Cediranib Monotherapy Safe, Effective in Endometrial Cancer

David P. Bender, MD

David P. Bender, MD

The angiogenesis inhibitor cediranib demonstrated acceptable activity and a tolerable safety profile as a monotherapy for patients with recurrent or persistent endometrial cancer, according to late-breaking phase II findings presented by David P. Bender, MD, at the 2015 Society of Gynecologic Oncology’s (SGO) Annual Meeting on Women’s Cancer.

In the phase II study, known as NRG/GOG 229J, partial responses were observed in 12.5% of patients (n = 6). The 6-month progression free survival (PFS) rate was 33.3% and the median overall survival (OS) was 12.5 months. The event-free survival (EFS) rate was 29.2%. The activity seen with single-agent cediranib warrants further exploration, particularly in combination with chemotherapy, Bender noted.

“There is a strong need for new therapies for women with metastatic, advanced or recurrent endometrial cancer because their long-term prognosis is poor,” said Bender, clinical associate professor of Obstetrics and Gynecology—Gynecologic Oncology at the University of Iowa Carver College of Medicine. “Cediranib as monotherapy for recurrent or persistent endometrial cancer meets the criteria for sufficient activity to warrant further investigation. It is a well-tolerated oral therapy with an acceptable toxicity profile.”

Cediranib is a multi-tyrosine kinase inhibitor that blocks VEGF, PDGF, and PGF receptors. Previously published preclinical and clinical data support the use of cediranib as monotherapy and in combination with chemotherapy in colon, breast, lung, ovarian, and cervical cancers.

Patients enrolled in the trial had recurrent or persistent endometrial cancer after receiving one or two rounds of prior chemotherapy, histologic confirmation of the primary tumor, measurable disease (RECIST 1.1), and a GOG Performance Group status of 0-2. The trial’s secondary objectives were to assess the toxicity of single-agent cediranib and to identify potential biomarkers related to cediranib activity in this population. The primary endpoint was 6-month PFS, while secondary endpoints were the durations of PFS, EFS, and OS.

Treatment consisted of cediranib at 30mg orally per day in a 28-day cycle. Dose modifications were based on toxicity assessments, with a single dose reduction permitted to 20mg per day. Treatment was stopped if grade 2 or greater toxicities occurred for more than two weeks.

Of 53 patients enrolled, 48 were evaluable, with a median age of 65.5 years. Just over half the patients (52.1%; n = 25) had received prior radiation and nearly three-quarters (72.9%; n = 35) had received only one prior chemotherapy regimen. Patients received a median of 2 cycles of cediranib (range, 1-15); 48% of patients received at least 3 cycles and 31% of patients received 6 or more cycles.

No fatal events occurred as a result of cediranib; however, 30 patients died from disease. No grade 4 or 5 toxicities were attributed to cediranib. Vascular disorders were the most common grade 3 toxicity: hypertension occurred in 16 patients and pulmonary emboli in 3. Grade 3 fatigue occurred in 10 patients and grade 3 diarrhea in 7 patients.

Colonic perforation, rectal fistula, and ischemic bowel were observed in 3 patients, although none of these events were attributed to cediranib. Reversible posterior leukoencephalopathy was observed in 1 patient.

MVD was measured in the initial hysterectomy specimens and correlated with clinical outcomes. The median PFS for trial patients whose samples showed low MVD was 3.5 months, while those whose samples showed high MVD was 4.3 months.

“A trend toward improved PFS was found in patients whose tumors expressed high MVD,” Bender said at the conference. “This measure may be a useful discriminator of tumors most likely to respond to anti-angiogenic agents.”

Clinical trials continue to assess the combination of cediranib as a treatment for patients with gynecologic and other cancer. Studies have demonstrated promising looking a cediranib in combination with chemotherapy and the PARP inhibitor. An ongoing study is examining the combination of cediranib and olaparib for patients with recurrent ovarian, fallopian tube, or peritoneal cancer and those with recurrent triple-negative breast cancer. Deleterious BRCA mutations will be assessed in the study (NCT01116648).

“Future trials are warranted to evaluate cediranib in combination with chemotherapy,” Bender said during his presentation regarding endometrial cancer.

The combination of cediranib and chemotherapy as a treatment for patients with advanced cervical cancer was presented during the 2014 ESMO Congress. The addition of cediranib reduced the risk of progression by 39% compared with chemotherapy alone (P= .046).

Additionally, at the 2014 ASCO Annual Meeting, the combination of cediranib and olaparib demonstrated a near doubling in median PFS compared with olaparib alone in women with recurrent ovarian cancer. The median PFS was 17.7 months among patients treated with the combination compared with 9 months for olaparib alone. In patients with BRCA-positive tumors, the PFS was 19.4 months with the combination versus 16.5 months with olaparib alone.

Bender DP, Sill M, Lankes H et al. A phase II evaluation of cediranib in the treatment of recurrent or persistent endometrial cancer: an NRG Oncology/Gynecologic Oncology Group study. Presented at: 2015 Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer; March 28-31, 2015; Chicago, IL. Late Breaking Abstract.

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