Worden Reviews Positive Data of Cabozantinib in RAI-Refractory DTC

Francis P. Worden, MD

Cabozantinib (Cabometyx) continued to improve progression-free survival (PFS) vs placebo when used as treatment for patients with radioiodine-refractory differentiated thyroid cancer (RAIR-DTC), irrespective of the duration of prior lenvatinib (Lenvima), according to findings from the phase 3 COSMIC-311 trial (NCT03690388).¹

In the phase 3 COSMIC-311 study, patients aged 16 years old and older with RAIR-DTC who progressed on prior lenvatinib and/or sorafenib were randomized in a 2:1 fashion to receive either oral cabozantinib tablets at a dose of 60 mg/day or a placebo. The primary end points were objective response rate (ORR) and PFS in the intent-to-treat population, both according to RECIST v1.1 by blinded, independent review.

A total of 258 patients were randomized at the data cutoff date of February 8, 2021, to receive cabozantinib (n = 170) or placebo (n = 88). At a median follow-up of 10.1 months, the median PFS was 11.0 months (96% CI, 7.4-13.8 months) with cabozantinib vs 1.9 months (96% CI, 1.9-3.7 months) with the placebo, making for a hazard ratio of 0.22 (96% CI, 0.15-0.32; P <.0001).

With cabozantinib vs placebo, the ORRs were 11.0% (95% CI, 6.9%-16.9%) vs 0% (95% CI, 0.0%-4.1%; P = .0003). One patient treated with cabozantinib had a complete response. Among the patients treated with placebo, 40 crossed over to open-label cabozantinib.

For safety, grade 3/4 treatment-emergent adverse events (AEs) were observed in 62% of patients treated with cabozantinib and 28% treated with placebo.The most common AEs observed in the cabozantinib vs placebo arms were hypertension (12% v 2%), palmar-plantar erythrodysesthesia (10% v 0%), and fatigue (9% v 0%). Moreover, no grade 5 treatment-related AEs were seen.

With extended follow-up, patients with RAIR-DTC treated with cabozantinib experienced better efficacy vs patients treated with placebo, and no new safety signals were observed. These data support the 2021 FDA approval of cabozantinib for the treatment of adult and pediatric patients aged 12 years and older with locally advanced or metastatic differentiated thyroid cancer that has progressed after prior VEGF-targeted therapy and who are RAI-refractory or ineligible.2

“Overall, for second-line therapy, patients did quite well with this agent, and it should be considered once people fail first-line therapy with lenvatinib,” said Francis P. Worden, MD, in an interview with Targeted Oncology^TM.

In the interview, Worden, professor of medicine at the University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, discussed data from the COSMIC-311 study which support treatment with cabozantinib for patients with radioiodine-refractory differentiated thyroid cancer.

Thyroid Gland: © Anatomy Insider - stock.adobe.com

Targeted Oncology: Can you provide background on the COSMIC-311 study?

Worden: The COSMIC-311 study was a study that was conducted in patients in the secondline, so patients who had failed [tyrosine kinase inhibitor] therapy, primarily sorafenib or lenvatinib. They were randomized to Cabometyx [cabozantinib], which is different from Cometriq, as the formulations are different. The salt is a little different, and it is 60 mg. Just a little bit about that, the old formulation of cabozantinib or Cometriq, which is the trade name used in medullary thyroid cancer, is kind of a difficult drug to tolerate. When the companies were thinking about redesigning agents, this agent was developed.

Essentially, it's about half the dose, but a different formulation. There is a study in thyroid cancer, but other cancers that show Cabometyx is a little bit better tolerated than Cometriq. Nonetheless, Cometriq was compared with placebo in patients who were progressing on first-line therapy.

What were the methods and designs utilized in the study and what end points were evaluated?

Patients were randomized 2:1 to the drug vs placebo, and the response rates were somewhere around 13% for those receiving the cabozantinib vs 0% response rates in those who were receiving placebo. The primary end point was a dual end point. They looked at response as well as improvement in progression-free survival.

Can you explain the efficacy findings from COSMIC-311?

The median progression-free survival on placebo was 1.9 months, and on the cabozantinib arm, and it was 11 months, so that was exceeding the expectations. The study was stopped early and declared a positive trial. Had it originally been based on response alone, the study probably would have been negative. I think it was well conducted in looking at those dual end points.

This study also shows in that placebo arm that patients, if you look at the Kaplan-Meier plots, they are dropping off quickly in terms of of death and progression on the placebo arm, because we're talking about a group of patients that now has transforming disease or more aggressive disease and those people are in need of therapy. That does provide the benefit here. What's also important if we look at the subgroup analysis from the study is, interestingly enough, the people who attained the best benefit in progression-free survival were those who received prior sorafenib compared with lenvatinib. I think that goes back to the data that we had previously talked about with robust responses we see with lenvatinib and improvement in progression-free survival. Patients, when treated with placebo vs cabozantinib, did better with cabozantinib, but their overall progression-free survival was not necessarily as robust as with sorafenib.

If we look at the data, the median progression-free survival with prior lenvatinib was 5.8 months vs 16.6 months with sorafenib. But overall, again, we see the total improvement when the 2 drugs are combined together.

What safety findings can you highlight?

Tolerability is similar to what we see with the other multi-targeted kinase inhibitors. Hypertension and hand-foot syndrome can be an issue, as we know, with cabozantinib, as well as general fatigue. Overall, for second-line therapy, patients did quite well with this agent, and it should be considered once people fail first-line therapy with lenvatinib.

REFERENCES

1. Brose MS, Robinson BG, Sherman SI, et al. Cabozantinib for previously treated radioiodine-refractory differentiated thyroid cancer: Updated results from the phase 3 COSMIC-311 trial [published correction appears in Cancer. 2023 Jan 13;:]. Cancer. 2022;128(24):4203-4212. doi:10.1002/cncr.34493

2. 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 October 24, 2023. https://tinyurl.com/bp78c8sf