Decrease in tumor content assessed in biopsies is associated with improved treatment outcome response to pembrolizumab in patients with rare tumors

Abstract

Background: Decreased tumor content (TC) in resection specimens after neoadjuvant therapy is used to predict prognosis. We investigated whether TC assessed in biopsy specimens or the shift in TC from baseline to on-treatment can be used accordingly to predict response in patients with rare tumors who were treated with pembrolizumab.

Methods: A total of 57 tumors (represented by 173 baseline and 179 on-treatment biopsies) from 57 patients with rare tumors participating in an ongoing phase II clinical trial of pembrolizumab were evaluated. TC was estimated on H&E-stained slides and tumors were dichotomized into low and high TC according to a cut-off of 10%. Necrosis, proliferative fibrosis (PF) and normal tissue were assessed in on-treatment biopsies. TC at baseline and on-treatment, as well as the shift in TC from baseline to on-treatment, was correlated with clinical response defined according to Response Evaluation Criteria in Solid Tumors.

Results: A decrease in TC was seen in 14% (n=8); no change in TC was seen in 75% (n=43); and an increase in TC from baseline to on-treatment was seen in 11% (n=6). Objective response was significantly associated with decrease in TC from baseline to on-treatment (38%, 3/8) compared with no change/increase in TC (6%, 3/49) (p=0.031). Patients with a decrease in TC had a significantly increased time to progression (TTP) (75% probability) compared with patients with an increase (20% probability) or no change in TC (19% probability) (p=0.0042). Low TC was seen in 23% (13/57) of the tumors at baseline and in 26% (15/57) on-treatment. High TC was seen in 77% (44/57) of tumors at baseline and in 74% (42/57) on-treatment. No significant associations with response were seen for necrosis, PF or normal tissue in on-treatment biopsies.

Conclusion: Patients with a decrease in TC from baseline to on-treatment had a significant improvement in objective response and a longer TTP. Our data suggest that the shift in TC might be used to predict response to pembrolizumab in rare tumors. However, further investigations in larger cohorts are needed to determine the clinical value of TC, the shift in TC and the cut-off of 10% assessed in biopsies.

Trial registration number: NCT02721732.

Keywords: immunotherapy; translational medical research; tumor biomarkers.

Conflict of interest statement

Competing interests: Merck was the sponsor of the drug pembrolizumab. CT had salary support on this study.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Example of a patient with partial response and decrease in TC from baseline to on-treatment. Shown are overviews (A+C: ×2 magnification) and detail (B+D: ×20 magnification) of H&E-stained biopsy specimens. (A+B) Baseline biopsy specimen with ≥10% TC (category: high TC). (C+D) On-treatment biopsy specimen does not contain any tumor, but fibrosis and inflammatory cells are visible (category: low TC). TC, tumor content.

Figure 2

Kaplan-Meier plots for patients with low versus high TC at baseline and on-treatment. Kaplan-Meier plots showing time to progression for tumors with low TC (green) versus high TC (orange). (A) Only baseline biopsy specimens have been taken into account. (B) Only on-treatment biopsy specimens have been taken into account. TC, tumor content

Figure 3

Kaplan-Meier plot showing probability estimates to remain progression-free for 6 months: Patients with decrease in TC from baseline to on-treatment (orange), increase in TC (green), and no change in TC (red).