While continuing trastuzumab after disease progression may provide clinical benefit in HER2-positive breast cancer, results of a phase 2 study failed to show the same in patients with HER2-positive gastric cancers.
Second-line treatment with paclitaxel plus trastuzumab didn’t improve progression-free survival, compared with paclitaxel alone, in the small, randomized study of patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) cancers who progressed on trastuzumab.
The failure of the paclitaxel/trastuzumab regimen in this study might be because of reduced HER2 positivity rather than acquired resistance to trastuzumab, according to the researchers, led by Akitaka Makiyama, MD, PhD, of Kyushu University Hospital in Fukuoka, Japan.
In any case, this approach of continuing trastuzumab beyond progression can’t be recommended as a standard of care, Dr. Makiyama and coauthors wrote in their report, which appears in the Journal of Clinical Oncology.
Drug development is meanwhile proceeding rapidly for several novel HER2-targeted treatments in this setting, the authors noted, including trastuzumab deruxtecan, an antibody-drug conjugate; ZW25, a bispecific antibody; and margetuximab, a chimeric monoclonal antibody with a modified Fc domain.
“We hope these new agents could confer survival benefit in HER2-positive gastric cancer by large-scale clinical trials comparing paclitaxel with ramucirumab as a standard arm,” the authors wrote, noting that paclitaxel with ramucirumab is considered a standard second-line regimen for advanced disease, regardless of HER2 status, based on analysis of the RAINBOW trial (Lancet Oncol. 2014 Oct;15[11]:1224-35).
The approval of novel therapies could be a significant advance for tumors in which HER2 is overexpressed or amplified, which represents about 10%-20% of gastric/GEJ cancers, according to Dr. Makiyama and coauthors.
In their phase 2 study, known as T-ACT (Trial to Assess the Concept of Using Trastuzumab Beyond Progression), Dr. Makiyama and colleagues included patients with HER2-positive advanced gastric or GEJ cancer that had progressed on a standard first-line chemotherapy regimen containing trastuzumab. Patients were enrolled at 52 centers in the West Japan Oncology Group.
A total of 91 patients were randomized to receive either paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 4 weeks or the same paclitaxel dose and schedule plus trastuzumab, given at an initial dose of 8 mg/kg and subsequently at 6 mg/kg every 3 weeks.
The median progression-free survival was 3.2 months in the paclitaxel arm and 3.7 months in the paclitaxel/trastuzumab arm (P = .33). The median overall survival was 10.0 months and 10.2 months, respectively (P = .20). Responses were seen in about a third of patients in each group, and adverse events were similar between arms.
In biomarker analyses of tumor tissue samples obtained after first-line treatment, only 5 of 16 patients (31%) maintained HER2 positivity. Of those five patients, two received paclitaxel plus trastuzumab, and one had long-term stable disease (9.4 months).
“Reevaluation of HER2 expression status would be essential, particularly for developing new generations of HER2-targeted therapeutic agents in patients treated with prior trastuzumab,” Dr. Makiyama and colleagues concluded.
Partial support for this study came from a Japan Society of Clinical Oncology grant program. The authors disclosed relationships with Chugai Pharma, Lilly, Takeda, and numerous other companies.
SOURCE: Makiyama A et al. J Clin Oncol. 2020 Mar 24. doi: 10.1200/JCO.19.03077.