Immune Modulators in the Survival of Complex Thyroid Cancer

The results of a multicenter phase II clinical trial led by the University of Chicago Medicine Comprehensive Cancer Center show that adding an immunomodulatory agent to treatment with the targeted tyrosine kinase inhibitor (TKI) cediranib did not improve outcomes for patients with differentiated thyroid cancer (DTC), which develops from thyroid follicular cells.

On May 13, 2023, the findings were published in Annals of Oncology.

The majority of DTC patients are successfully treated. However, a tiny percentage of people acquire cancer that recurs or spreads to other parts of the body, rendering standard treatments such as surgery, hormone therapies, chemotherapy, and radioactive iodine (RAI) therapy ineffective.

TKIs that target vascular endothelial growth factor receptor (VEGFR) signaling in the tumor microenvironment have received considerable attention in recent years. These strong angiogenesis mediators aim to promote the production of new blood cells, a process that is critical in the evolution of thyroid cancer.

Ari Rosenberg, MD, and Everett Vokes, MD, of UChicago Medicine, set out to assess the safety and efficacy of cediranib, a TKI that targets several VEGFRs. Furthermore, the researchers predicted that combining the medicine with an immunomodulatory treatment known as lenalidomide would provide an additional advantage to this group of individuals. This medicine is also known to inhibit angiogenesis and have anti-tumor characteristics in other malignancies, and preliminary clinical trials suggest that it has similar effectiveness against DTC. Recent combination medicines that combine standard and immunotherapies have produced superior results in several cancer situations.

“With this scope, we set out to evaluate whether immunomodulation by lenalidomide in combination with cediranib would improve disease-free survival over cediranib alone,” said Rosenberg, Assistant Professor in the Section of Hematology and Oncology at the University of Chicago Medicine Comprehensive Cancer Center.

A total of 108 patients from various hospitals in the United States and Canada were included in a phase II clinical trial. They were randomly randomized to one of two treatment arms: cediranib alone (39 patients) or cediranib plus lenalidomide (69 patients). The cediranib alone group had a median progression-free survival (PFS) of 14.8 months, and 44% of patients experienced tumor elimination as measured by the objective response rate (ORR). Surprisingly, adding lenalidomide to cediranib did not appear to be any better than cediranib alone.

“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 said. “And yet, this strategy does not appear to work in this particular disease with lenalidomide.”

The data analysis revealed that cediranib is an active agent, which indicates that its ORR and PFS are comparable to other approved VEGFR-targeted tyrosine kinase inhibitors in DTC, such as lenvatinib, sorafenib, and vandetanib.

Rosenberg went on to say that this study emphasizes the necessity of randomized trial design, as single-arm trials can produce false-positive outcomes and immunomodulation has proven unsatisfactory in thyroid cancer thus far.

“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,” said Rosenberg.

Despite developments in the field from the time of conceptualization and patient enrollment from 2010 to 2015, the implications remain extremely pertinent, according to Rosenberg, because results beyond single VEGFR-targeted TKIs in DTC have not improved.

“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 said.

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