FLT-PET At 6 Weeks Predicts Response Assessed by CT at 12 Weeks in Melanoma Patients Treated With Pembrolizumab

Abstract

Purpose: Investigate the ability of F-fluorothymidine (FLT) PET combined with CT at 6 weeks to predict treatment response at 12 weeks after treatment with pembrolizumab.

Methods: Five patients with unresectable stage IV melanoma were included in this single-institution pilot study. Patients underwent FLT-PET/CT (baseline and 6 weeks) and CT (baseline and 12 weeks). FLT-PET/CT response and CT response were assessed using PET Response Criteria in Solid Tumors and immune Response Evaluation Criteria in Solid Tumors, respectively. Patients were categorized as responders (complete response, partial response) and nonresponders (stable disease, progressive disease). Agreement between 6-week FLT-PET/CT and 12-week CT was calculated using Cohen kappa's agreement. Eight baseline FLT-PET/CT parameters were extracted: SUVmax, SUVpeak, SUVSD, SUVmean, proliferative tumor volume, total lesion proliferation, bone marrow-to-liver SUVmax ratio, and spleen-to-liver SUVmax ratio. Eight delta-parameters were extracted at 6 weeks by calculating variation in FLT uptake as percentage change from baseline.

Results: Agreement between 6-week FLT-PET/CT and 12-week CT was kappa = 0.615, P = 0.025. Three of 5 patients were categorized as responders on CT by immune Response Evaluation Criteria in Solid Tumors. At baseline, responders had a lower mean proliferative tumor volume and a higher bone marrow-to-liver SUVmax ratio. At 6 weeks, responders demonstrated a decrease in tumor volume and tumor proliferation.

Conclusions: Our study illustrates the potential for FLT-PET/CT as an early predictor of response for patients with metastatic melanoma on anti-PD1 immunotherapy. Larger studies are indicated to confirm these findings.

Figure 1:

Timeline of treatment and imaging procedures.

Figure 2:

Left to right images: CT, FLT-PET, and FLT-PET whole body maximum intensity projection (MIP). A and B) A shows the baseline scans and B shows the follow-up scans. Patient 4’s dominant lesion in the right subcutaneous back increased in size on CT during the follow up FLT-PET scan from 52 mm to 72 mm, however the SUV of the lesion decreased by −14.4%. Thus, there was a discordance between CT size and FLT-PET SUV on that scan. Ultimately, the patient had stable disease on follow up CT 12 weeks later which suggests that the FLT was a better and earlier predictor of the ultimate outcome. C and D) C shows the baseline scans and D shows the follow-up scans. The patient’s left inguinal node did not change on CT during the follow up FLT-PET and remained at 19 mm short axis but FLT SUV decreased 21.9%. Ultimately, the patient had partial response on follow up CT 12 weeks later which again demonstrates the advantage of FLT over CT as an early predictor of response.

Figure 3:

Association between pre-therapy FLT-PET vs. CT objective response at 12 weeks. A) Baseline markers in FLT-PET include PTV, BLR, and SUV. Delta-biomarkers are calculated as the change from baseline to 6 weeks. B) Responders have a trend towards greater BLR at baseline and lower PTV at baseline. C) Responders have a trend toward lower delta-PTV compared to non-responders.

Figure 4:

A) Percent change in FLT SUVmax from baseline to early FLT-PET/CT at 6 weeks. Upper limit of the y-axis is 250%, but the value of patient 5 was +2800%. B) Percent change in FLT PTV from baseline to early FLT-PET/CT at 6 weeks. C) Overall survival of patients in months.

Figure 5:

Correlogram between baseline and delta imaging biomarkers. Correlation between pretreatment imaging biomarkers: FDG uptake of tumor, bone marrow, spleen (SUV), metabolic tumor burden (PTV, TLP), HISUV and metabolic proliferative biomarkers in hematopoietic tissues (BLR, SLR). Spearman’s correlation coefficients were used. The strength of each statistically significant correlation is displayed using a color code and the size of the circle. Clusters are performed using an unsupervised approach. A. Per patient analysis (n=5 pts) B. Per lesion analysis including PET at 6 weeks (n=13 lesions) C. Per lesion analysis including PET at 6 weeks and CT at 12 weeks (n=8 lesions)

Figure 6:

Disease-specific survival curve showing percent survival for responders (complete response and partial response) and non-responders (stable disease and disease progression)