From the Journals

VEGF inhibitor shows promise in platinum resistant/refractory ovarian cancer


Key clinical point: The VEGF receptor tyrosine kinase inhibitor apatinib in combination with oral etoposide in people with platinum resistant or refractory ovarian cancer has shown promising efficacy and manageable toxicity.

Major finding: Nineteen of 35 patients with heavily pretreated ovarian cancer refractory or resistant to platinum achieved an objective response (54%; 95% CI 36.6-71.2) in an intention-to-treat analysis.

Study details: A single arm prospective phase 2 study of 35 women aged 18-70 years with heavily pretreated platinum resistant or refractory ovarian cancer.

Disclosures: Jiangsu Hengrui Pharmaceuticals discounted apatinib to patients enrolled in the study.

Source: Lan CY et al. Lancet Oncol. 2018 Aug 3. doi: 10.1016/ S1470-2045(18)30349-8.

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‘Surprising’ efficacy with oral combination

In the study by Chun-Yan Lan and colleagues, an “impressive” number of patients in the intention to treat analysis achieved an objective response (54%; 95% confidence interval, 36.6%-71.2%). Given that the response to standard cytotoxic therapies in ovarian cancer is reported to be between 0-30%, the combination of apatinib with etoposide should be studied further.

The median progression-free survival of 8.1 months indicates the responses observed are durable, particularly against the backdrop of survival rates seen in other studies, such as 6.7 months in AURELIA and 6.4 months in MITO 11. However, the dangers of comparing results across trials when patient populations are different should be acknowledged.

The levels of neutropenia and anemia and fatigue seen in study participants is acceptable, but the grade 3 or 4 mucositis in 8 of 34 patients is of concern given the need for patients to take oral medications long term.

It is noteworthy that the number of patients requiring a dose reduction of apatinib was high – at 82% of patients, with 76% needing a dose reduction of etoposide. Although the authors do suggest that future studies should use a lower starting dose. Further studies should also include patient reported outcomes in order to ensure that the convenience of this combination of apatinib with etoposide is not at the expense of toxicity.

These comments were excerpted from an accompanying commentary (Lancet Oncol. 2018 Aug 3. doi: 10.1016/S1470-2045[18]30444-3) by Charlie Gourley, MD, of University of Edinburgh, U.K.



Combining the vascular endothelial growth factor (VEGF) receptor–targeting tyrosine kinase inhibitor apatinib with oral etoposide in people with platinum resistant or refractory ovarian cancer has shown promising efficacy and manageable toxicity in a Phase 2 study.

Angiogenesis was a “hallmark” process in cancer, and antiangiogenic therapy, including anti-VEGF antibodies and multireceptor tyrosine kinase inhibitors, has been shown to be an attractive therapeutic strategy for ovarian cancer.

“Increasing evidence suggests that the combination of antiangiogenic therapy and single-agent chemotherapy improves the outcome of platinum-resistant ovarian cancer,” Chun-Yan Lan, MD, of the Collaborative Innovation Center for Cancer Medicine at Sun Yat-sen University Cancer Center in Guangzhou, China, and colleagues wrote in Lancet Oncology.

The investigators chose apatinib because it has shown encouraging antitumor activities and tolerable toxicities in several malignant tumors and was available in mainland China, they said.

The single-arm prospective study enrolled 35 women aged 18-70 years with heavily pretreated ovarian cancer that was refractory to platinum (defined as progression during the initial platinum-based treatment) or resistant to platinum (defined as progression within 6 months after the last platinum treatment).

Women were treated with apatinib at an initial dose of 500 mg once daily on a continuous basis and with oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Dose modifications, including dose interruptions, were allowed in order to manage adverse events.

Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint of the study was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST). The study authors analyzed efficacy data using three populations: intention-to-treat, per-protocol, and safety populations.

Results showed that 19 of 35 patients achieved an objective response (54%; 95% confidence interval, 36.6%-71.2%) in an intention-to-treat analysis. In the per-protocol population, 19 of 31 patients (61%; 95% CI, 42.2%-78.2%) achieved an objective response.

Median progression-free survival was 8.1 months (interquartile range, 4.3-14.6; 95% CI, 2.8-13.4), and the median duration of response was 7.4 months (IQR, 4.0-13.0; 95% CI, 2.3-12.0).

The most common grade 3 or 4 adverse events reported were neutropenia (n = 17), fatigue (n = 11), anemia n = 10), and mucositis (n = 8). Serious adverse events were reported in two patients who were admitted to the hospital.

Dose reductions were required in 82% (n = 28) of 34 patients on apatinib and 77% (n = 26) for etoposide. The authors said they would suggest future studies use a lower starting dose of apatinib and give etoposide for 10 days rather than 14.

“Our study showed that the combination therapy of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory recurrent ovarian cancer and further study in phase 3 trials is warranted,” the study authors concluded.

They said that a strength of their study was that both apatinib and oral etoposide were able to be given orally without the need for hospital admission or an infusion pump, factors that could improve adherence and cost effectiveness for patients.

However, they noted that one limitation was that it was a single-arm study with no control group, which meant the selection bias could not be ruled out.

Source: Lan CY et al. Lancet Oncol. 2018 Aug 3. doi: 10.1016/ S1470-2045(18)30349-8.

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