- To be presented at the American Society of Clinical Oncology’s (ASCO) Annual Meeting, 03 – 07 June 2022, Chicago (IL, USA), results of prespecified subgroup analysis by disease classification show that targeted therapy with cabozantinib improves outcomes in RAIR DTC patients irrespective of histological subtype.
- Data from a second VHIO-led study of prespecified subgroups of patients based on previous VEGFR-targeted therapy show that cabozantinib achieved superior survival independently of prior treatment with tyrosine kinase inhibitors lenvatinib, sorafenib, or both.
The most common subtype of thyroid cancer is differentiated thyroid cancer (DTC), which has a good prognosis and a survival rate of over 85%. The initial treatment approach is surgery followed, in some cases, by adjuvant radioactive iodine (RAI) therapy. A subset of patients develop RAI-refractory progressive disease, and, until the advent of multikinase inhibitors, lenvatinib and sorafenib, treatment options were limited for these patients.
“One of the major challenges in improving outcomes for patients is acquired cancer drug resistance. Up until very recently, for patients with radioiodine-refractory differentiated thyroid cancer (RAIR DTC) with disease progression during or after treatment with VEGFR-targeted therapies, there were no other effective treatment options available,” observes Jaume Capdevila, a Medical Oncologist and Clinical Investigator at the Vall d’Hebron Institute of Oncology’s (VHIO) Gastrointestinal and Endocrine Tumors Group, and Head of the Vall d’Hebron University Hospital’s (HUVH) Neuroendocrine Tumors Unit, Vall d’Hebron Barcelona Hospital Campus.
Ringing in a new standard of care, the multikinase inhibitor cabozantinib was approved last year by the U.S. Food and Drug Administration (FDA), for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic DTC that has progressed following prior VEGFR-targeted therapy and who are ineligible or refractory to RAI. Most recently, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) followed suit by approving cabozantinib in this patient population.
These developments were based on the results of the pivotal double-blind phase III COSMIC-311 clinical trial (1) that evaluated the efficacy and safety of this targeted therapy in this patient population. cabozantinib in patients with radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) who had progressed during/after prior VEGFR-targeted therapy, for whom there was no standard of care.
The final data of this study, presented by Jaume Capdevila at the virtual 2021 annual Congress of the European Society for Medical Oncology (ESMO), confirmed the superior efficacy and manageable safety profile of cabozantinib as reported in the interim analysis, with improved progression-free survival, irrespective of prior VEGFR-targeted therapy. Achieving a striking 80% reduction in the risk of disease progression in these patients, this multikinase inhibitor has stepped up as a new treatment option for RAIR-DTC patients.
Cabozantinib’s superior efficacy independently of tumor subgroup and previous treatment type
The results of two VHIO-led studies to be presented on the ground at this year’s American Society of Clinical Oncology (ASCO) Annual Meeting, 03 – 07 June, Chicago (IL, USA), now show extended follow-up data from the COSMIC-311 study in prespecified subgroups of RAIR DTC patients. Findings to be presented by Jaume Capdevila (2) reveal outcomes of treatment with cabozantinib versus placebo in subgroups of patients based on histological subtypes.
To be presented by Jorge Hernando, a Medical Oncologist and Clinical Investigator of the same group at Vall d’Hebron, a second study (3) explored the efficacy of cabozantinib in subgroups of RAIR DTC patients who received prior treatment with VEGFR-targeted therapies, lenvatinib, sorafenib, or both, with disease progression during/after 1-2 prior lines of therapy.
Both studies used data obtained after a median follow-up of more than 10 months of 258 patients, and further confirm the superior efficacy of cabozantinib.
Outperforming placebo irrespective of DTC subtype
DTC comprises multiple histological subtypes. Papillary thyroid cancer is the most common, accounting for between 80 and 85% of all cases, and can often spread to lymph nodes of the neck. Follicular thyroid cancer represents 5% of DTCs. Distant metastases from these tumors are mainly hematogenous and are commonly observed in the lungs and bones.
“We sought to establish if patients with different histological subtypes of differentiated thyroid cancer respond differently to treatment with cabozantinib. To do so we assessed the clinical outcomes in prespecified subgroups of patients based on classification of disease,” says Jaume Capdevila, co-Principal Investigator of the phase III international COSMIC-311 trial.
Patients were subdivided into groups according to tumor subtypes, papillary or follicular thyroid cancers. The follicular thyroid subgroup also included patients with Hurthle cell cancer and poorly differentiated variants, a rare and aggressive tumor type. After a median follow-up of more than 10 months, data showed that cabozantinib maintained superior efficacy versus placebo, irrespective of histological subtype, including patients in the follicular thyroid Hurthle cell carcinoma subgroup.
Specifically, median progression-free survival (mPFS) in papillary thyroid cancer patients was 9.2 months for cabozantinib compared to 1.9 months for placebo, and in patients with follicular thyroid cancer mPFS was 11.2 months versus 2.6 months for placebo. Patients with Hurthle cell and poorly differentiated variants receiving cabozantinib achieved mPFS of 11.1 months compared to 1.9 months for placebo.
“Cabozantinib significantly outperformed placebo confirming the previously observed potency of this multikinase inhibitor. Results show that superior efficacy is maintained in this patient population, regardless of histological subtype,” adds Jaume Capdevila.
Cabozantinib also achieved better overall response rates (ORR) versus placebo, independently of histological subtype. In patients with papillary thyroid cancer ORR was 15% versus 0% for placebo, and 8% compared to 0% for placebo in the follicular thyroid cancer subgroup. Data showed that the only difference observed were moderately higher rates of grade 3/4 treatment-emergent adverse events in the follicular thyroid cancer subgroup comparted with the papillary thyroid cancer group that could be attributed to the longer median duration of exposure to cabozantinib in the follicular subgroup.
Exploring patient outcomes based on prior VEGFR-targeted therapy
The indication investigated for cabozantinib therapy was that patients must have received prior treatment with VEGFR-targeted therapies including lenvatinib or sorafenib, with disease progression during or after treatment with 1-2 prior VEGFR inhibitors.
“The aim of our subgroup analysis by prior therapy was to establish whether the type of therapy received prior to treatment with cabozantinib influenced response. This strategy would enable us to identify a subgroup of patients in which treatment was less effective,” says Jorge Hernando, lead investigator of this study.
Patients were subdivided based on the type of prior VEGRF-targeted therapy and data showed that cabozantinib also maintained superior progression-free survival compared to placebo, irrespective of the previous treatment that they received.
The mPFS with cabozantinib in patients who had previously been treated with sorafenib was 16.6 months versus 3.2 months for placebo. In those who had received prior treatment with lenvatinib the median was 5.8 months compared to 1.9 months for placebo, and in those patients who had received prior therapy with both VEGFR-targeted therapies it was 7.6 months versus 1.9 months.
“While data showed better results in those patients who had previously received sorafenib, populations can differ in subgroup analysis. The clinical benefit of cabozantinib was nonetheless significantly superior, irrespective of prior treatment type. These findings further support the use of cabozantinib as the new standard of care for these patients,” concludes Jorge Hernando.
- Brose MS, Robinson B, Sherman SI, Krajewska J, Lin CC, Vaisman F, Hoff AO, Hitre E, Bowles DW, Hernando J, Faoro L, Banerjee K, Oliver JW, Keam B, Capdevila J. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COSMIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2021 Aug;22(8):1126-1138.
- Jaume Capdevila, Bruce Robinson, Steven I. Sherman, Barbara Jarzab, Chia-Chi Lin, Fernanda Vaisman, Ana O. Hoff, Erika Hitre, Daniel W. Bowles, Denise Williamson, Jennifer Oliver, Bhumsuk Keam, Marcia S. Brose. 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. ASCO Annual Meeting. https://meetinglibrary.asco.org/record/207045/abstract.
- Jorge Hernando, Jaume Capdevila, Bruce Robinson, Steven I. Sherman, Barbara Jarząb, Chia-Chi Lin, Fernanda Vaisman, Ana Hoff, Erika Hitre, Daniel W. Bowles, Suvajit Sen, Jennifer Wright Oliver, Bhumsuk Keam, Marcia S. Brose. Cabozantinib (C) versus placebo (P) in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy: Outcomes in prespecified subgroups based on prior VEGFR-targeted therapy. ASCO Annual Meeting. 2022. https://meetinglibrary.asco.org/record/207078/abstract.