Patients with heavily pretreated hormone receptor (HR)-positive breast cancer lived twice as long without disease progression with the novel antibody-drug conjugate (ADC) izalontamab brengitecan (iza-bren), a randomized trial from China showed.
Median progression-free survival (PFS) increased from 4 months with chemotherapy to 8.2 months with iza-bren. The advantage favoring the ADC persisted across all prespecified subgroups. Twice as many patients responded to iza-bren, leading to a disease control rate of 86.3% versus 63.7% for the chemotherapy arm. Overall survival (OS) data remained immature and did not differ significantly between treatment groups.
The benefits of iza-bren came with a price of increased toxicity, including substantially more grade ≥3 treatment-related adverse events (TRAEs) and serious TRAEs, but TRAE-related discontinuation was similar in the two groups, reported Bo Lan, MD, of Peking Union Medical College in Beijing, at the European Society for Medical Oncology congress in Madrid.
“In this prespecified analysis, iza-bren demonstrated a statistically significant and clinically meaningful improvement in PFS versus chemotherapy in previously treated, HR-positive, HER2-negative breast cancer, meeting the primary endpoint,” said Lan. “Iza-bren demonstrated an improved confirmed ORR [objective response rate] and more durable responses… . The safety profile of iza-bren was manageable and consistent with previous studies.”
“The results support iza-bren as a potential new standard-of-care option in this population,” he added.
Results of the PANKU-Breast01 trial were published simultaneously in The Lancet. The results added to a survival win in advanced triple-negative breast cancer (TNBC) reported earlier this year. The ADC also has demonstrated activity in advanced bladder cancer and received breakthrough therapy designation from the FDA for non-small cell lung cancer.
Despite the “impressive efficacy” of iza-bren in PANKU-Breast01, the PFS advantage came from a comparison with chemotherapy, not another ADC, such as trastuzumab deruxtecan (T-DXd), noted ESMO invited discussant Fumikata Hara, MD, of Aichi Cancer Center in Nagoya, Japan.
“Therefore, [iza-bren’s] relative efficacy and its optimal position in ADC sequencing remains unknown,” said Hara. “Can a different target overcome resistance to a previous ADC? Possibly, but cross-resistance to the same topoisomerase-1 payload remains an important question.”
“Toxicity is another concern,” he continued. “Hematologic toxicity was substantial, with frequent dose reduction. Only about 12% of the [PANKU] patients were aged 65 years or older, so the safety and feasibility of iza-bren in older patients remain unknown.”
By way of introduction to the study, Lan noted that the addition of CDK4/6 inhibitors to first-line endocrine therapy has improved outcomes in HR-positive/HER2-negative breast cancer. Even so, resistance inevitably develops, and subsequent therapies have yet to improve historically poor outcomes.
A first-in-class ADC, iza-bren consists of an EGFRxHER3 bispecific antibody conjugated to a novel topoisomerase I inhibitor. In a phase I study, the ADC demonstrated promising activity in HER2-negative locally advanced or metastatic breast cancer.
PANKU-Breast01, conducted at 72 centers in China, included 383 patients with unresectable/metastatic HR-positive/HER2-negative breast cancer that had progressed after at least one line of endocrine therapy and one or two lines of chemotherapy. All of the patients had exposure to a CDK4/6 inhibitor and taxane chemotherapy.
The patients were randomized to single-agent iza-bren or multiagent chemotherapy. The primary endpoint was PFS by independent review, and OS was the key secondary endpoint.
The study population had a median age of 54, with 85-90% under 65 years, 70% had one prior line of chemotherapy, and HER2 expression was evenly distributed between IHC 0, 1+ and 2+/ISH negative. About half of the patients had received a CDK4/6 inhibitor for at least 12 months, 85% had endocrine therapy duration of at least 6 months. About 70% of the patients had liver metastasis at baseline.
The primary analysis showed a 4.2-month absolute difference in PFS in favor of iza-bren, representing a 59% reduction in the PFS hazard (95% CI 0.33-0.53, P<0.0001). Landmark analyses at 6, 9, and 12 months showed a two- to three-fold difference in PFS in favor of iza-bren.
Grade ≥3 TRAEs occurred in 85% of the iza-bren arm versus 66% of the control group, and rates of serious TRAEs were 42% and 11%, respectively. Two-thirds of patients in the iza-bren arm had TRAEs necessitating dose reduction versus 29% of the control group, and rates of TRAE-associated dose interruption were 56% and 38%, respectively. Hematologic AEs occurred in 80 to >90% of patients in the iza-bren arm and were grade ≥3 in most cases. Other common AEs (≥30) in the iza-bren arm included alopecia, asthenia, gastrointestinal AEs, and increased liver enzymes.
Non-hematologic AEs were mostly grade 1/2, and treatment-related interstitial lung disease happened in two patients (1.1%) versus one patient in the control group.
