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Apatinib/Chemotherapy Combination Achieves Durable Response in Platinum-Resistant/Refractory Ovarian Cancer

Shannon Connelly
Published Online:1:22 PM, Fri August 10, 2018
The combination of apatinib and oral etoposide showed promising efficacy and a manageable safety profile in patients with platinum-resistant or platinum-refractory ovarian cancer, according to findings from the phase II AEROC trial recently published in The Lancet Oncology.

The single-arm prospective study, conducted at the Sun Yat-sen University Cancer Center in Guangzhou, China, examined the safety and efficacy of anti-angiogenic therapy with the oral tyrosine kinase inhibitor (TKI) apatinib in combination with oral etoposide chemotherapy in patients with platinum-sensitive or platinum-refractory ovarian cancer. Patients who progressed within 6 months of treatment with a non–platinum-containing regimen were also eligible for the study.  

Investigators took into account that the combination could be administered orally at home and would not require patients to be admitted to the hospital.

“The data in our study, together with the results from other trials with anti-angiogenic TKI combined with chemotherapy, support the investigation of the combination therapy of apatinib with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer in a large phase III trial,” wrote corresponding author Xin Huang, MD, of the Department of Gynecologic Oncology, State Key Laboratory of Oncology in South China, and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, and colleagues.

Between August 2016 and November 2017, investigators screened 38 patients and enrolled 35 to the study to be included in the intention-to-treat analysis. Patients received apatinib, which inhibits VEGFR2, at an initial dose of 500 mg once daily continuously, and oral etoposide at a dose of 50 mg once daily on days 1 through 14 of a 21-day cycle, for a maximum of 6 cycles. Both treatments were continued until disease progression, patient withdrawal, or unacceptable toxicity.

The median age of women enrolled on the trial was 55 (range, 39-68). The majority of patients (57%) had International Federation of Gynecology and Obstetrics (FIGO) stage IIIc ovarian cancer with high-grade serous carcinoma at diagnosis (77%). Most patients (31%) obtained their first remission <6 months.

Patients were also required to have received ≥1 prior line of platinum-based chemotherapy and to have progressed during their last treatment before enrollment. Patients were excluded from the trial if they had prior exposure to apatinib. The primary endpoint of the trial was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), duration of response (DOR), proportion of disease control, and safety.

At the December 2017 data cutoff, 20 patients (57%) had discontinued treatment, and 15 patients (43%) remained on treatment. The median duration of follow-up at the time of data cutoff was 4.5 months (range, 3.4-5.7). Half of the patients who discontinued treatment discontinued as a result of adverse events (AEs). The other half discontinued for a variety of reasons, including withdrawal of consent (n = 2), lost to follow-up (n = 2), receiving other anticancer therapy (n = 1), and having dose interruption exceeding 14 days without toxicity (n = 1).

The ORR in the first 8 assessable patients on the study was 63%. As such, the threshold for Simon’s 2-stage design, which was used in this study, was reached, and the trial continued to full accrual of 35 patients.

Nineteen (54%) of the 35 patients (95% CI, 36.6%-71.2%) achieved an objective response and 19 (61%) of 31 patients (95% CI, 42.2%-78.2%) in the per-protocol population achieved an objective response. Among the 19 patients who had an objective response, 6 (32%) had progression of their disease or had died as of the data cutoff. The median DOR was 7.4 months (range, 4.0-13.0; 95% CI, 2.3-12.0).

Of the 31 patients who had at least 1 post-baseline efficacy assessment, 29 (94%) had tumor shrinkage.

Across the study, 13 (37%) had disease progression or had died as of the data cutoff, including 1 patient who discontinued treatment before progression. Eighteen patients had no disease progression, 15 (83%) of whom remained on the study. The median PFS was 8.1 months (95% CI, 2.8-13.4).

The overall incidence of AEs of any grade was 100%, regardless of causality. One patient was excluded from the safety analysis and no safety data were collected. Four (12%) of the 34 patients included in the safety analysis discontinued the study because of AEs.

The most common grade 3/4 AEs were neutropenia (50%), fatigue (32%), anemia (29%), and mucositis (24%). Two patients experienced serious AEs and were admitted to the hospital. One of the patients had anemia and anorexia, which was considered to be possibly treatment-related, and the other had increased ascites due to disease progression, which was not considered to be related to treatment. No fatal AEs were reported.

Investigators noted that some clinical trials of various solid tumors have suggested a dose of 500 mg to 850 mg of apatinib once daily, which is why they chose to use 500 mg once daily as the initial dose on this study. Additionally, several past studies have recommended 50 mg to 75 mg once daily of oral etoposide (1-21 days, every 28 days). However, the investigators suggested that most patients with ovarian cancer in China were not able to tolerate this dosage. As such, they chose to use oral etoposide at a dose of 50 mg once daily (1-14 days, every 21 days), which they said has also been used in previous studies.

Despite this, most patients in this study underwent dose modifications. Treatment was continued in nearly all of the patients following dose modifications. However, investigators noted that the proportion of patients who needed dose modifications was higher than expected.

“Taking these findings into account, we suggest that the initial doses for apatinib should be 500 mg and 250 mg taken on alternate days and the dose for oral etoposide should be 50 mg from day 1 to day 10, repeated in every 3 weeks, in subsequent phase III studies,” the investigators wrote.

Investigators concluded that the combination showed promising efficacy with a manageable toxicity profile; however, further data in phase III trials are needed.
 
 
Reference:
Lan CY, Wang Y, Xiong Y, et al. Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm prospective study [published online August 3, 2018]. Lancet.  doi: 10.1016/S1470-2015(18)30349-8.


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