Clinical implications for cediranib in advanced cervical cancer
Authors: Krishnansu S Tewari
Journal: The Lancet Oncology (2015)

For decades, the management of women with recurrent or persistent cervical cancer not amenable to surgery and women who present with metastatic disease has constituted a high unmet clinical need, with platinum-based chemotherapy being palliative and associated with short-lived responses, rapid deterioration in quality of life, and early death (median overall survival 7–12 months).1Tewari KS Sill MW Long 3rd, HJ et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (931) Google Scholar Some progress has been made following the publication of the phase 3 randomised Gynecologic Oncology Group (GOG) 240 trial;1Tewari KS Sill MW Long 3rd, HJ et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (931) Google Scholar patients who received the anti-angiogenic drug bevacizumab in addition to chemotherapy had a significant overall survival advantage over those who did not (median 17 months vs 13·3 months; HR 0·71 [98% CI 0·54–0·95]; p=0·004). In addition to overall survival, both progression-free survival (median 8·2 months vs 5·9 months) and the proportion of patients who achieved an objective tumour response (48% vs 36%) were significantly improved with the combination of bevacizumab with either of two chemotherapy doublets (cisplatin–paclitaxel or topotecan–paclitaxel).1Tewari KS Sill MW Long 3rd, HJ et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (931) Google Scholar None of these findings were accompanied by a significant deterioration in quality of life.2Penson RT Huang HQ Wenzel LB et al.Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240).Lancet Oncol. 2015; 16: 301-311Summary Full Text Full Text PDF PubMed Scopus (104) Google Scholar These results led directly to the approval of bevacizumab by the US Food and Drug Administration and the European Medicines Agency. In The Lancet Oncology, Paul Symonds and colleagues3Symonds RP Gourley C Davidson S et al.Cedirinib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Oncol. 2015; (published online Oct 14.)http://dx.doi.org/10.1016/S1470-2045(15)00220-XSummary Full Text Full Text PDF Scopus (82) Google Scholar report the results of the randomised phase 2, double-blind, placebo-controlled CIRCCa trial. The authors report significantly improved progression-free survival with six cycles of carboplatin–paclitaxel plus daily administration of cediranib, continued until disease progression or the development of intolerable toxicity (hazard ratio 0·58 [80% CI 0·40–0·85]; p=0·032).3Symonds RP Gourley C Davidson S et al.Cedirinib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Oncol. 2015; (published online Oct 14.)http://dx.doi.org/10.1016/S1470-2045(15)00220-XSummary Full Text Full Text PDF Scopus (82) Google Scholar Cediranib, a VEGFR1–3 oral tyrosine kinase inhibitor, joins TNP-470,4Kudelka AP Verschraegen CF Loyer E Complete remission of metastatic cervical cancer with the angiogenesis inhibitor TNP-470.N Engl J Med. 1998; 338: 991-992Crossref PubMed Scopus (124) Google Scholar pazopanib,5Monk BJ Sill MW Burger RA Gray HJ Buekers TE Roman LD Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study.J Clin Oncol. 2009; 27: 1069-1074Crossref PubMed Scopus (281) Google Scholar and bevacizumab1Tewari KS Sill MW Long 3rd, HJ et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (931) Google Scholar, 6Monk BJ Mas Lopez L Zarba JJ et al.Phase II, open-label study of pazopanib or lapatinib monotherapy compared with pazopanib plus lapatinib combination therapy in patients with advanced and recurrent cervical cancer.J Clin Oncol. 2010; 28: 3562-3569Crossref PubMed Scopus (206) Google Scholar as an anti-angiogenic drug with demonstrable activity in cervical cancer, with the latter two drugs also inhibiting VEGF-dependent signalling.7Liu FW Cripe J Tewari KS Anti-angiogenesis therapy in gynecologic malignancies.Oncology. 2015; 29: 350-360PubMed Google Scholar Although this trial was not powered to assess overall survival, the proportion of patients with a response (64%) in the cediranib group is the highest reported for any regimen in this disease.3Symonds RP Gourley C Davidson S et al.Cedirinib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Oncol. 2015; (published online Oct 14.)http://dx.doi.org/10.1016/S1470-2045(15)00220-XSummary Full Text Full Text PDF Scopus (82) Google Scholar The use of carboplatin in CIRCCa deserves comment. Although the Japanese Clinical Oncology Group (JCOG) have shown significant non-inferiority of carboplatin in JCOG 0505, a phase 3 randomised trial comparing cisplatin–paclitaxel with carboplatin–paclitaxel, they also reported that in patients who had never received platinum treatment, the cisplatin–paclitaxel treatment was superior.8Kitagawa R Katsumata N Shibata T et al.Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505.J Clin Oncol. 2015; 33: 1-9Crossref PubMed Scopus (235) Google Scholar Although the carboplatin–paclitaxel doublet is certainly easier to administer than cisplatin–paclitaxel, caution should be exercised in women who have not previously received any platinum-based therapy (eg, those treated with radiotherapy alone for locally advanced disease and those who present with FIGO IVB tumours), and also in elderly patients and those previously treated with extended-field radiation for whom carboplatin could prove to be intolerable owing to vastly diminished bone marrow reserves. Unlike in GOG 240, febrile neutropenia was an important problem in CIRCCa.1Tewari KS Sill MW Long 3rd, HJ et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (931) Google Scholar, 3Symonds RP Gourley C Davidson S et al.Cedirinib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Oncol. 2015; (published online Oct 14.)http://dx.doi.org/10.1016/S1470-2045(15)00220-XSummary Full Text Full Text PDF Scopus (82) Google Scholar In addition, diarrhoea induced by cediranib significantly affected one quality-of-life measure (p=0·030).3Symonds RP Gourley C Davidson S et al.Cedirinib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Oncol. 2015; (published online Oct 14.)http://dx.doi.org/10.1016/S1470-2045(15)00220-XSummary Full Text Full Text PDF Scopus (82) Google Scholar Finally, although the authors indicate that cross-trial comparisons are rarely valid, treatment-induced grade 2 or greater hypertension (34% in CIRCCa vs 25% in GOG 240) might indicate that this side-effect is a greater problem with cediranib than with bevacizumab.1Tewari KS Sill MW Long 3rd, HJ et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (931) Google Scholar, 3Symonds RP Gourley C Davidson S et al.Cedirinib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Oncol. 2015; (published online Oct 14.)http://dx.doi.org/10.1016/S1470-2045(15)00220-XSummary Full Text Full Text PDF Scopus (82) Google Scholar By contrast, cediranib was not associated with the development of fistulae—a disorder that occurred in 8·6% of patients treated with chemotherapy plus bevacizumab in GOG 240.1Tewari KS Sill MW Long 3rd, HJ et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (931) Google Scholar, 3Symonds RP Gourley C Davidson S et al.Cedirinib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Oncol. 2015; (published online Oct 14.)http://dx.doi.org/10.1016/S1470-2045(15)00220-XSummary Full Text Full Text PDF Scopus (82) Google Scholar Although at quite an early stage in its life cycle, cediranib has already had an interesting history. An absence of perceived benefit in colorectal cancer, lung cancer, and glioblastoma curtailed enthusiasm for further development until the results of CIRCCa and the ICON6 ovarian cancer study were made available. Importantly, ICON6 represents one of eight pivotal phase 3 anti-angiogenesis trials in ovarian cancer, all of which met their primary endpoint (progression-free survival), with ICON6 being the only study to show an overall survival advantage.9Eskander RN Tewari KS Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—mechanistics, review of phase III randomized clinical trials, and regulatory implications.Gynecol Oncol. 2014; 132: 496-505Summary Full Text Full Text PDF PubMed Scopus (90) Google Scholar Stalled development of cediranib had implications for CIRCCa, but fortunately development of the drug has since been resurrected to focus on gynaecological malignancies. Similarities in eligibility criteria between CIRCCa and GOG 240 (eg, ECOG performance status restricted to 0–1 and no previous chemotherapy allowed for recurrent disease) suggest that a correlation of the progression-free survival results might be reasonable (ie, 8·1 months in CIRCCa is similar to 8·2 months in GOG 240).1Tewari KS Sill MW Long 3rd, HJ et al.Improved survival with bevacizumab in advanced cervical cancer.N Engl J Med. 2014; 370: 734-743Crossref PubMed Scopus (931) Google Scholar, 3Symonds RP Gourley C Davidson S et al.Cedirinib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trial.Lancet Oncol. 2015; (published online Oct 14.)http://dx.doi.org/10.1016/S1470-2045(15)00220-XSummary Full Text Full Text PDF Scopus (82) Google Scholar Cost-effectiveness remains an issue,10Minion LE Bai J Monk BJ et al.A Markov model to evaluate cost-effectiveness of antiangiogenesis therapy using bevacizumab in advanced cervical cancer.Gynecol Oncol. 2015; 137: 490-496Summary Full Text Full Text PDF PubMed Scopus (54) Google Scholar especially for low-income nations where the incidence of cervical cancer is highest. Given a new treatment standard of chemotherapy plus bevacizumab, where to position cediranib is not readily discernible. Potential future trial designs might use strategies to study chemotherapy plus bevacizumab with and without cediranib, or randomisation to cediranib maintenance therapy in patients who derive clinical benefit from chemotherapy plus bevacizumab (eg, stable disease). If active as a monotherapy, a maintenance strategy containing cediranib could have major toxicology implications given that the median duration of cediranib treatment in both groups in CIRCCa was 19 weeks and overlapped with chemotherapy. Clearly, the results of CIRCCa provide additional clinical evidence that VEGF-dependent tumour angiogenesis remains a valid target in cervical cancer and that the need to explore novel anti-angiogenesis combinations and sequencing is implicit. I have participated on two advisory boards for Genentech/Roche (March, 2014, and July, 2014). I declare no other competing interests. Cediranib combined with carboplatin and paclitaxel in patients with metastatic or recurrent cervical cancer (CIRCCa): a randomised, double-blind, placebo-controlled phase 2 trialCediranib has significant efficacy when added to carboplatin and paclitaxel in the treatment of metastatic or recurrent cervical cancer. This finding was accompanied by an increase in toxic effects (mainly diarrhoea, hypertension, and febrile neutropenia). Full-Text PDF Open Access