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'Important' Advance in Tough-to-Treat Thyroid Cancer

— Targeted therapy cabozantinib may represent a new standard in heavily pretreated patients

Last Updated June 12, 2021
Ƶ MedicalToday

Treatment with cabozantinib (Cabometyx) significantly improved progression-free survival (PFS) in patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer, an interim analysis of a phase III study found.

In the intent-to-treat population of , median PFS was not reached with cabozantinib, as compared to 1.9 months with placebo (HR 0.22, 96% CI 0.13-0.36, P<0.0001), reported Marcia Brose, MD, PhD, of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, at the virtual American Society of Clinical Oncology (ASCO) annual meeting.

But the study's second co-primary endpoint, overall response rate (ORR), failed in meeting prespecified criteria for statistical significance, with an ORR of 15% in the cabozantinib arm versus 0% in the placebo arm.

Treatment with cabozantinib -- a multikinase (MKI) inhibitor of VEGFR2, MET, AXL, and RET -- showed consistent PFS superiority versus placebo in prespecified subgroups, including among patients previously treated with lenvatinib (Lenvima) and other VEGFR-targeting therapies.

A favorable overall survival (OS) trend was also seen with cabozantinib versus placebo (HR 0.54, 95% CI 0.27-1.11), but Brose cautioned that OS may not become significant due to crossover in the placebo arm.

"The significant improvement in PFS and favorable trend for OS suggest cabozantinib could be an important new option for these patients," Brose said in a . "Following disease progression on anti-VEGFR therapy, patients with radioactive iodine-refractory DTC [differentiated thyroid cancer] currently have no standard of care available to them, making the positive results of the COSMIC-311 trial an important clinical advance for this community in need of additional treatment options."

ASCO discussant Nicole Chau, MD, of the University of British Columbia/BC Cancer Agency in Vancouver, said the study was "noteworthy for meeting its co-primary endpoint of PFS ... in this heavily pretreated patient population."

"Due to these impressive findings at the first interim analysis, at only 6.2 months median follow-up, the independent data monitoring committee recommended enrollment be stopped," said Chau.

She noted that the disease control rate of 60% (versus 27% with placebo) is clinically meaningful in this heavily pretreated population.

Given the unmet clinical need, said Chau, "these exciting results at first interim analysis of COSMIC-311 support cabozantinib as a potential second- or third-line VEGFR/MKI option."

Cabozantinib is FDA approved as first-line treatment in advanced renal cell carcinoma (RCC) in combination with nivolumab (Opdivo), and carries other indications for pretreated RCC and in hepatocellular carcinoma. In February, the FDA granted the agent a in differentiated thyroid cancer that has progressed following prior therapy and is RAI, according to developer Exelixis.

The current trial enrolled randomized patients 2:1 to receive oral cabozantinib (60 mg daily) or placebo. Patients were stratified by prior lenvatinib treatment and age (≤65 and >65).

Patients with RAI-refractory differentiated thyroid cancer must have received lenvatinib or sorafenib (Nexavar) for differentiated thyroid cancer, and progressed during or following treatment with no more than two prior VEGFR inhibitors.

Patients randomized to placebo could cross over to open-label cabozantinib upon disease progression per blinded independent radiology committee. The trial's primary endpoints were ORR in the first 100 randomized patients and PFS in all randomized patients.

As of August 2020, 125 patients (median age 66, 55% female, 63% with prior lenvatinib) were in the investigational arm and 62 were in the placebo arm.

The authors reported that PFS benefit was seen in all prespecified subgroups, including those who had prior lenvatinib treatment (HR 0.26, 95% CI 0.15-044) and those who did not (HR 0.11, 95% CI 0.04-0.35). Based on age, the HRs were 0.16 (95% CI 0.08-0.33) for those ≤65 and 0.31 (95% CI 0.16-0.60) for those >65.

Treatment-emergent adverse events (AEs) of any grade were seen more often with the study agent versus placebo:

  • Diarrhea: 51% vs 3%
  • Hand-foot skin reaction: 46% vs 0%
  • Hypertension: 28% vs 5%
  • Fatigue: 27% vs 8%
  • Nausea: 24% vs 2%

Grade 3/4 AEs were experienced by 57% of patients on cabozantinib versus 26% with placebo. Also, dose reductions due to AEs occurred in 57% versus 5%, respectively. No treatment-related deaths occurred in either arm.

Chau noted that other issues with cabozantinib require evaluation, such as quality of life and financial toxicity.

  • author['full_name']

    Ed Susman is a freelance medical writer based in Fort Pierce, Florida, USA.

Disclosures

COSMIC-311 was funded by Exelixis and Ipsen. Some co-authors are employees of Exelixis.

Brose disclosed relationships with, and/or support from, Bayer, Eisai, Lilly, Blueprint Medicines, Exelixis, and Loxo.

Chau disclosed relationships with Merck.

Primary Source

American Society of Clinical Oncology

Brose M, et al "Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: Results from the phase 3 COSMIC-311 trial" ASCO 2021; Abstract 6001.