Phase II Trial of Cediranib in Combination With Cisplatin and Pemetrexed in Chemotherapy-Naïve Patients With Unresectable Malignant Pleural Mesothelioma (SWOG S0905)

Abstract

Purpose: Antiangiogenic agents combined with chemotherapy have efficacy in the treatment of unresectable malignant pleural mesothelioma (MPM). Cediranib (AstraZeneca, Cheshire, United Kingdom), a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, demonstrated therapeutic potential in a prior phase I trial. We evaluated a phase II trial for efficacy.

Patients and methods: SWOG S0905 (ClinicalTrials.gov identifier: NCT01064648) randomly assigned cediranib or placebo with platinum-pemetrexed for six cycles followed by maintenance cediranib or placebo in unresectable chemotherapy-naïve patients with MPM of any histologic subtype. Primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 progression-free survival (PFS). Secondary end points included overall survival, PFS by modified RECIST v1.1, response (modified RECIST and RECIST v1.1), disease control, and safety/toxicity. The trial was designed to detect a difference in RECIST v1.1 PFS at the one-sided 0.1 level using a stratified log-rank test.

Results: Ninety-two eligible patients were enrolled (75% epithelioid and 25% biphasic or sarcomatoid). The cediranib arm had more grade 3 and 4 diarrhea, dehydration, hypertension, and weight loss. Cediranib improved PFS by RECIST v1.1 (hazard ratio, 0.71; 80% CI, 0.54 to 0.95; P = .062; 7.2 months v 5.6 months) and increased modified RECIST v1.1 response (50% v 20%; P = .006). By modified RECIST v1.1, cediranib numerically increased PFS (hazard ratio, 0.77; 80% CI, 0.59 to 1.02; P = .12; median, 6.9 months v 5.6 months). No significant difference in overall survival was observed.

Conclusion: The addition of cediranib to platinum-pemetrexed improved PFS by RECIST v1.1 and response rate by modified RECIST in patients with unresectable MPM. Whereas adding antiangiogenics to chemotherapy has been a successful strategy for some patients, the cediranib toxicity profile and small incremental survival benefit precludes additional development in MPM.

Conflict of interest statement

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Figures

FIG 1.

CONSORT diagram. (*) Patients’ off-treatment notice indicated off because of disease progression, but additional documentation of progression is needed; (n = 4); physician decision (n = 1); treatment delay greater than protocol defined (n = 1). (†) Surgical intervention (n = 1); physician decision (n = 1); patient’s off-treatment notice indicated off because of disease progression, but additional documentation of progression is needed. (n = 1).

FIG 2.

Progression-free survival outcomes by (A) RECIST v1.1 and (B) modified RECIST 1.1. (C) Overall survival curves. HR, hazard ratio.

FIG 3.

Waterfall plots by (A) RECIST v1.1 and (B) modified RECIST v1.1. Each vertical bar represents a patient’s best percentage of decrease in tumor burden compared with baseline as defined by RECIST v1.1 or modified RECIST v1.1 measurements. Only patients with measurable disease at baseline are presented in these plots. Patients who did not have follow-up tumor disease assessment data are coded as inadequate assessment (NA). Patients who had new lesions appear at their first follow-up assessment or who died before the first scheduled disease assessment and whose death can reasonably be assumed to be a result of disease progression are represented graphically as a 100% increase in tumor burden. Patients who had symptomatic deterioration at first disease assessment are coded as symptomatic deterioration. (A) Per RECIST v1.1, in the cediranib arm, there were a total of 35 patients evaluable for response. In the placebo arm, there were a total of 40 patients evaluable for response. (B) Per modified RECIST, there were 36 patients in the cediranib arm evaluable for response. In the placebo arm, there were a total of 30 patients evaluable for response.

FIG 4.

Forest plot subgroup analysis. (A) Progression-free survival (PFS) by RECIST 1.1, (B) PFS by modified RECIST, and (C) OS. CPC, carboplatin-pemetrexed-cediranib; CPP, carboplatin-pemetrexed-placebo; HR, hazard ratio; PS, performance status; RT, radiation therapy.