Early disease progression and treatment discontinuation in patients with advanced ovarian cancer receiving immune checkpoint blockade

Abstract

Objective: Delayed responses observed with immune checkpoint blockade (ICB) present a challenge for patients with peritoneal malignancies, who risk early symptomatic disease progression requiring treatment discontinuation. While efforts are ongoing to define the biomarkers of response, it is equally important to identify patients at risk for early discontinuation. We sought to investigate the timing of disease progression in epithelial ovarian cancer (EOC) patients treated with ICB and to identify pre-treatment clinical parameters associated with early discontinuation.

Methods: Retrospective analysis was performed on EOC patients treated with ICB at MSKCC from January 2013 to May 2017. Cutoffs for early and very early discontinuation due to disease progression were defined at 12 and 8 weeks, respectively. Univariate and multivariate logistic regression models were built based on pre-treatment clinical variables.

Results: Of 108 identified patients, 89 were included in the analysis. Forty-six (51.7%) patients discontinued therapy early, 30 of which (33.7%) discontinued therapy very early. Eight patients (9.0%) died within 12 weeks of ICB initiation from disease progression. In multivariate analyses, bulky peritoneal disease (p = 0.009, OR: 4.94) and liver parenchymal metastases (p = 0.001, OR: 8.08) were associated with early discontinuation. Liver parenchymal metastases (p = 0.001, OR 6.64), and high neutrophil-to-lymphocyte ratio (p = 0.021, OR: 3.54), were associated with very early discontinuation.

Conclusions: Over 50% of EOC patients suffer disease progression requiring early discontinuation of ICB. Pre-treatment prognostic clinical characteristics may identify patients at highest risk for early discontinuation due to disease progression and warrant caution in using these agents in late line patients with advanced disease.

Keywords: CTLA-4; Immunotherapy; Ovarian cancer; PD-1.

Fig. 1

Study flow diagram and summary of 12-week outcomes in the study cohort. A. CONSORT diagram. B. Swimmers plot for the entire study cohort summarizing length of therapy, reason for treatment discontinuation, and disease-related deaths occurring before 12 weeks. C. Number of patients who discontinue therapy secondary to asymptomatic (radiographic) or symptomatic disease progression at or before 8 and 12 weeks. D. Top reasons for discontinuation due to clinical progression before 12 weeks. E. Clinical disease progression in the setting of baseline bulky disease. Baseline CT scan demonstrates bulky disease with 8 × 3 cm metastatic implant along the lesser curvature of the stomach. A CT scan at approximately 6 weeks of treatment demonstrated disease progression resulting in small bowel obstruction. SBO: small bowel obstruction.

Fig. 2

Pre-treatment clinical parameters can predict early and very early treatment discontinuation. The receiver-operating characteristic (ROC) curves were used to plot the sensitivity along the y-axis and the “1-specificity” along the x-axis for comparing the multivariate model prediction versus the true binary outcome for both: A. 12-week (bulky disease and liver metastases), and B. 8-week (NLR and liver metastases) variables. The area under the ROC curve (AUC) is a measure of predictive accuracy where a value of 1 corresponds to a perfect prediction and a value of 0.5 to a totally random prediction.