TOPLINE:

In a meta-analysis of trials involving patients with ERBB2-positive advanced breast cancer, the use of trastuzumab emtansine, an antibody-drug conjugate (ADC), was associated with the lowest incidence of decrease in left ventricular ejection fraction (LVEF) at 0.94%, whereas the use of other treatments including trastuzumab deruxtecan, trastuzumab plus chemotherapy, and trastuzumab plus pertuzumab plus chemotherapy showed similar incidence rates ranging from 4.20% to 5.52%.

METHODOLOGY:

• Breast cancer is the most common cancer, and ERBB2‑positive tumors (15%-20% of breast cancers) are aggressive. ERBB2‑targeted antibodies (eg, trastuzumab and pertuzumab) improve outcomes but can cause dose‑independent cardiotoxicity, especially after anthracycline therapy. ADCs (eg, trastuzumab emtansine and trastuzumab deruxtecan) deliver cytotoxic payloads more selectively and have shown efficacy; however, their cardiotoxic profiles vs standard regimens require evaluation.
• Researchers conducted a systematic review and meta-analysis of phase 3 clinical trials that investigated locally advanced or metastatic ERBB2-positive breast cancer with clearly defined LVEF monitoring and heart failure criteria.
• The control group included 15 studies: 10 evaluated trastuzumab plus chemotherapy (n = 2929), three evaluated trastuzumab plus pertuzumab plus chemotherapy (n = 2411), and two evaluated both regimens. The experimental group included six studies: Four investigated trastuzumab emtansine (n = 3531), one investigated trastuzumab deruxtecan (n = 667), and one evaluated both agents.

TAKEAWAY:

• Across five studies that evaluated trastuzumab emtansine, the pooled incidence of decrease in LVEF was 1.09% (95% CI, 0.63%-1.88%), and after trim‑and‑fill adjustment, the estimate was 0.94%, which was the lowest observed incidence of decrease in LVEF. From two studies that evaluated trastuzumab deruxtecan, the pooled incidence of decrease in LVEF was 4.20% (95% CI, 2.91%-6.01%).
• The lower incidence of cardiotoxic effects with trastuzumab emtansine could be explained by the absence of the bystander effect with trastuzumab emtansine in contrast to trastuzumab deruxtecan, which exhibits this effect.
• Across 12 studies that evaluated trastuzumab plus chemotherapy, the pooled incidence of decrease in LVEF was 4.14% (95% CI, 2.26%-5.23%) before adjustment and 4.85% (95% CI, 3.73%-6.28%) after trim‑and‑fill.
• Five studies evaluated trastuzumab plus pertuzumab plus chemotherapy, and the pooled incidence of decrease in LVEF was 5.52% (95% CI, 3.41%-8.83%).

IN PRACTICE:

This meta-analysis “found that trastuzumab emtansine had the lowest incidence of LVEF decrease; trastuzumab deruxtecan, trastuzumab plus chemotherapy, and trastuzumab plus pertuzumab plus chemotherapy had similar incidences of LVEF decrease,” the authors wrote. “This is an important comparison because ADCs like trastuzumab emtansine and trastuzumab deruxtecan have a favorable safety profile and have shown promise in efficacy as a therapy for previously treated ERBB2-positive BC [breast cancer] that has progressed on standard-of-care regimens, but there is a paucity of data comparing the safety profile and clinical efficacy among ADCs, the safety profile and clinical efficacy of ADCs vs the standard-of-care trastuzumab-containing chemotherapy regimens, and the potential of these agents to be used as a first-line therapy for both early-stage and metastatic ERBB2-positive BC.”

SOURCE:

The study, led by Lakshya Seth, MD, University of Texas Southwestern Medical Center in Dallas, was published online in JAMA Network Open.

LIMITATIONS:

A major limitation was the inability to directly compare the incidence of LVEF decrease between ADCs and standard-of-care regimens as only one study investigated this comparison. The meta-analysis used study-level data, limiting the ability to account for differences in baseline characteristics across trials. The median age of participants being the mid-fifties (less than that of the community population) may have led to underestimation of cardiotoxicity in real-world settings. Additionally, the number of patients who received prior anthracyclines was unknown, preventing evaluation of how anthracycline use impacts LVEF dysfunction.

DISCLOSURES:

The authors did not disclose any funding information. Some authors reported receiving grants or consulting fees from and having other ties with various sources. Full disclosures are noted in the original article. 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.