1. Fuerst, Mark L.

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SAN FRANCISCO-A combination immunotherapy with trastuzumab plus a HER2-targeted vaccine appears to prolong remission in triple-negative breast cancer (TNBC).

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Patients with HER2 low-expressing breast cancer are not eligible for adjuvant trastuzumab, which includes approximately 60-70 percent of those patients. The NSABP B-47 trial confirmed trastuzumab does not improve outcomes in HER2 low-expressing breast cancer.


"Preclinical data showed synergism between trastuzumab and HER2-targeted vaccines. We evaluated adjuvant nelipepimut-S (NPS) plus granulocyte-macrophage colony-stimulating factor (GM-CSF) with trastuzumab compared to trastuzumab with GM-CSF alone in HER2 low-expressing breast cancer patients to prevent recurrences," said co-author Guy T. Clifton, MD, of San Antonio Military Medical Center in Texas. NPS is a vaccine designed to stimulate CD8 T cells, he explained.


A planned interim analysis showed the vaccine combination led to a benefit in TNBC patients, and the decision was made to close the trial in consultation with a data safety monitoring board. TNBC may be a more immunogenic subtype of breast cancer and therefore more responsive to immunotherapy, Clifton noted.


Study Details

At the 2019 ASCO-Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Symposium, Clifton reported the final analysis of the trial with 7 months of added follow-up (Abstract 1). The prospective, randomized, blinded multicenter phase IIb trial enrolled clinically disease-free breast cancer patients after standard therapy. Patients were HLA-A2, A3, A24, and/or A26+, had HER2-low expressing (IHC 1-2+, FISH non-amplified) breast cancer, and were node-positive and/or TNBC. During screening, only 17 percent were excluded for HLA status.


Over the time period of 2013 to 2018, the researchers enrolled high-risk, invasive breast cancer patients with HER2 expression levels of 1-2 on immunohistochemical staining across 26 U.S. centers. High-risk was defined as node-positive, regardless of hormone receptor status, or node-negative for TNBC patients. Patients were well-matched for stage and just over half of patients in each arm received neoadjuvant chemotherapy.


The patients were randomized to NPS with GM-CSF (vaccine group) or placebo with GM-CSF (control group). All patients received trastuzumab every 3 weeks for 1 year. NPS plus GM-CSF or GM-CSF were given every 3 weeks for 6 cycles starting with the third trastuzumab dose, and boosters every 6 months for 4 cycles. Patients were followed clinically for recurrences and the primary outcome was disease-free survival (DFS) at 24 months.


A total of 589 patients were screened and 275 patients were randomized (136 patients in the vaccine group, median age 52.2 years; 139 patients in the control group, median age 50.5 years). There were no clinicopathologic differences between the groups.


In the intent-to-treat (ITT) analysis, after a median follow-up of 25.7 months, the estimated DFS was favorable, but did not reach significance in the vaccine group as compared with the control group. Recurrences occurred in 8.8 percent of patients in the vaccine group as compared to 14.4 percent of patients in the control group.


In a subgroup of patients with hormone receptor-positive disease, there was also no DFS difference between groups, with the vaccine arm numerically worse at 24 months but better at 36 months.


However, among TNBC patients, the vaccine group had statistically improved DFS compared to the control group. Among the 97 TNBC patients, DFS was 92.6 percent versus 70.2 percent at 24 months and 82.3 percent versus 70.2 percent at 36 months.


Concurrent trastuzumab and NPS was safe, with no added overall or cardiac toxicity compared to the control group and no grade 4 or 5 toxicities. Virtually all (94.3%) of patients who received an intervention experienced at least one treatment-related adverse event, but there was no difference between the two groups. The majority of treatment-related adverse events were grade 1 or 2, including local injection site reactions, skin induration, pruritus, and fatigue. No difference was found between treatment arms in cardiac ejection fraction over time and at each time point. "The addition of NPS to trastuzumab did not result in any additional cardiotoxicity compared with trastuzumab alone," Clifton explained.


Summary Thoughts

"The NPS plus trastuzumab combination is safe; there were no notable differences between treatment arms and no added cardiac toxicity," Clifton stated. "NPS plus trastuzumab may provide clinically meaningful benefit to patients with HER2 low-expressing breast cancers. The NPS plus trastuzumab combination demonstrated a statistically significant improvement in DFS in patients with TNBC."


He added that a "future confirmatory phase III study in this underserved population with high risk of recurrence and death is warranted.


"In this final analysis, there was a trend towards benefit in the ITT population that improved since the interim analysis with added follow-up. The significant benefit seen at interim in the TNBC patients continued to strengthen in the vaccine group. These findings could position the NPS plus trastuzumab combination as an adjuvant therapy for early-stage TNBC," Clifton concluded.


Mark L. Fuerst is a contributing writer.