Immune-related [18F]FDG PET findings in patients undergoing checkpoint inhibitors treatment: correlation with clinical adverse events and prognostic implications

Abstract

Background: Direct comparisons between [¹⁸F]FDG PET/CT findings and clinical occurrence of immune-related adverse events (irAEs) based on independent assessments of clinical and imaging features in patients receiving immune checkpoint inhibitors (ICIs) are missing. Our aim was to estimate sites, frequency, and timing of immune-related PET findings during ICIs treatment in patients with melanoma and NSCLC, and to assess their correlation with clinical irAEs. Prognostic implications of immune-related events were also investigated.

Methods: Fifty-one patients with melanoma (47%) or NSCLC (53%) undergoing multiple PET examinations during anti-PD1/PDL1 treatment were retrospectively included. Clinical irAEs were graded according to CTCAE v.5.0. Abnormal PET findings suggestive of immune activation were described by two readers blinded to the clinical data. Progression-free survival (PFS) and overall survival (OS) were analyzed with the Kaplan-Meier method in patients stratified according to the presence of irAEs, immune-related PET findings or both.

Results: Twenty-one patients showed clinical irAEs only (n = 6), immune-related PET findings only (n = 6), or both (n = 9). In patients whose imaging findings corresponded to clinical irAEs (n = 7), a positive correlation between SUV_max and the severity of the clinical event was observed (r_s=0.763, p = 0.046). Clinical irAEs occurred more frequently in patients without macroscopic disease than in metastatic patients (55% vs. 23%, p = 0.039). Patients who developed clinical irAEs had a significantly longer PFS than patients who remained clinically asymptomatic, both in the overall cohort (p = 0.011) and in the subgroup of (n = 35) patients with metastatic disease (p = 0.019). The occurrence of immune-related PET findings significantly stratified PFS in the overall cohort (p = 0.040), and slightly missed statistical significance in patients with metastatic disease (p = 0.08). The best stratification of PFS was achieved when all patients who developed immune-related events, either clinically relevant or detected by PET only, were grouped together both in the overall cohort (p = 0.002) and in patients with metastatic disease (p = 0.004). In the whole sample, OS was longer in patients who developed any immune-related events (p = 0.032).

Conclusion: Patients with melanoma or NSCLC under ICI treatment can develop clinical irAEs, immune-related PET findings, or both. The occurrence of immune-related events has a prognostic impact. Combining clinical information with PET assessment improved outcome stratification.

Keywords: Anti-PD1/PDL1; FDG PET; Immune checkpoint inhibitors; Immune-related adverse events; Prognosis.

Fig. 1

Sequential FDG PET imaging of patient #13, with stage IIIC melanoma under adjuvant Nivolumab following complete surgical resection of the primary tumor. At 3-month PET/CT follow-up an increased thyroid uptake was detected (red circle). Laboratory tests confirmed clinical hyperthyroidism, grade 2. On the same PET scan, left axillary lymph node uptake was shown (blue arrow). A biopsy confirmed the inflammatory nature of the finding. The 6-month PET scan showed a sarcoid-like reaction (green square) and increased uptake by the pectoral muscles bilaterally (yellow arrows), consistent with immune-related myositis, clinically unconfirmed

Fig. 2

Correlation between the clinical grade of the adverse event and the maximum standardized uptake value (SUV_max) extracted from [¹⁸F]FDG PET/CT at the time of clinical onset

Fig. 3

Exemplary cases of three patients who developed diarrhea with corresponding FDG colic uptake (expressed as maximum standardized uptake value - SUV_max) and colic wall thickness diameter (T) measured on low-dose co-registered CT. The uptake as well as the colic wall thickness increase with the growing severity of the clinical irAEs

Fig. 4

Kaplan-Meier curves of PFS in the whole sample stratified based on the occurrence of clinical irAEs (a), immune-related PET-findings (b) or on the presence of any immune-related findings (c). Note that the absence of immune-related events identifies a subgroup of patients with higher likelihood of early progression

Fig. 5

Kaplan-Meier curves of PFS in patients with metastatic disease stratified based on the occurrence of clinical irAEs (a), immune-related PET findings (b) or on the presence of any immune-related findings (c). Note that the absence of immune-related events identifies a subgroup of patients with higher likelihood of early progression also in patients with metastatic disease at baseline