig. 6

A 68-year-old patient with metastatic BRAF-wild-type melanoma who was treated with ipilimumab/nivolumab combination. Serial 18F-FDG PET maximum intensity projections during ICI treatment are shown in (a). The baseline image (day 11) shows sites of metastatic disease in the pelvis and left lower extremity. Day 84 after treatment initiation, the patient has a near complete response (CR) of their disease and a moderate increase in 18F-FDG uptake in the bowel (SUV95%=3.1 g/mL). Day 173 scan indicates continued disease response but marked increased bowel uptake (SUV95%=4.0 g/mL) is apparent. Coronal slices from the day 173 study are shown for CT (b), PET (c), and fused PET/CT (d). The patient developed a grade 3 rash and was started on systemic corticosteroids 3 weeks before the day 173 scan. The patient was hospitalized on day 195 due to diarrhea with blood in the stool (grade 3 colitis) and irColitis was confirmed via colonoscopy and biopsy. Day 273 scan shows continued response and elevated bowel uptake as well as diffuse increase tracer uptake in the lungs indicating irPneumonitis. Axial slices from the day 273 imaging study are shown for CT (e), PET (f), and fused PET/CT (g). Day 399 scan shows ongoing disease response, partial resolution of irColitis, and complete resolution of irPneumonitis. The patient had a complete clinical resolution of irColitis after completing a course of corticosteroid therapy with a slow taper in addition to a course of Budesonide treatment. Quantification of organ 18F-FDG uptake demonstrated that elevated uptake in the bowel preceded clinical diagnosis of irColitis (h) and elevated uptake in the lung corresponded with the time of clinical diagnosis of irPneumonitis (i)

Fig. 7

A 54-year-old patient with metastatic BRAF wild-type melanoma who developed immune-related thyroiditis during treatment with immunotherapy with pembrolizumab. Serial 18F-FDG PET maximum intensity projections before starting and during ICI therapy are shown in (a). The baseline scan from the day 26 shows metastases in soft tissues and lung (both histologically proven). First follow-up scan (day 120) is indicating partial metabolic response in all metastatic lesions and increase in 18F-FDG uptake in the thyroid gland (SUV75%=2.5 g/mL). On day 154, patient was diagnosed with irThyroiditis according to thyroid hormone laboratory results and endocrinologist’s examination. Next 18F-FDG PET/CT (day 246) shows a marked progression disease with new metastatic lesions in bones, liver, lung, right adrenal gland, and soft tissues with decreased 18F-FDG uptake in the thyroid gland (SUV75%=1.7 g/mL). Coronal slices from day 120 are shown for CT (b), PET (c), and fused PET/CT (d). Increase in 18F-FDG uptake in the thyroid gland was seen on PET 34 days before clinical detection (e)