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Omitting Chemo Feasible in First-Line HER2+ Breast Cancer?

— De-escalation showed mixed results in metastatic disease

Last Updated July 8, 2019
MedpageToday

Dropping chemotherapy from a first-line regimen of trastuzumab (Herceptin) and pertuzumab (Perjeta) didn't compromise overall survival at 2 years in advanced HER2-positive breast cancer, although disease progression resumed much faster, a randomized phase II trial found.

Progression-free survival (PFS) was 8.4 months in patients treated with trastuzumab and pertuzumab alone versus 23.3 months for those also assigned to chemotherapy, while rates of 2-year overall survival were the same (77% and 76%, respectively), according to Jens Huober, MD, of University Hospital Ulm in Germany.

Both groups of patients received ado-trastuzumab emtansine (Kadcyla) as second-line therapy following disease progression, and PFS and overall survival findings were similar regardless of hormone receptor (HR) status. Findings from the trial will be presented this week at the European Society for Medical Oncology's in Berlin.

"The short overall survival endpoint did not capture if denying a treatment which is demonstrated to be meaningfully most effective impacts on long-term survival," ESMO spokesperson Carmen Criscitiello, MD, PhD, of the European Institute of Oncology in Milan, said in a . "In addition, the sample size is very small to detect a difference in overall survival. Avoiding chemotherapy in HER2-positive disease is appealing for patients and investigators, but it has to be done safely."

Criscitiello explained that the gains in survival with the introduction of anti-HER2 therapies for patients with early and advanced HER2-positive breast cancer have led to efforts aimed at reducing the intensity of treatments and their associated toxicities.

"The priority is to identify which patients might be spared some toxic therapies without worsening the survival benefit," she said, noting that the current trial did not incorporate patient selection based on tumor characteristics.

Median PFS in the chemotherapy-free group was 8.3 months in HR-positive patients versus 8.8 months in HR-negative patients. For the chemotherapy group, PFS was 23.7 and 22.2 months, respectively.

Two-year survival in the chemotherapy-free group was 81.1% for HR-positive patients and 75.0% in HR-negative patients. For the chemotherapy group, overall survival at 2 years was 79.5% and 74.2%, respectively.

Given the wide PFS difference, the investigators are now profiling patients' tumors using the PAM50 gene signature assay to determine whether certain patients could skip chemotherapy without the increased risk of disease progression.

"Trials of HER2-positive breast cancer in the neoadjuvant setting have shown that the HER2 enriched subtype is the most sensitive to anti-HER2 therapy," Huober said. "Our hypothesis is that this also applies to the metastatic setting. If the progression-free survival difference is smaller in this subtype, then omitting chemotherapy in the first line may be a good option for these patients."

From 2013 to 2016, PERNETTA randomized 210 women with metastatic HER2-positive breast cancer to trastuzumab plus pertuzumab with or without weekly chemotherapy -- paclitaxel (Abraxane) in 46 patients and vinorelbine (Navelbine) in 59. Most patients (63%) had HR-positive disease, and the median age was 58.

Examining NFBSI-16 scores for quality of life during first-line therapy revealed small improvements in the chemotherapy-free arm while scores were stable in the chemotherapy arm. A number of adverse events -- alopecia, mucositis, nausea, and fatigue -- were more frequent among those that received chemotherapy during the first 6 months, but similar thereafter. Following disease progression as second-line ado-trastuzumab emtansine, the next treatment was determined by physician choice.

Disclosures

The study was funded by Roche.

Huober disclosed relationships with Roche, Novartis, Lilly, Pfizer, Celgene, and AstraZeneca. Two co-authors also reported relationships with Roche.

Primary Source

ESMO Breast Cancer Congress

Huober J, et al "Pertuzumab (P) + trastuzumab (T) with or without chemotherapy both followed by T-DM1 in case of progression in patients with HER2-positive metastatic breast cancer (MBC)- The PERNETTA trial (SAKK 22/10), a randomized open label phase II study (SAKK, UNICANCER, BOOG)" ESMO Breast 2019; Abstract 150O_PR.