A multicenter phase II clinical trial led by the University of Chicago Medicine Comprehensive Cancer Centre investigated the efficacy of combining an immunomodulatory agent with the targeted tyrosine kinase inhibitor (TKI) cediranib in patients with differentiated thyroid cancer (DTC), a type of cancer originating from thyroid follicular cells. Despite the potential promise of this combination therapy, the study’s findings, published in Annals of Oncology on May 13, 2023, did not show improved outcomes for DTC patients who typically experience limited treatment options after standard therapies fail.
In recent years, there has been growing interest in using TKIs that target vascular endothelial growth factor receptor (VEGFR) signaling to treat patients with recurrent or metastatic thyroid cancer. These drugs aim to inhibit angiogenesis, a process crucial for cancer progression.
“With this scope, we set out to evaluate whether immunomodulation by lenalidomide in combination with cediranib would improve disease-free survival over cediranib alone,” stated Rosenberg, Assistant Professor in the Section of Hematology and Oncology at the UChicago Medicine Comprehensive Cancer Center.
“There are many recent examples in the literature demonstrating the combination of VEGF-targeted TKIs and immunotherapeutic strategies can be very effective, both preclinically and clinically, in multiple cancer conditions, like renal cell carcinoma and hepatocellular carcinoma,” Rosenberg stated. “And yet, this strategy does not appear to work in this particular disease with lenalidomide.”
Oncologists Ari Rosenberg, MD, and Everett Vokes, MD, from UChicago Medicine designed the study to assess the safety and efficacy of cediranib, a TKI targeting multiple VEGFRs. They also explored the hypothesis that combining cediranib with the immunomodulatory agent lenalidomide might offer added benefits. Lenalidomide is known for its anti-angiogenic properties and has shown promise in early clinical trials for DTC. The trial enrolled 108 patients from various hospitals in the United States and Canada, randomly assigning them to two treatment groups: cediranib alone (39 patients) or cediranib with lenalidomide (69 patients).
“The most important point of this study is that the addition of lenalidomide, an immunomodulatory agent, didn’t improve the progression-free survival over cediranib alone, despite what appeared to be promising single-agent activity in DTC, and should not be combined with VEGFR-targeted TKIs,” stated Rosenberg.
Surprisingly, the study’s results revealed that the addition of lenalidomide did not improve outcomes when compared to treatment with cediranib alone. The cediranib-alone group achieved a median progression-free survival (PFS) of 14.8 months, with 44% of patients experiencing complete or partial tumor disappearance as assessed by the objective response rate (ORR). The data analysis confirmed that cediranib is an active agent, demonstrating ORR and PFS similar to other approved VEGFR-targeted TKIs in DTC, such as lenvatinib, sorafenib, and vandetanib.
“Our study results highlight an unmet need with the current strategies of harnessing the body’s immune system to treat thyroid cancer and the need to evaluate new combinations and new mechanisms, in particular new immunotherapeutic strategies that may be more effective than immunomodulatory strategies or immune checkpoint inhibitors alone,” he tated.
Importantly, this study underscores the significance of randomized trial designs, as single-arm studies can yield misleading results. Additionally, it highlights that immunomodulation has not yet proven successful in treating thyroid cancer. Despite advances in the field and patient enrollment from 2010-2015, the study’s implications remain relevant, as outcomes for DTC patients beyond single VEGFR-targeted TKIs have not seen significant improvement.
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