Dual Anti-HER2 Therapy Boosts Progression-Free Survival in Advanced Breast Cancer

Charles Bankhead

April 2017, Vol 8, No 2 - Breast Cancer

San Antonio, TX—Two HER2-targeted drugs improve progression-free survival (PFS) compared with a single drug when combined with an aromatase inhibitor in patients with advanced breast cancer, as reported at the 2016 San Antonio Breast Cancer Symposium.

The combination of pertuzumab (Perjeta), trastuzumab (Herceptin), and a nonsteroidal aromatase inhibitor led to a median PFS of 18.9 months versus 15.8 months with trastuzumab plus an aromatase inhibitor. At the investigators’ discretion, patients also received taxane chemotherapy.

“Pertuzumab plus trastuzumab plus an aromatase inhibitor was superior to trastuzumab plus an aromatase inhibitor in postmenopausal women with HER2-­positive, hormone receptor–positive, locally advanced or metastatic breast cancer. Secondary efficacy end points supported the primary PFS analysis. Subgroup analyses were generally consistent with the primary analysis,” said Grazia Arpino, MD, PhD, Medical Oncologist, Università degli Studi di Napoli Federico II, Italy.

The combination of pertuzumab, trastuzumab, and an aromatase inhibitor did not result in any new or unexpected toxicities, she added.

The rationale for combining HER2-targeted therapies came from preclinical evidence that bidirectional cross talk between HER2 and estrogen receptors may facilitate resistance to endocrine or to anti-HER2 drugs in patients with breast cancer. Clinical support came from the 2009 TAnDEM trial, which showed that the combination of trastuzumab and anastrozole (Arimidex) improved PFS compared with anastrozole alone. In addition, the 2015 CLEOPATRA trial showed that the combination of pertuzumab and trastuzumab plus a taxane significantly improved PFS and overall survival compared with a single anti-HER2 drug plus a taxane.

Dr Arpino reported findings from the primary analysis of the PERTAIN trial, which involved 258 patients with locally advanced or metastatic hormone receptor–positive, HER2-positive breast cancer. Eligible patients had received no previous systemic nonhormonal therapy for advanced disease.

All patients received trastuzumab plus either letrozole (Femara) or anastrozole, and were randomized to receive pertuzumab or placebo. Optionally, some patients also received a taxane. The primary end point was PFS, and key secondary end points included overall response rate (ORR) and duration of response.

The intention-to-treat analysis showed that the triplet therapy led to a 35% reduction in the risk for progression or death (P = .007). The pertuzumab-containing regimen demonstrated superiority, or a trend toward advantage, in all prespecified subgroups, including patients who received induction chemotherapy (hazard ratio [HR], 0.75) and those who did not (HR, 0.55).

The ORR was 63.3% in the pertuzumab group, which was similar to the ORR in patients who received trastuzumab and placebo (55.7%). However, the median duration of response was 27.1 months with pertuzumab versus 15.1 months with placebo (HR, 0.57; P = .0181).

Grade 3 or 4 adverse events were more common with the 3-drug regimen (50.4% vs 38.7% with placebo), as were serious adverse events (33.1% vs 19.4%, respectively). Dr Arpino reported that 13 patients in the pertuzumab group discontinued the drug because of toxicity, and 34 patients required treatment interruptions. The most common (≥20% of patients) adverse events in the pertuzumab group were diarrhea, alopecia, nausea, asthenia, arthralgia, peripheral edema, vomiting, and anemia.

The eligibility criteria included a left-ventricular ejection fraction (LVEF) of ≥50% at enrollment. During the trial, 87% of patients in the pertuzumab group and 90% in the placebo group maintained LVEF >45%. Dr Arpino characterized the 3-drug combination as “generally well-tolerated.”