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Pembrolizumab combination shows early potential for trastuzumab-resistant breast cancer
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SAN ANTONIO — Pembrolizumab plus trastuzumab appeared well-tolerated and showed clinical benefit among women with advanced HER-2-positive breast cancer with PD-L1-positive tumors that were resistant to trastuzumab, according to results from the PANACEA study presented at the San Antonio Breast Cancer Symposium.
“HER-2-posiitve breast cancers have been observed to contain high-levels of T-cell infiltration. We wanted to investigate if immunotherapy approaches can work in patients with advanced HER-2-positive breast cancer that is resistant to trastuzumab [Herceptin, Genentech],” Sherene Loi, MD, PhD, associate professor at Peter MacCallum Cancer Centre in Melbourne, Australia, said during a press briefing.
The single-arm phase 1b/phase 2 trial included 58 patients (median age, 50.5 years) with advanced breast cancer who progressed on prior trastuzumab-based therapies. Researchers assessed tumors centrally for HER-2 positivity and PD-L1 status, and for quantity of tumor-infiltrating lymphocytes (TILs).
In the phase 1b portion of the trial, patients received 2 mg/kg pembrolizumab (Keytruda, Merck) plus 10 mg/kg IV trastuzumab every 3 weeks. In the phase 2 portion, patients received 200 mg IV pembrolizumab with trastuzumab every 3 weeks.
Researchers did not observe any dose-limiting toxicities in the phase 1b phase.
Objective response by RECIST served as the study’s primary outcome; secondary outcomes included PFS, OS, disease-control rate, duration of response and duration of disease control.
Researchers reported an ORR of 15.2% and a disease control rate of 24% in the PD-L1-positive cohort. In a subgroup of these patients with 5% of more TILs present in the metastatic lesion, ORR increased to 39% and disease control rate to 47%.
“Stromal TIL levels in the metastatic lesion were associated with response, and a TIL level greater than 5% could enrich this cohort for a high response rate,” Loi said.
However, no objective responses were observed in the PD-L1-negative cohort.
Disease control appeared durable among those patients in the PD-L1-positive cohort who experienced an objective response or stable disease, with a median duration of 11.1 months.
“At the time I am reporting these data, five patients continue with no disease progression and at least two patients have completed 2 years on pembrolizumab,” Loi said.
Adverse outcomes included grade 1/grade 2 fatigue (21%), grade 1/grade 2 hyper- and hypothyroidism (6.9%) and grade 3/ grade 4 pneumonitis (3.4%).
“Future directions for immuno-oncology in HER-2-positive metastatic disease should focus on combinations with an effective anti-HER-2 therapy, particularly in low TIL patients,” Loi said. – by Jennifer Southall
Reference:
Loi S, et al. Abstract GS2-06. Presented at: San Antonio Breast Cancer Symposium; Dec. 5-9, 2017; San Antonio.
Disclosures: The study was sponsored and managed by the International Breast Cancer Study Group in collaboration with the Breast International Group, and funded by a Merck subsidiary. Loi reports no relevant financial disclosures. Please see the abstract for all other others’ relevant financial disclosures.
Perspective
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Debu Tripathy, MD
This study was very interesting. Loi and colleagues evaluated patients with HER-2-positive breast cancers who had already progressed on trastuzumab. It has been known for some time now that these tumors are immunogenetic and may respond to some of the new immunotherapies.
The researchers treated these patients with pembrolizumab plus trastuzumab. They actually showed response rates, but only in the group of patients who expressed PD-L1, which we see on TILs and, in some studies, has been associated with improved responses to immunotherapy.
This study tells us that patients who are refractory to trastuzumab with HER-2-negative cancers may actually benefit from immunotherapy; however, currently this only appears to hold true if they have PD-L1 expression.
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