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Cediranib plus chemotherapy effective for cervical cancer
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The addition of cediranib to a conventional carboplatin and paclitaxel chemotherapy regimen appeared to prolong PFS yet increase toxicity among patients with metastatic or recurrent cervical cancer, according to findings of the phase 2, randomized CIRCCa study.
OS is less than 1 year for patients treated with standard chemotherapy for metastatic or relapsed cervical cancer, according to study background. Adverse prognostic factors in this setting include high tumor angiogenesis and high concentrations of intratumoral VEGF.
Thus, R. Paul Symonds, MD, FRCP, FRCR, professor of clinical oncology in the department of cancer studies at University of Leicester in the United Kingdom, and colleagues sought to assess the outcomes associated with the addition of cediranib (AZD2171, AstraZeneca) — a potent tyrosine kinase inhibitor of VEGF receptors 1, 2 and 3 — to chemotherapy among adult patients with metastatic, persistent or locally recurrent cervical cancer resistant to radical treatment.
All patients received carboplatin area under the curve (AUC) of 5 plus paclitaxel 175 mg/m2 — infused over 3 hours — for up to six cycles, which was repeated every 3 weeks until progression or adverse effects. Researchers randomly assigned patients 1:1 to receive this chemotherapy regimen with 20 mg oral cediranib (n = 34) or placebo (n = 35), administered once daily until disease progression.
PFS served as the study’s primary endpoint. Secondary endpoints included decrease in sVEGFR2 levels from baseline to 28 days after the start of chemotherapy, best response to chemotherapy, OS, toxicity and quality of life.
Researchers conducted the efficacy analysis in the intention-to-treat population and the safety analysis in all participants who received a minimum of one dose of the study drug.
After a median follow-up of 24.2 months, patients assigned cediranib experienced longer median PFS vs. patients assigned placebo (8.1 months vs. 6.7 months; HR = 0.58; 80% CI, 0.4-0.85).
Twenty-seven patients in the placebo group died vs. 25 in the cediranib group, and researchers observed no significant difference in OS between the groups. Based on an exploratory analysis of heterogeneity, researchers inferred that the effect of cediranib on OS might depend upon disease site, but not on age, histological subtype, length of DFS, number of previous treatments or ECOG performance status.
Overall response rate was 64% in the cediranib group, with 9% of patients achieving a complete response and 55% achieving a partial response. In the placebo group, the overall response rate was 45%; no patients had a complete response and 45% had a partial response.
Based on data from 69 patients, mean sVEGFR2 concentrations appeared to increase in the placebo cohort but decrease in the cediranib cohort. The point estimate for the cediranib–placebo difference in change in sVEGFR2 from baseline to day 28 was –0.108 (80% CI, –0.147 to –.07).
Common grade 3 or worse adverse events that occurred more frequently in the cediranib arm included diarrhea (16% vs. 3%), fatigue (13% vs. 6%), leucopenia (16% vs. 9%), neutropenia (31% vs. 11%) and febrile neutropenia (16% vs. 0%).
Grade 2 to grade 3 hypertension also appeared more prevalent in the cediranib group (34% vs.11%).
Nineteen patients in the cediranib group and 18 patients in the control group experienced serious adverse events.
“An investigator-led phase 3 trial in women with recurrent ovarian cancer showed that cediranib given concurrently with platinum-based chemotherapy improved PFS and, when continued as maintenance therapy, significantly improved both PFS and OS,” Symonds and colleagues wrote. “More recently, a phase 2 trial showed that the combination of cediranib with olaparib [Lynparza, AstraZeneca] nearly doubled PFS compared with olaparib alone in women with platinum-sensitive recurrent ovarian cancer.
Krishnansu S. Tewari
“As a result, the present focus of cediranib development in gynecological cancers is in combination with a PARP inhibitor in patients with either platinum-sensitive or platinum-resistant ovarian cancer,” the researchers concluded. Our finding supports the ongoing assessment cediranib in patients with cervical cancer.”
These findings support the need for additional studies of VEGF inhibition for metastatic or recurrent cervical cancer, Krishnansu S. Tewari, MD, of the University of California, Irvine, wrote in a related editorial.
“Clearly, the results of CIRCCa provide additional clinical evidence that VEGF-dependent tumor angiogenesis remains a valid target in cervical cancer and that the need to explore novel antiangiogenesis combinations and sequencing is implicit,” Tewari wrote. – by Jennifer Byrne
Disclosure: Symonds reports no relevant financial disclosures. Tewari reports an advisory board role with Genentech/Roche. Please see the full study for a list of all other researchers’ relevant financial disclosures.
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