3rd Trial to Show: Trastuzumab + AI Better than AI Alone

Field: Medicine (Health Sciences)

SAN ANTONIO—The combination of letrozole and trastuzumab is superior to letrozole alone as first-line treatment in patients with HER2-positive and hormone receptive (HR)-positive metastatic breast cancer, researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium. “Endocrine therapy alone is not very effective in this HER2-positive, HR-positive population. Adding trastuzumab produces a greater benefit,” said Jens B. Huober, MD, PhD, Professor of Gynecologic Oncology at Kantonsspital in St. Gallen, Switzerland. “This is now the third trial to reach that conclusion and establishes that dual therapy [with trastuzumab or other HER2-directed therapy and an aromatase inhibitor] is better than an aromatase inhibitor by itself in terms of progression-free survival and objective response rates.” The randomized Phase III TANDEM trial in 207 patients with HER2-positive, HR-positive metastatic breast cancer demonstrated a doubling of progression-free survival time with the addition of trastuzumab over anastrozole alone (Kaufman B et al: JCO 2009; 27: 5529–5537). The other study compared letrozole with letrozole plus lapatinib (Johnston S et al: JCO 2009; 27:5538-5546). eLEcTRA Trial Known as eLEcTRA (The Study of the Efficacy and Safety of Letrozole Combined with Trastuzumab in Patients with Metastatic Breast Cancer (eLEcTRA), the new trial enrolled 92 women at 32 sites with metastatic breast cancer from 2003 to 2007. Initially, enrollment of 370 patients was planned; however, due to slow recruitment, the trial was prematurely closed to further enrollment in 2007, Dr. Huober said. A total of 58 patients had tumors that were both HER2-positive and HR-positive. Of those, 31 patients were randomized to letrozole monotherapy and 26 patients to letrozole plus trastuzumab as first-line treatment. In addition, 35 patients with HER2-negative and HR-positive tumors were assigned to receive letrozole alone as first-line treatment. Trastuzumab Extends TTP The median time to progression, the primary endpoint, was 3.3 months in patients with dual positivity that received letrozole alone, compared with 14.1 month in patients with dual positivity who received trastuzumab plus letrozole and 15.2 months in patients with HER2-negative disease who received letrozole monotherapy. The clinical benefit rate—defined as a complete or partial response or stable disease for more than six months—was 39%, 65%, and 77% in each of the three arms, respectively. The overall response rates were 13%, 27%, and 11% in the three groups. There was no difference in overall survival times between the groups. Left ventricular ejection fraction, which was used as a cardiac safety parameter, showed no change from baseline to the minimum value during treatment for patients in either group receiving letrozole monotherapy. There was a slight decrease by 5% in the combination-therapy group.JENS B. HUOBER, MD, PHD: “In patients with both HER2-positive and HR-positive disease, dual therapy with trastuzumab and an aromatase inhibitor is superior to an aromatase inhibitor alone in terms of progression-free survival and objective response rates.”Other cardiac adverse events were comparable in all arms (10%, 8%, and 9%, respectively). Patients in the combination-treatment arm were at slightly increased risk of GI disorders, musculoskeletal and connective tissue disorders, and hot flashes. HER2, HR Crosstalk “Endocrine treatment alone with letrozole had little efficacy in patients with both HER2- and HR-positive tumors, with a time to progression of only 3.3 months,” Dr. Huober said. “Therefore endocrine treatment alone may not be sufficient in the majority of patients with both HR-positive and HER2-positive tumors.” On the other hand, he added, patients with HER2-negative, HR-positive tumors do seem to benefit from endocrine therapy alone. But for patients with dual positivity, “the combination of letrozole and trastuzumab is well tolerated and can be safely administered,” he concluded. The results support preclinical data suggesting that cross talk between HER2 and HR signaling pathways contribute to resistance to hormonal therapy, commented Jose Baselga, MD, Chairman of the Medical Oncology Service and Director of the Division of Medical Oncology, Hematology, and Radiation Oncology at Vall d'Hebron University Hospital in Barcelona. Several ongoing studies are also looking at trastuzumab in combination with aromatase inhibitors, the researchers noted. The current study was sponsored by Novartis Pharma AG.