Cediranib Alone Yields Promising Efficacy in Differentiated Thyroid Cancer

"Antiangiogenic TKIs are reaffirmed as the standard-of-care treatment approach in RAI-refractory DTC, while the addition of immunomodulatory agents does not improve PFS," according to the authors of a phase 2 trial (NCT01208051) published in Annals of Oncology.

The VEGFR-targeting tyrosine kinase inhibitor (TKI) cediranib (AZD-2171; Recentin) was more efficacious as a single agent, and notably did not yield meaningful improvement when combined with lenalidomide (Revlimid) for patients with radioactive iodine (RAI)–refractory differentiated thyroid cancer (DTC), according to findings from a phase 2 trial (NCT01208051) published in the Annals of Oncology.

The median progression-free survival (PFS) in the single-agent arm was 20.9 months (95% CI, 10.9-not reached [NR]) at the time of the futility analysis compared with 10.6 months (95% CI, 7.3-14.6) in the combination arm (P = .26). At the time of the final follow-up analyses, the median PFS was 14.8 months (95% CI, 8.5-23.8) vs 11.3 months (95% CI, 8.7-18.9) in the single-agent and combination arms (P = .36), respectively, after a median follow-up of 11 months.

Cediranib alone produced a partial response (PR) in 17 of 39 patients and an objective response rate (ORR) of 44%. Of the 69 patients in the combination arm, treatment yielded a complete response in 1, a PR in 30, and an ORR of 43% (P = .99). The 2-year overall survival (OS) rate was 64.8% (95% CI, 43.3%-86.4%) with cediranib alone and 75.3% (95% CI 59.4%-91.0%) with cediranib plus lenalidomide (P = .80).

Cediranib alone yielded a median change in tumor size of –12.5% (interquartile range (IQR), –26.0% to 0.0%), whereas the combination yielded a median change of –4.2% (IQR, –25.0% to 0.0%; P = .83).

The incidence of serious adverse effects (AEs) was 41% in the single-agent arm vs 46% in the combination arm.

“Despite results of early-phase, single-arm trials suggesting the efficacy of lenalidomide and thalidomide in RAI-refractory DTC, our randomized results did not demonstrate an improvement in PFS with the addition of lenalidomide to cediranib alone in this patient population, highlighting the importance of randomized trials in this setting,” the investigators wrote.

These data come from an evaluation of outcomes in 108 patients who enrolled in this multicenter, open-label phase 2 study from 2010 to 2015, of whom 39 received the single-agent treatment and 69 received the combination. The population included 96 patients from the United States (89%) and 12 from Canada (11%).

The median patient age was 63 years (range, 24-86). Most patients were male (59%) and White (82%). Additionally, the majority of the population had received no prior VEGF-targeted therapy (77%), an ECOG performance status of 0 or 1 (95%), and had papillary thyroid cancer (64%).

In the phase 2 portion of the trial, the single-agent regimen consisted of oral cediranib maleate at a dose of 30 mg daily for the first 28 days of each 4-week cycle. The combination regimen added oral lenalidomide at a dose of 15 mg daily to the single-agent regimen, and called for treatment on the first 21 days of each 4-week cycle.

The combination regimen had been discontinued after the interim analysis, with those patients crossing over to receive cediranib alone.

The study’s primary end point was PFS at the time of the futility and final analyses. Secondary end points included ORR and OS, as well as percent change in tumor size.

The most frequent treatment-related AEs of grade 3 or higher in the single-agent and combination arms, respectively, were fatigue (26% vs 26%), hypertension, (26% vs 28%), and diarrhea (15% vs 12%).

The combination therapy yielded higher rates of proteinuria (8.7%) than the single-agent therapy (5.1%); the same was true of generalized muscle weakness (5.8% vs 0%), neutropenia (16% vs 2.6%), thrombocytopenia (4.3% vs 0%), and lymphopenia (4.3% vs 0%), respectively.

“Antiangiogenic TKIs are reaffirmed as the standard-of-care treatment approach in RAI-refractory DTC, while the addition of immunomodulatory agents does not improve PFS,” the investigators concluded.

Reference

Rosenberg AJ, Liao CY, Karrison T, et al. A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer. Ann Oncol. Published online May 12, 2023. doi:10.1016/j.annonc.2023.05.002