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At ESMO, Multiple Enhertu Studies Highlight Challenges of Selecting, Managing Breast Cancer Patients

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NEW YORK – The recent expansion of AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) as a treatment for low HER2-expressing metastatic breast cancer has upended established testing and treatment strategies.

At the European Society for Medical Oncology Congress in Barcelona, Spain, researchers discussed the challenges they are facing in identifying patients likely to respond to this antibody-drug conjugate (ADC) due to lab discordance in gauging HER2-low status and highlighted the need for predictive biomarkers beyond HER2. Researchers are gathering data so they can understand and address the extent of these challenges in the community and better manage patients.

At the meeting on Sunday, researchers presented data from some of these studies, including the Phase III DESTINY-Breast06 trial, which looked at the agreement between local and central labs in determining HER2-low and -ultralow status and evaluated patients quality of life on Enhertu; the Phase II DAISY trial, which explored biomarkers of response to Enhertu; and a real-world study evaluating the risk of interstitial lung disease with this drug.

In recent years, more breast cancer patients have become eligible for Enhertu as its indication has expanded. In the US and Europe, regulators have widened the drug's indication from HER2-positive metastatic breast cancer to include HER2-low expressing tumors. In an attempt to further grow the market for this drug, AstraZeneca and Daiichi Sankyo have shared data suggesting Enhertu's activity in patients with ultralow HER2 expression.

However, the new HER2-low and -ultralow categories have upset established processes pathologists use to determine whether patients' tumors are HER2 positive or negative, prompted concern about discrepancies in the immunohistochemistry testing used to gauge the biomarker, and raised questions about how to address these changes in guidelines.

Christos Sotiriou, research director at the National Fund for Scientific Research in Belgium, who discussed several of the abstracts on Enhertu at the ESMO Congress, emphasized the importance of correctly assessing patients' HER2 status and understanding their responses and resistance to the drug to improve patient selection.

"The question is: Are we measuring the [HER2] target correctly?" Sotiriou asked his colleagues at the meeting. "We want to minimize the false negatives in order to increase the patients that are eligible for trastuzumab deruxtecan. Also, you want to minimize the false positives. You don't want to give a drug without any benefit."

Managing discordance

In the DESTINY-Breast06 trial, researchers examined how readily IHC test results from local labs agreed with centralized lab test results for the biomarker when gauging patients' HER2 low and ultralow status across more than 1,600 samples. Other studies have suggested that there is greater test variability when gauging lower HER2 expression levels, prompting concern about whether current test methods are good enough to reliably select patients for HER2-targeted treatment.

The DESTINY-Breast04 trial, which supported the approval of Enhertu in HER2-low breast cancer, established the IHC cutoffs for this new biomarker category. Using the same criteria, in DESTINY-Breast06, HER2-low was defined as an IHC staining result of 1+ or if patients were IHC 2+; they also had to be negative for HER2 gene amplification by in situ hybridization (ISH). The HER2-ultralow category was defined as patients with a HER2 IHC expression score greater than 0 and less than 1 or an IHC 0 result with membrane staining. However, this category is difficult to differentiate from true IHC 0 due to the small number of cells with membrane staining, and joint guidelines from American Society of Clinical Oncology and the College of American Pathologists currently recommend that pathologists take extra steps to examine samples that fall between IHC 0 and 1+, but still to report an IHC 0 or 1+ result as HER2-negative.

To enroll in the study, patients tested at a local facility for HER2 expression also had to have their biomarker status confirmed at a central lab.

The overall agreement in HER2-low status between local and central testing was 77.8 percent. Nearly all samples, 94 percent, that were scored at HER2-low by local testing met the inclusion criteria for DESTINY-Breast06, according to Giuseppe Viale, professor of pathology and director of the Post-graduate Medical School in Pathology at the University of Milan, who presented the research on Sunday.

Central testing determined that 12 percent of patients were IHC 0, 67 percent were HER2-low, and 21 percent were HER2-ultralow. Out of 349 patients scored as HER2 IHC 0 locally, 64 percent were found to be HER2-low or HER2-ultralow by central testing. A quarter of these local IHC 0 samples were centrally determined as HER2-low and 40 percent deemed HER2-ultralow.

Based on the variability seen, Viale concluded that "for patients with metastatic hormone receptor-positive breast cancer [who are] scored IHC 0, it may be very useful to reassess HER2 status in order to see whether the patient is eligible for trastuzumab deruxtecan."

Sotiriou, who was not involved in the DESTINY-Breast06 analysis, noted that reproducibility of HER2-low status can vary widely, with some studies finding very low pathologist agreement in determining HER2-low status, around 26 percent, and others finding high agreement, around 82 percent.

He noted this discrepancy could come down to technical issues with testing platforms or tumor samples, such as errors in tissue collection, fixation, or processing, or biological differences in tumors, including intra-tumor heterogeneity, changes in HER2 expression in patients with disease progression or after they receive certain treatments, or differences in expression between primary and metastatic tumors.

Sotiriou noted that these issues could be addressed by creating and adhering to standard operating procedures within pathology labs, taking a new biopsy of tumors once patients progress, and training pathologists to more consistently score HER2-low to -very low expression.

On a positive note, in DESTINY-Breast06, researchers showed that HER2-low and -ultralow status can be determined regardless of the age of sample, the site of sample, the region of accrual, and whether the tissue sample came from a biopsy or resection or from a primary or metastatic tumor.

Sotiriou also highlighted efforts to develop new methodologies for more reliably quantifying HER2 expression, including mRNA expression assays, artificial intelligence-supported digital pathology, and other tools. "We need to have more predictive assays, rather than more precise assays [for measuring HER2]," he said.

Biomarkers beyond HER2

In the Phase II DAISY trial, researchers evaluated Enhertu in three metastatic breast cancer cohorts according to HER2 expression: HER2 positive, HER2 low, and HER2 negative. Researchers also evaluated other predictive biomarkers, including ERBB2, immune markers, and certain mutational signatures and found several associated with Enhertu response.

In whole-exome sequencing data from pretreatment samples from 92 patients, there was a "significant association" between ERBB2 amplifications and responders, said Maria Fernanda Mosele, a researcher at Gustave Roussy in Paris, who presented the biomarker analysis on Sunday.

ERBB2 amplification occurred in 26 patients who responded to Enhertu, representing 56.5 percent of all responders. In nonresponders, 28 percent, or 13 patients, were found to have ERBB2 amplifications.

They also assessed 17 mutational signatures that are known to be active in breast cancer based on a 2020 publication. They found two signatures associated with response to Enhertu in the HER2-low and HER2 IHC 0 cohorts: one linked with DNA mismatch repair deficiency and another associated with oxidative stress.

The researchers did not find any significant associations between the immune markers CD3 and CD8 and Enhertu response or resistance or any genomic alterations significantly associated with resistance.

While such efforts to look for more biomarkers of response and resistance to Enhertu are important, Sotiriou noted that this analysis was limited by small patient numbers and that the identified biomarkers need further validation. "We have to continue to understand the mechanisms of resistance and response to ADCs for better patient selection in the future," he said.

Insights from real-world data

As Enhertu's indication expands and more breast cancer patients become eligible to receive it, oncologists want to better understand the extent to which this drug is benefiting patients, particularly their quality of life in light of treatment-associated toxicities.

In another analysis from DESTINY-Breast06, researchers evaluated patient-reported outcomes using quality-of-life questionnaires from the European Organization for Research and Treatment of Cancer. The researchers, led by Xichun Hu, director of the department of medical oncology at Fudan University in Shanghai, surveyed patients at baseline, every three weeks during treatment, at the end of treatment, and every three weeks until a second progression or death.

They found that quality of life was largely consistent between the Enhertu and chemotherapy arms. However, Enhertu reduced the risk of clinically meaningful deterioration in several areas compared to chemo.

Enhertu reduced the risk of deterioration due to pain by 49 percent compared to chemo, with a median time to deterioration of 22 months on Enhertu compared to 6.3 months on chemo. Enhertu also reduced the risk of deterioration in physical, emotional, social, and cognitive functioning, and patients on Enhertu reported less fatigue, pain, and breathing and sleep problems compared to those on chemo. However, patients reported experiencing more gastrointestinal issues with Enhertu, such as nausea, loss of appetite, and constipation, compared to chemo. Hu added that these gastrointestinal symptoms did not appear to be detrimental to patients' overall quality of life, however.

"The [patient-reported outcome] results, describing the patient's perspective, further support trastuzumab deruxtecan as a new therapeutic option [for HER2-expressing breast cancer patients]," Hu said.

In a real-world cohort of 600 breast cancer patients in France, 93 percent of which had HER2-driven disease and received Enhertu, researchers explored the risk of interstitial lung disease (ILD). It is a known adverse event associated with Enhertu and other ADCs. The drug's label contains a boxed warning about the risk of ILD, and AstraZeneca and Daiichi Sankyo provide guidance to physicians on how to identify and manage ILD or pneumonitis.

In this cohort, 11.2 percent experienced ILD, which comprises more than 200 inflammatory conditions that scar the lungs and damage the tissues between small air sacs called alveoli and the blood vessels around them.

This real-world study finding is consistent with the incidence reported in the DESTINY-Breast06 study. The researchers found that patients who had ILD before getting Enhertu, had lung metastases, and had a history of smoking were more likely to develop ILD with Enhertu treatment, said Lana Elu, a researcher at Tenon Hospital in Paris, during a presentation of the real-world study data.

In these patients, the median time-to-confirmed ILD was 82 days, with HER2-positive breast cancer patients seeing an earlier onset of ILD than the overall cohort, with a median time-to-confirmed ILD of 60 days. Half of patients with ILD didn't have respiratory symptoms, Elu noted.

Patricia LoRusso, associate director of innovative medicine at Yale Medicine, who was not involved with the research, noted that the time to ILD was shorter in this real-world analysis compared to what's been seen in prior trials, because real-world studies include sicker patients who may not meet the inclusion criteria for a trial.

Most ILD cases in this study (81 percent) were low severity, grade 1 or grade 2, but six patients experienced fatal ILD in the study, representing 9 percent of patients who developed the condition.

Elu noted that the most common symptoms were shortness of breath, cough, and fever, and the most common radiological features observed in imaging for ILD patients was ground glass opacities, which signals inflammation in lung tissues (87 percent) and consolidations, which show that alveolar airspaces are filled with fluid (61 percent).

In three-quarters of patients who developed ILD, Enhertu treatment was withdrawn, Elu said, and half of patients received corticosteroids, which improved ILD for 58 percent. Doctors tried Enhertu treatment again for 18 patients, but 42.9 percent relapsed into ILD. Based on this, Elu noted that "rechallenging with [Enhertu] should be approached with caution."

She added that close surveillance using imaging, performing scans every six weeks during the first six months of treatment, is important for identifying and managing ILD.

"Prior ILD emerged as a significant risk factor [in this real-world study], hence it is important to screen patients at baseline [for this adverse event] before giving them the first cycle of treatment," Elu said. "As [Enhertu's] indications expand, early detection and tailored treatment strategies are essential for improving patient outcomes."