Between June 2017 and June 2019, 115 patients were enrolled in this study (Figure 1; Table 1) and included in the ITT analysis. Ninety-two patients with a confirmed post-baseline efficacy assessment were included in the PP population. A total of 101 patients were included in the safety analysis.
The median follow-up time (data cutoff was on June 2, 2019) was 4 months (IQR 2–6 months, range 1-22 months). At the data cutoff point, 22 patients were still receiving treatment (Figure 1). Fifteen patients (13.0%), including 2 patients (1.7%) who died before the efficacy evaluation during treatment, were lost to follow-up, and 6 patients (5.2%) withdrew consent. Twenty-one patients (18.3%) discontinued PLD because of progressive disease (PD), and 19 patients (16.5%) received other anticancer therapies based on the decision of the investigator, 16 patients of whom (84.2%) received platinum-based chemotherapy.
In the ITT analysis, the confirmed ORR was 37.4% (95% CI, 28.4%-46.4%): as best responses, 2 patients (1.73%) had confirmed CR, and 41 patients (35.65%) had PR, with a DCR of 65.2% (95% CI, 56.4%-74.1%). Of the 43 patients with a confirmed objective response, 31 (72.1%) achieved a confirmed objective response after 2 cycles of PLD, 9 (20.9%) after 4 cycles and 3 patients (7.0%) after 6 cycles. Fourteen patients who received fewer than 2 cycles of PLD and 7 patients who did not undergo efficacy assessments after 2 cycles of PLD were excluded from the PP population. Moreover, 2 patients had post-baseline efficacy assessments that could not be confirmed and thus were excluded. In the PP analysis, the ORR was 46.7% (95% CI, 36.3%-57.1%), and the DCR was 81.5% (95% CI, 73.4%-89.6%) (Table 2).
The outcomes of the exploratory analyses examining the predictive impact of the following factors on efficacy in the PP population using binary logistic regression are presented in Table 3: age, ECOG performance status, histology, International Federation of Gynecology and Obstetrics (FIGO) stage, neoadjuvant therapy, residual tumor during the initial surgery, response status to platinum-based chemotherapy and CA125 level. The response status to platinum-based chemotherapy and baseline CA125 levels were significantly correlated with the ORR (Table 3). Table 4 and Figure 2 show detailed efficacy results based on the response status to platinum-based chemotherapy. The ORRs in patients with platinum-refractory and -resistant relapse were 16.7% and 45.2% respectively. In addition, of 67 patients with platinum refractory or resistant relapse, 20 patients achieved an objective response, and the total ORR was 29.9% (95% CI, 18.6%-41.1%). Moreover, considering the biological differences between different pathologic histology types, the efficacy analysis was performed only on patients with only high-grade serous cancer, as shown in Supplementary table 1.
This is the preliminary analysis of the response data and the survival data have not been completely analyzed. In addition, many patients in this study switched to other anticancer therapies based on the decision of the investigator, not because of PD. Therefore, we analyzed the time interval between the date of the last first-line platinum-based chemotherapy treatment and the date at which the patient was switched to another therapy after PLD (Figure 3A) and the time interval between the date of enrollment and the date at which the patient was switched to another therapy (Figure 3B). The time interval from the date of the last platinum-based chemotherapy treatment to the date of changing to another therapy after PLD was divided into 3 periods: 0-5 months, 6-11 months, and 12 months or more months. In total, PLD treatment prolonged the platinum-free time intervals to at least 12 months in 39.9% of patients and to 6-11 months in 34.5% of patients. Only 25.7% of patients failed to prolong the platinum-free interval to at least 6 months. For the patients with platinum-refractory and-resistant relapse, PLD treatment prolonged the platinum-free interval to at least 6 months in 32.3% and 80.7%, respectively. Figure 3B shows the proportion of patients who were switched to another therapy over time. The median time intervals for patients with platinum-refractory relapse, platinum-resistant relapse and platinum-sensitive relapse were 4 (3-6), 8 (4-~) and 6 (5-12) months, respectively (refractory vs. resistant, P=0.018; refractory vs. sensitive, P=0.033; resistant vs sensitive, P=0.435).
The outcomes of the exploratory analyses examining the trend of CA125 levels are detailed below. In the PP population, we observed a reduction in CA125 after the first cycle of PLD in 39 patients (42.4%). As is shown in Table 5, the ORR was significantly higher in patients with a CA125 decrease after the first cycle than that in the patients with a CA125 increase (66.7% vs.32.1%, P =0.001).
The numbers of patients in whom efficacy was evaluated by the GCIG criteria are listed in Figure 1. Totally, efficacy was evaluated by the GCIG criteria in 7 patients, 8 patients and 9 patients after the cycle 2, cycle 4 and cycles 6-8, respectively. Two patients underwent two successive efficacy evaluations by the GCIG criteria. Totally, efficacy was evaluated by the GCIG criteria at least once in 22 patients and by only the RECIST in 70 patients. In terms of the predictive role of baseline CA125, for the 70 patients in whom efficacy was evaluated by the RECIST, the ORR in patients with a low CA125 level at baseline was higher than that in patients without, though the difference was not statistically significant (48.6%, 42.9% and 30.0% in patients with baseline CA125≤200, 200-500 and ≥500 U/mL, respectively). For the 22 patients in whom efficacy was evaluated by the GCIG criteria, since the number of patients was not large enough, only a univariate analysis was performed with binary logistic regression, and the predictable role of baseline CA125 was true for these patients (Supplementary table 2). In terms of the predictive role of a decrease in CA125 after the first cycle, this was true for patients in whom efficacy was evaluated by the RECIST (Supplementary table 3), and the ORR was higher in patients with a CA125 decrease after the first cycle than that in patients without a CA125 decrease (67.6% vs. 34.7%, respectively, P=0.005). For patients in whom efficacy was evaluated by the GCIG criteria, though the difference was not statistically significant, the ORR was higher in patients with a CA125 decrease after the first cycle (87.5% vs. 42.9%, respectively, P=0.074).
The CA125 variations in each patient who achieved an objective response are shown in Figure 4A. As is shown in Figure 4B, 40.5%, 28.6%, 22.0%, 21.1%, 19.2% and 30.0% of patients who achieved an objective response had increases in CA125 relative to baseline after the cycles 1, 2, 3, 4, 5 and 6, respectively.
As shown in Figure 5, the most common grade 3 or higher AE regardless of causality was hand-foot syndrome (3 [3.0%] of 101 patients), followed by mucositis (2 [2.0%] of 101 patients), thrombocytopenia (2 [2.0%] of 101 patients), neutropenia (2 [2.0%] of 101 patients), an anemia event (1 [1.0%] of 101 patients) and diarrhea (1 [1.0%] of 101 patients). The most commonly reported all-grade AEs regardless of causality included neutropenia (46 [45.6%] of 101 patients), mucositis (18 [17.8%] of 101 patients), hand-foot syndrome (14 [13.9%] of 101 patients), anemia events (12 [11.9%] of 101 patients) and nausea (12 [11.9%] of 101 patients).
Severe adverse effects regardless of causality were noted in 3 (3.0%) of 101 patients. Of these patients, 1 (1.0% of 101 patients) had a small intestinal obstruction, 1 (1.0% of 101 patients) had a fever due to a peritoneal infection and 1 (1.0% of 101 patients) had a fever due to a viral infection. No patients were reported to have left ventricular systolic dysfunction and no treatment-related deaths were reported. Based on the clinical assessment, the two patients who died before the postbaseline efficacy assessment may have died from disease progression.
Quality of life assessment
Regarding the QOL assessment, 82 patients (71.9% of 115 patients) completed the QOL questionnaire at baseline, 52 patients (64.2% of 81 patients) before the third cycle of PLD, and 29 patients (64.4% of 45 patients) before the fifth cycle. Regarding the global health status, physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning, higher scores represent better QOL and functioning. For fatigue, nausea/vomiting, pain, appetite, constipation, diarrhea, insomnia, dyspnea and financial problems, higher scores represent worse symptoms. No statistically significant differences existed in any scores between the baseline and the any post-baseline questionnaires (P>0.05, Figure 6).