Adjuvant Ibandronate Plus Capecitabine Does Not Significantly Improve OS in Elderly Patients With Early Breast Cancer

Although adjuvant treatment with ibandronate (Boniva) plus capecitabine resulted in a numerical improvement in overall survival (OS) vs ibandronate alone in elderly patients with moderate or high-risk early breast cancer, this did not reach statistical significance, according to long-term data from the phase 3 ICE study (GBG 32, BIG 4-04; NCT00196859).

Data presented at the 2023 ESMO Breast Cancer Congress showed that at a median follow-up of 74 months (interquartile range, 56-126), the 7-year OS rate was 83.5% (95% CI, 79.7%-86.6%) with the addition of capecitabine to ibandronate (n = 677) vs 80.9% (95% CI, 76.9%-84.2%) with ibandronate alone (n = 681). Moreover, the 10-year OS rates were 73.1% (95% CI, 68.1%-77.5%) with the doublet vs 70.8% (95% CI, 65.6%-75.4%) with the monotherapy.

The improvement did not reach significance because of the relatively small sample size and the fact that OS did not serve as the primary end point of the trial, according to the study authors.

Notably, the OS improvement achieved with the addition of capecitabine to ibandronate vs ibandronate alone was noted to be more pronounced in the hormone receptor–negative subgroup (n = 258) and to almost reach statistical significance, with a hazard ratio of 0.630 (95% CI, 0.394-1.01).

“ICE is still the largest ever conducted randomized phase 3 trial in elderly breast cancer patients,” lead study author Marcus Schmidt, MD, of the Universitätsklinikum Mainz in Mainz, Germany, and colleagues, wrote in a poster of the data. “The adjuvant combination of capecitabine and ibandronate resulted in a numerically improved OS by 2.9% at 5 years compared to ibandronate alone in elderly [patients with] breast cancer. Overall, mono-chemotherapy added to a bone modifying-agent is a well-tolerated treatment option and might be an alternative to standard chemotherapy in elderly patients in need [of] chemotherapy.”

Although most women with breast cancer are diagnosed after the age of 65 years, older patients with this disease are largely underrepresented in clinical trials. Because the incidence of hormone receptor–positive tumors is rising, and sensitivity to endocrine therapy is known to increase with age, this treatment has been solidified as a key tool in the arsenal for elderly patients with this subtype. Moreover, data from a large meta-analysis showed that the use of adjuvant chemotherapy resulted in improved long-term outcomes for patients with breast cancer who were older than 70 years, irrespective of disease characteristics.

Accordingly, Schmidt and colleagues set out to investigate the safety and efficacy of pairing capecitabine with ibandronate in the adjuvant setting for patients aged 65 years and older with early breast cancer. To be eligible for the prospective, multicenter, controlled, randomized, open-label, phase 3 trial, patients needed to have early node-positive/high-risk node-negative breast cancer and a Charlson comorbidity index of up to 2.

A total of 1358 patients were randomly assigned in a 1:1 fashion to receive capecitabine at 2000 mg/m² on days 1 to 14 every 3 weeks for 6 cycles plus ibandronate at a daily oral dose of 50 or 6 mg intravenously every 4 weeks for 2 years vs ibandronate monotherapy at the same dosing options and schedule.

Patients were stratified by the center at which they received treatment, their nodal status, age, and receptor status. Notably, those with hormone receptor–positive disease received additional adjuvant endocrine therapy.

The primary end point of the trial was to examine invasive disease-free survival, and the key secondary end point was OS. Additional end points included assessing bone-related events such as fractures, surgery, and new osteoporosis; the preference of oral vs intravenous ibandronate; compliance; and safety.

In the overall population, the median age was 71 years (range, 64-88); 81% of patients had hormone receptor–positive disease and 51.9% had node-negative disease. Moreover, 18.8% of patients had HER2-positive disease, and 14.1% had triple-negative disease. Additionally, 58.5% of patients had a Charlson comorbidity index of 0, 31.5% had an index of 1, and 9.9% had an index of 2.

Of the 1409 patients who were eligible for the trial, 702 were assigned to the capecitabine arm and 707 were assigned to the control arm; 677 patients and 681 patients, respectively, started treatment and provided documentation and they comprised the intention-to-treat populations. Of those who received treatment in the doublet arm, 83.4% completed treatment with capecitabine and 77.7% completed treatment with ibandronate. Of those treated in the monotherapy arm, 78.8% completed treatment with ibandronate.

“Lack of effect was independent from age, nodal, and hormone receptor status,” the study authors wrote.

Notably, the addition of capecitabine resulted in a significantly higher incidence of skin and gastrointestinal adverse effects.

Reference

Schmidt M, Nitz UA, Reimer T, et al. Updated long-term overall survival of older adjuvant ibandronate-treated patients with intermediate- or high-risk early breast cancer compared with additional adjuvant capecitabine treatment- The ICE Randomized Clinical Trial. ESMO Open. 2023;8(suppl_1):101333. doi:10.1016/j.esmoop.2023.101333