Pembrolizumab Maintenance Yields Enduring Responses in HER2– Breast Cancer

“While the findings are promising, further research, including a large prospective clinical trial, is necessary to validate the identified biomarkers and refine patient selection criteria for pembrolizumab therapy,” according to study author Toshiaki Iwase, MD, PhD.

Maintenance treatment with pembrolizumab (Keytruda) conferred enduring responses in a cohort of patients with HER2-negative breast cancer, according to findings from a phase 2 trial (NCT02411656) published in Clinical Cancer Research.¹

With a median follow-up of 14.8 months, the median overall survival (OS) with pembrolizumab monotherapy was 26.0 months (95% CI, 11.0-34.7). Additionally, the disease control rate (DCR) was 58.1% (95% CI, 43.4%-72.9%, P = .4805), and the median progression-free survival (PFS) was 4.8 months (95% CI, 3.0-7.1). Specifically, the median PFS was 9.9 months for those with a complete response (CR) to prior therapy, 10.3 months in those with a prior partial response (PR), and 3.4 months in those who had stable disease following prior treatment.

A survival analysis highlighted that PFS tended to be longer in those with PD-L1–positive tumors compared with those who had PD-L1–negative disease. However, investigators noted that differences in PFS outcomes based on PD-L1 expression status did not reach statistical significance (P = .14). Following 2 cycles of pembrolizumab therapy, investigators reported significant reductions in immune checkpoint markers CTLA-4 (P = .034) and TIM3 (P = .016) in CD4+ T cells as well as CD244 (P = .032) and TIM3 (P = .013) in CD8+ T cells.

“While the findings are promising, further research, including a large prospective clinical trial, is necessary to validate the identified biomarkers and refine patient selection criteria for pembrolizumab therapy,” Toshiaki Iwase, MD, PhD, an associate professor and medical director of Translational and Clinical Research at the University of Hawai’i Cancer Center, said in a press release on these findings.²

In this trial, 43 patients were assigned to receive pembrolizumab intravenously at 200 mg every 3 weeks until progressive disease, unacceptable toxicity, or the completion of 2 years of treatment. The treatment schedule later switched to 400 mg every 6 weeks.

The trial’s primary end point was DCR at 4 months following the beginning of study treatment. Secondary end points included PFS and OS. Exploratory end points included safety as well as response and resistance biomarkers from patient blood.

Patients with inflammatory breast cancer (IBC; n = 11) or non-IBC triple-negative breast cancer (TNBC; n = 32) with an initial response to 2 or more cycles of standard chemotherapy were eligible for enrollment on the trial. Additional eligibility criteria included having an ECOG performance status of 0 or 1 and adequate organ function.

Across the overall population, the median age was 54 years (range, 34-77). Additionally, most patients were postmenopausal (86.0%), White (83.7%), had prior breast surgery (88.4%), and recurrent metastases (81.4%). Most patients also had stable disease before receiving maintenance therapy (55.8%), negative estrogen receptor status (97.7%), and PD-L1–negative disease (46.5%).

Data showed that patients with T-cell clonality above the median value at baseline experienced significantly longer PFS compared with patients whose T-cell clonality was lower than the median value at baseline (P = .04). Additionally, significantly higher levels of productive rearrangements (P = .014), productive Simpson clonality (P = .021), and maximum productive frequency (P = .034) occurred in patients who had disease control at 4 months.

Overall, 83.7% (n = 31/37) of patients who discontinued study treatment did so due to progressive disease, and 2 patients discontinued therapy due to adverse effects (AEs) consistent with prior reports of pembrolizumab’s safety. Grade 1/2 AEs affected 86.7% of patients, and 13.3% had grade 3/4 toxicity.

Irreversible endocrinopathies requiring hormone replacement affected 3 patients and resulted in treatment discontinuation for 1. Another patient discontinued pembrolizumab following optic neuritis that needed to be managed with steroids.

References

1. Iwase T, Cohen EN, Gao H, et al. Maintenance pembrolizumab therapy in patients with metastatic HER2-negative breast cancer with prior response to chemotherapy. Clin Cancer Res. Published online April 17, 2024. doi:10.1158/1078-0432.CCR-23-2947
2. Immunotherapy shows promise for aggressive breast cancer. News release. University of Hawai’i News. April 17, 2024. Accessed April 22, 2024. https://tinyurl.com/k7ks74dh