Etirinotecan Pegol No Help in Breast Cancer With Brain Metastases

Early promise for etirinotecan pegol in breast cancer patients with brain metastases hit the harsh reality of a confirmatory trial, researchers reported.

In the open-label, phase III ATTAIN study, median overall survival was a similar 7.8 months with etirinotecan pegol -- a long-acting polymer conjugate of the topoisomerase I inhibitor irinotecan -- and 7.5 months with physician's choice of chemotherapy (HR 0.90, 95% CI 0.61-1.33, P=0.60), according to the team led by Debu Tripathy, MD, of the University of Texas MD Anderson Cancer Center in Houston.

For the secondary endpoint of progression-free survival, the etirinotecan pegol group had a non-significant median improvement of less than a month for non-central nervous system (CNS) metastases (2.8 vs 1.9 months; P=0.18) and CNS metastases (3.9 vs 3.3 months; P=0.07), they wrote in JAMA Oncology.

The findings failed to confirm the promising results with etirinotecan pegol from the phase III BEACON trial, where the subgroup with brain metastases reached a median overall survival of 10 months with the pegylated irinotecan, as compared with 4.8 months with standard chemotherapy options.

"Did differences in patient populations contribute to the different outcomes between studies? Despite few differences in eligibility (ATTAIN allowed a shorter interval between definitive local treatment for BM [brain metastases] and randomization than BEACON), the studies enrolled noncomparable populations," the group noted.

Tripathy's group argued that confirmatory studies should "closely mirror" the original trial designs, and pointed to the fact that ATTAIN had more triple-negative breast cancer patients compared with the BEACON subset (40% vs 27%), more patients who had previously received regimens containing eribulin (42% vs 24%), and nearly half as many who had been treated with whole-brain radiotherapy (49% vs 91%). They also cited the possibility of insufficient time for stabilization of brain lesions prior to randomization, as well as the lack of consensus on what truly constitutes a stable lesion.

From March 2017 to November 2019, the ATTAIN trial randomized 178 breast cancer patients at nearly four dozen sites across 10 countries. Patients all had stable brain metastases and were randomized 1:1 to either etirinotecan pegol or physician's choice of chemotherapy, which included eribulin, vinorelbine, gemcitabine, nab-paclitaxel (Abraxane), paclitaxel, ixabepilone, and docetaxel.

Patients were heavily pretreated, with 88-91% having received four or more prior lines of therapy. Median age was 52-53 years, a little more than two-thirds were white, and about half were treated at U.S. centers. For tumor-receptor status, 57% were estrogen-receptor positive, 16% were ERBB2 positive, and 44-49% were progesterone-receptor positive.

"It is possible that the broad eligibility criteria that permitted all breast cancer subtypes may have distorted the interpretation of our study results given that the standard-of-care treatment for ERBB2-positive and negative disease is substantially different," Tripathy's group wrote. "There is also the possibility that the BEACON BM subgroup results were a false-positive (chance) outcome."

Median duration of treatment exposure was 1.4 months with etirinotecan pegol and 1.6 months with physician's choice of chemotherapy (median three cycles for both).

Few patients showed objective responses to treatment: 4.8% of those assigned etirinotecan pegol and 2.7% of those in the physician's choice arm for non-CNS metastases (all partial responses), with stable disease as best response in 19.3% and 6.8%, respectively. No objective responses for CNS lesions were observed, while stable disease was achieved in 13.3% and 4.1%.

Patients reported significantly more vomiting with etirinotecan pegol than physician's choice of chemotherapy (34.4% vs 19.5%).

Grade 3/4 adverse event rates were a similar 56.7% in the etirinotecan pegol group and 63.6% in the physician's choice group, with the most common including diarrhea (13.3% vs none, respectively), neutropenia (7.8% vs 16.9%), fatigue (6.7% vs 6.5%), anemia (5.6% vs 6.5%), asthenia (5.6% vs 2.6%), and decreased neutrophil count (2.2% vs 9.1%).

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