Cabozantinib Demonstrates Long-Term PFS Benefit in Radioiodine-Refractory Differentiated Thyroid Cancer

Jaume Capdevila, MD, PhD

Cabozantinib (Cabometyx) monotherapy maintained continued to provide a superior progression-free survival (PFS) benefit to that achieved with placebo in adults with locally advanced or metastatic differentiated thyroid carcinoma, irrespective of histology, according to updated data from the phase 3 COSMIC-311 trial (NCT03690388).¹

At a median follow-up of 10.1 months (range 0.2-23.4), the median PFS was 9.2 months (95% CI, 5.6-13.8) in those with papillary thyroid cancer who received the multikinase inhibitor (n = 96) vs 1.9 months (95% CI, 1.8-3.7) in those who were given placebo (n = 54; HR, 0.27; 95% CI, 0.17-0.43). In those with follicular thyroid cancer who received cabozantinib (n = 78), the median PFS was 11.2 months (95% CI, 7.5–not evaluable [NE]) vs 2.5 months (95% CI, 1.8-4.6) in those who were given placebo (n = 35; HR, 0.18; 95% CI, 0.10-0.31).

Of those with follicular thyroid cancer, 63 patients had Hurthle cell carcinoma or poorly differentiated variants. Those in this subset who received cabozantinib (n = 44) experienced a median PFS of 11.1 months (95% CI, 5.8-NE) vs 1.9 months (95% CI, 1.6-3.6) in those who were administered placebo (n = 19; HR, 0.12; 95% CI, 0.05-0.27).

“These data further support cabozantinib as a treatment option for patients with [radioiodine-refractory] differentiated thyroid cancer who progressed after VEGFR-targeted therapy, irrespective of disease histology,” lead study author Jaume Capdevila, MD, PhD, medical oncologist at Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology, and colleagues, wrote in a poster on the data.

To be eligible for participation on COSMIC-311, patients needed to be at least 16 years of age, be radioactive iodine refractory or ineligible, and have experienced radiographic progression during or following treatment with up to 2 VEGFR multikinase inhibitors that must have included lenvatinib (Lenvima) or sorafenib (Nexavar). Patients also needed to have an ECOG performance status of 0 or 1 and a serum thyroid stimulating hormone of less than 0.5 mIU/L.

The trial included 150 patients with papillary thyroid cancer (PTC) and 113 with follicular thyroid cancer (FTC) who were refractory to or ineligible for radioactive iodine and who have progressed during or following previous systemic treatment.

Study participants were randomized 2:1 to cabozantinib at a once-daily dose of 60 mg or placebo. Stratification factors included prior receipt of lenvatinib (yes vs no) and age (younger than 65 years vs older than 65 years).

Crossover from the control arm to the cabozantinib arm was permitted if disease progression was confirmed by blinded independent review committee (BICR) assessment and RECIST v1.1 criteria.

The co-primary end points of the trial included BIRC-assessed PFS and ORR by RECIST v1.1 criteria in the intention-to-treat population. Investigators also examined overall survival (OS) and safety.

Across the treatment arms, the median age of study participants was 65.5 years, and 47.5% had an ECOG performance status of 0. Thirty-seven percent of patients previously received sorafenib but not lenvatinib and 39.8% received prior lenvatinib and not sorafenib; 23.5% received both agents. Additionally, 74.8% of patients previously received 1 VEGFR multikinase inhibitor, and 25.3% received 2 or more prior VEGFR TKIs. Just under half of patients, or 43%, had metastatic lesions in the bone, 16.8% had lesions in the liver, 74% had them in the lung, and 59.5% had them in the lymph nodes.

Additional data showed that within those with papillary thyroid cancer who received cabozantinib or placebo, the overall response rates were 15% (95% CI, 8%-23%) and 0% (95% CI, 0%-7%), respectively. The median time to an objective response with cabozantinib was 3.4 months (range, 1.7-7.5), and the disease stabilization rate (DSR) was 50% (95% CI, 40%-60%).

In those with follicular thyroid cancer, the ORR achieved with cabozantinib was 8% (95% CI, 3%-16%) vs 0% (95% CI, 0%-10%) with placebo. The median time to objective response with cabozantinib was 3.8 months (range, 1.7-5.6), and the DSR was 59% (95% CI, 47%-70%). In those with Hurthle cell carcinoma or poorly differentiated carcinoma who received cabozantinib, the ORR was 7% (95% CI, 1%-19%) vs 0% (95% CI, 0%-18%) with placebo. The median time to objective response with cabozantinib was 1.8 months (range, 1.7-3.8) and the DSR was 64% (95% CI, 48%-78%).

Investigators observed grade 3/4 treatment-emergent adverse effects (TEAEs) in 59% of patients with papillary thyroid cancer in the investigative arm vs 24% in the control arm. Sixty-eight percent of those with follicular thyroid cancer assigned to cabozantinib experienced grade 3/4 TEAEs vs 34% of those who were assigned to placebo. Among those with Hurthle cell carcinoma or poorly differentiated carcinoma, grade 3 or 4 TEAEs were reported in 73% of those who received cabozantinib vs 47% with placebo. No grade 5 TEAEs were reported.

Investigators suggested that the higher rates of grade 3/4 TEAEs in the follicular thyroid cancer group could be due to longer median duration of exposure. The median duration of exposure was 7.3 months (range 0.6-18.8) in this group vs 5.5 months (range 0.2-18.3) in the papillary thyroid cancer group.

In May 2022, European Commission approved the use of cabozantinib in those with locally advanced or metastatic differentiated thyroid carcinoma who are refractory or not eligible to receive radioactive iodine and who have progressed during or following prior systemic therapy based on previous data from COSMIC-311.²

At the time of the planned interim analysis, which was conducted at a median follow-up of 8.9 months (interquartile range, 7.1-10.5), the median PFS had not been reached (96% CI, 5.7-NE) in the investigative arm vs 1.9 months (96% CI, 1.8-3.6) in the control arm (HR, 0.22; 96% CI, 0.13-0.36; P < .0001), meeting the primary end point of the trial.³

“The nature of radioiodine-refractory differentiated thyroid cancer means that this condition does not respond to the most commonly used standard of care for [this] cancer. As a result, people living with this form of the disease have had limited treatment options should their disease progress,” Capdevila stated in a press release at the time. “I am pleased to see the entrance of a new innovative treatment in [cabozantinib], following limited progress for patients in this area for such a significant amount of time and I look forward to sharing more positive conversations with my patients on the number of options available to them.”

In September 2021, the FDA approved cabozantinib for patients aged 12 years or older with locally advanced or metastatic differentiated thyroid cancer who progressed following treatment with VEGFR targeted therapy and whose disease is refractory to radioactive iodine based on these data.

References

1. Capdevila J, Robinson, B, Sherman SI, et al. Cabozantinib versus placebo in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who progressed after prior VEGFR-targeted therapy: Outcomes in prespecified subgroups based on histology subtypes. J Clin Oncol. 2022;40(suppl 16):6081. doi:10.1200/JCO.2022.40.16_suppl.6081
2. European Commission approves Cabometyx as a second-line treatment for people living with radioactive iodine-refractory differentiated thyroid cancer. News release. Ipsen. May 3, 2022. Accessed July 12, 2022. https://bit.ly/3LFktWl
3. Brose MS, Robinson B, Sherman SI, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021;22(8):1126-1138. doi:10.1016/S1470-2045(21)00332-6
4. Exelixis Announces US FDA approval of Cabometyx (cabozantinib) for patients with previously treated radioactive iodine-refractory differentiated thyroid cancer. News release. Exelixis. September 17, 2021. Accessed July 12, 2022. https://bwnews.pr/2VNSZJw