BERLIN — Adding the immune checkpoint inhibitor nivolumab to the antibody drug conjugate (ADC) trastuzumab deruxtecan does not improve outcomes for patients with advanced, pretreated breast cancer, a new analysis suggests.

Preclinical data suggested possible “synergy” between nivolumab and trastuzumab deruxtecan, said Rebecca Dent, MD, senior consultant and head of the Medical Oncology Department, National Cancer Center, Singapore, who was not involved in the study.

However, the latest evidence regarding pretreated patients with advanced HER2-expressing breast cancer found that while the combination “showed antitumor activity,” the addition of nivolumab provided “no discernible benefit” for patients, according to lead author Erika P. Hamilton, MD, director of the Breast and Gynecologic Cancer Program, Sarah Cannon Research Institute/Tennessee Oncology, Nashville.

Hamilton presented the findings from the trial at the European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress 2022 on May 3.

In “compelling” data from a 2019 trial, trastuzumab deruxtecan monotherapy demonstrated strong antitumor activity in women with previously treated HER2-positive metastatic breast cancer. The drug yielded an objective response rate of 61%; median progression-free survival (PFS) was 16 months.

The results led the US Food and Drug Administration to grant accelerated approval for the treatment of unresectable or metastatic HER2-positive breast cancer that year.

The latest research examined whether adding nivolumab to the regimen could improve outcomes. In the two-part, open-label, multicenter, phase 1b study, Hamilton and colleagues analyzed outcomes from 48 patients with HER2-expressing locally advanced unresectable or metastatic breast. Overall, 32 patients were HER2-positive, and 16 had low levels of HER2 expression (HER2-low).

Patients were initially randomly assigned to receive trastuzumab deruxtecan 3.2 mg/kg or 5.4 mg/kg plus nivolumab. They subsequently entered a dose expansion phase, which differentiated patients with high levels and those with low levels of HER2 expression.

All patients were women; the median age was 53.6 years. The majority (70.8%) had received at least four prior lines of therapy, and 20.8% had a history of brain metastasis.

At the data cutoff on July 22, 2021, the median duration of follow-up was 18 months. Trastuzumab deruxtecan therapy was continued for 16.7% of patients, while 12.5% continued to receive nivolumab. The median treatment duration for trastuzumab deruxtecan was 8.9 months, while that for nivolumab was 5.5 months.

For the HER2-positive group, the researchers reported an objective response rate of 65.6%, which included 9.4% of patients with a complete response and 56.3% with a partial response. The mean best percentage reduction in tumor size was 53%.

The median PFS was 11.6 months; median duration of response and median overall survival were not evaluable.

Among patients with HER2-low disease, the objective response rate was slightly lower, at 50%; these only included partial responses. The mean best percentage reduction in tumor size was 29.2%. In this group, the median duration of response was 5.5 months, PFS was 7.0 months, and the median overall survival was 19.5 months.

An exploratory biomarker analysis indicated that the antitumor activity of trastuzumab deruxtecan plus nivolumab occurred regardless of programmed death ligand 1 (PD-L1) status.

In terms of safety, Hamilton noted that the overall profile “was generally consistent with previous studies for trastuzumab deruxtecan monotherapy” and that nivolumab “did not appear to cause an increased overall toxicity.”

More specifically, 50% of patients experienced a grade ≥3 treatment-emergent adverse event. Events leading to discontinuation of either drug occurred in 37.5% of patients, while 47.9% experienced an event that led to drug interruption.

The most common treatment-emergent adverse event of any grade was nausea, which was experienced by 56.3% of patients. Interstitial lung disease occurred in 14.6% of HER2+ patients, which was of grade 2 in all but one case.

Although the authors conclude that adding nivolumab to trastuzumab deruxtecan had “no discernible benefit,” Dent commented that the results may not be so clear-cut.

The combination, Dent explained, “is expected to affect the tumor microenvironment, with maybe little impact on the response rate.”

She said that perhaps it is “more realistic to expect a greater improvement in PFS and overall survival” with longer follow-up and that triple-negative breast cancer and other immunogenic subtypes may be better candidates for the combination.

Dent said she wouldn’t call the results “negative” but thinks “we need to evaluate [the combination] in a better context.”

The study was sponsored and designed by Daiichi Sankyo in collaboration with AstraZeneca. Hamilton has institutional relationships with AbbVie, Amgen, AstraZeneca, Daiichi Sankyo, and many other companies. Dent has relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer.

European Society for Medical Oncology (ESMO BCC) Breast Cancer Congress 2022: Abstract 162O. Presented May 3, 2022.

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