A subgroup analysis of the phase 3 COSMIC-311 study revealed no key differences in the survival and responses observed with cabozantinib based on the age of patients with RAI-refractory differentiated thyroid cancer.
Cabozantinib (Cabometyx) as treatment of patients with previously treated radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) maintained clinical benefit regardless of patient age, according to extended follow-up results from the phase 3 COSMIC-311 clinical trial presented in a poster during the 90th Annual Meeting of the American Thyroid Association (ATA).
“The most important findings of the study compare progression-free survival in the group of patients who are less than or equal to 65 years of age, or those patients who are greater than 65 years of age," explained said Bruce Robinson, MD, during the ATA presentation. “You can see the progression-free survival advantage is maintained in both of these groups of patients, regardless of their age.”
COSMIC-311, a randomized, double-blind study, investigated with safety and efficacy of cabozantinib compared with placebo in patients with RAI-refractory DTC who previously received a VEGFR-targeted therapy. Three hundred patients were included in the study and randomized 2:1 to receive cabozantinib or placebo, and all had locally advanced or metastatic disease, were either refractory to or ineligible for RAI and had radiographic progression during or after treatment with a maximum of 2 prior VEGF tyrosine kinase inhibitors (TKIs). The TKIs patients were required to have received include lenvatinib (Lenvima) or sorafenib (Nexavar). Patients must have also had an ECOG performance status of 0 or 1 and be at least 16 years of age.
Cabozantinib was administered at 60 mg once daily. Tumors were assessed every 8 weeks for 12 months followed by every 12 weeks per RECIST v1.1. Treatment continued until clinical benefit was no longer shown or until patients experienced intolerable toxicity. The study protocol also allowed for crossover in the case of blinded independent review committee-confirmed progression per RECIST v1.1.
Preplanned interim analysis results from COSMIC-311 showed that in 187 patients followed for a median of 6.2 months, cabozantinib extended progression-free survival (PFS) compared with placebo (HR, 0.22; 96% CI, 0.13-0.36; P <.0001), meeting 1 primary end point of the study. Extended follow-up of the overall population for a median of 10.1 months in 258 patients showed that the PFS benefit of cabozantinib was maintained in comparison with placebo (HR, 0.22; 96% CI, 0.15-0.32; P <.0001).
Following the positive interim findings investigators led by Robinson, professor of Medicine at the University of Sydney School of Medicine, conducted a subgroup analysis in which patients were stratified by age ≤ 65 versus > 65 years.
For the purpose of the subgroup analysis, the coprimary end points of objective response rate (ORR) in the first 100 randomized patients and PFS in the intent-to-treat were assessed along with the secondary end points of ORR in the ITT population, and overall survival (OS). Robinson et al also evaluated adverse events, which were reported according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.
At the data cutoff date of February 8, 2021, 170 patients were evaluated on treatment with cabozantinib, and 88 were evaluated on placebo. Forty patients from the placebo arm crossed over to cabozantinib of whom 19 were in the younger cohort and 21 were in the older cohort. Baseline demographics showed that of the 130 patients who we ≤ 65 years in age, 65% received prior sorafenib and 61 had prior lenvatinib. Among the 128 patients who were > 65 years in age, 55% had been previously treated with sorafenib and 65% received prior lenvatinib. The median age in the younger cohort in the cabozantinib arm was 57.0 years (range 31-65 years) and in the placebo arm, it was 55.0 years (range, 37-65 years). The median age of the older population of the cabozantinib arm was 72.0 years (range, 66-85 years) and in the placebo arm, it was 71.5 years (range, 66-83 years). The majority of the population assessed was female including 53% of young patients in the cabozantinib arm versus 50% in the placebo arm and 49% of the older patients in the cabozantinib arm versus 61% of the placebo arm.
In terms of clinical characteristics screened at baseline, more patients had an ECOG performance status of 1 compared with 0, and the majority of patients also had follicular histology compared with papillary. Metastases were most commonly present in the lungs and lymph nodes. In the younger cohort, 73% of patients in the cabozantinib arm compared with 61% in the placebo arm had lung metastases. In the older group, 69% of the cabozantinib arm had lung metastases versus 77% of the placebo arm. Metastatic lymph nodes were found in 58% of the younger cabozantinib arm versus 68% of the younger placebo arm, and 67% of the older cabozantinib arm versus 66% of the older placebo arm.
More patients in both the younger and older cohorts received 1 prior VEGFR TKI compared with 2 prior VEGFR TKIs, and lenvatinib was the most popular prior therapy. Notably, patients who received prior lenvatinib also had a longer treatment duration compared with sorafenib, regardless of age. All patients, despite their age, progressed on either sorafenib or lenvatinib in less than 2 months.
At a median extended follow-up of 10.1 months, patients ≤ 65 years of age who received cabozantinib had a median PFS of 11.1 months (95% CI, 7.2 to not evaluable [NE]) compared with 1.9 months (95% CI, 1.8-3.6) in the placebo arm (HR, 0.19; 95% CI, 0.12-0.32). Those > 65 years of age had a median PFS of 11.1 months (95% CI, 5.9-13.8) with cabozantinib treatment compared with 3.6 months (95% CI, 1.9-5.4) with placebo (HR, 0.27; 95% CI, 0.16-0.45).
Younger patients had a median OS of 19.4 months (95% CI, 14.5-NE) when treated with cabozantinib in the study versus a NE result in the placebo arm (HR, 0.76; 95% CI, 0.36-1.59). In the population > 65 years of age, the median OS was NE in both arms but trended longer in the cabozantinib arm compared with the placebo arm (HR, 0.80; 95% CI, 0.37-1.74).
During the ATA presentation, Robinson stated: “There is no overall survival benefit that can be demonstrated in these in either of these groups of patients at the moment. And that, of course, is partly due to the crossover nature of this study design.”
The cabozantinib-treated population who was ≤ 65 years of age had an ORR of 10% (95% CI, 4.9%-18.9%) compared with 0% (95% CI, 0.0%-8.0%) in the placebo group. Older patients with RAI-refractory DTC in the cabozantinib arm had an ORR of 12% (95% CI, 5.9%-20.8%) compared with 0% (95% CI, 0.0%-8.0%) with placebo.
Disease stabilization rates (DSRs) were similar between the 2 age groups and results for both age groups favored cabozantinib. The DSR in the younger cabozantinib group was 53% (95% CI, 42.4%-64.3%) compared with 14% (95% CI, 5.2%-27.4%) in the placebo arm. In the older subgroup of patients treated with cabozantinib, the DSR was 52% (95% CI, 41.2%-63.4%) compared with 25% (95% CI, 13.2%-40.3%) in the older placebo subgroup.
The median exposure to cabozantinib among the ≤ 65-year subgroup was 6.6 months (range, 0.6-18.8). In the placebo arm, younger patients were exposed for a median of 2.5 months (range 0.4-11.9). The older subgroup was exposed to cabozantinib for a median of 5.8 months (range, 0.2-18.3) compared with 2.8 months (0.2-15.2), in the placebo arm.
“The other important finding of this study is that there were no marked differences in the rate of dose reduction in the 2 groups of patients that is the elderly versus the not so elderly. Furthermore, that the safety profile of cabozantinib was generally very similar between these two groups of patients,” Robinson reported.
Cabozantinib showed a similar safety profile in both age subgroups with grade 3/4 events having occurred in 63% of the younger population compared with 62% of the older population.
Any grade treatment-emergent adverse events (TEAEs) occurred in 98% of the younger cabozantinib group, 93% of the younger placebo group, 98% of the older cabozantinib group, and 77% of the older placebo group. Further, no grade 5 treatment-related AEs (TRAEs) occurred. Six patients from the younger subgroup who were treated with cabozantinib discontinued treatment as a result of TRAEs, as did 6 older patients who were treated with cabozantinib. Sixty-five younger patients and 65 older patients who received cabozantinib and 2 younger patients and 5 older patients given placebo required dose reduction due to a TEAEs.
With cabozantinib treatment, common TEAEs observed during the subgroup analysis in the younger population versus the older population included diarrhea (59% vs 64%), hand-foot skin reaction (51% vs 43%), hypertension (34% vs 30%), and decreased appetite (29% vs 33%), respectively. Common TEAES experienced by patients in the placebo arm who were younger versus older included decreased appetite (18% versus 7%), asthenia (14% vs 14%), vomiting (11% vs 5%), and fatigue (7% vs 9%).
“Overall, this is now an ideal second-line agent for us to all be able to consider in our patients with differentiated thyroid cancer who have progressed on previous tyrosine kinase inhibitor therapy,” said Robinson concluded.
Robinson B, Sherman SI, Krajewska J, et al. Effect of age on efficacy and safety of cabozantinib versus placebo in patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) with progression after VEGFR-targeted therapy: subgroup analysis from the phase 3 COSMIC 311 Study. Presented at the 90th Annual Meeting of the American Thyroid Association; September 30-October 3, 2021; Virtual. Poster 9.