Continuing Trastuzumab After Progression Shows Promise in HER2+ Gastric/GEJ Cancer

Continuing trastuzumab (Herceptin)-containing therapy beyond progression led to encouraging progression-free survival (PFS) and overall survival (OS) rates in advanced HER2-positive gastric/gastroesophageal junction (GEJ) cancer, a small prospective study showed.

Patients in the second-line setting had a median PFS of 7.1 months and a median OS of 13.6 months with the addition of trastuzumab to the standard second-line doublet of ramucirumab (Cyramza) and paclitaxel. Objective responses occurred in more than half of patients, and all but two of 50 patients included in the study derived clinical benefit.

Loss of HER2 expression after first-line treatment did not appear to affect second-line treatment outcomes, reported Sun Young Rha, MD, PhD, of Yonsei University College of Medicine in Seoul, Republic of Korea, and co-authors in the Journal of Clinical Oncology (JCO).

"To our knowledge, to date, this is the first study to investigate the clinical implications of trastuzumab beyond progression, combined with ramucirumab and paclitaxel, the currently established second-line treatment," the authors concluded. "Our findings show that HER2 remains an actionable therapeutic target after progression on first-line therapy in HER2-positive gastric/GEJ cancer. The clinical benefits of combined blockade of HER2 and angiogenic pathways should be explored in the future, emphasizing the implications of HER2 heterogeneity and dynamics of advanced gastric/GEJ cancer."

According to JCO associate editor Andrew H. Ko, MD, "Continuation of trastuzumab in the second-line setting, in combination with paclitaxel/ramucirumab, represents a promising strategy for patients with advanced HER2-positive gastroesophageal cancer. Further prospective randomized data are required to validate this approach."

As many as a fourth of gastric/GEJ cancers exhibit HER2 overexpression or amplification, representing a distinct disease entity with therapeutic implications, Rha and co-authors noted in their introduction. Targeting HER2 with trastuzumab plus chemotherapy improved survival in HER2-positive gastric/GEJ cancer, but disease progression after first-line treatment is inevitable.

Extrapolating from landmark studies in HER2-positive breast cancer, multiple HER2-targeted agents have been evaluated in the second-line setting of advanced gastric/GEJ cancer, with limited success, the authors continued. The combination of paclitaxel and ramucirumab is the recommended second-line therapy, irrespective of HER2 expression status, leaving an unmet need among patients with previously treated HER2-positive gastric/GEJ cancer.

Building on preclinical evidence implicating crosstalk between HER2 signaling pathways and angiogenesis in anti-HER2 resistance, combination strategies have been evaluated in HER2-positive breast and colorectal cancers. However, data on combined angiogenesis and HER2 inhibition in the second line remain scarce, and previous work evaluating continuation of trastuzumab beyond progression in advanced gastric/GEJ cancer did not include ramucirumab.

Given the preceding background, Rha and colleagues conducted the phase Ib/II multicenter HER-RAM trial of second-line therapy with trastuzumab plus ramucirumab and paclitaxel in HER2-positive gastric/GEJ cancer that had progressed on first-line trastuzumab-containing therapy.

Treatment with all three drugs continued until disease progression or unacceptable toxicity, and the primary outcomes of interest were safety, treatment response (including stable disease), and PFS. The trial had statistical power to reject the null hypothesis of a PFS <3.8 months. The alternative hypothesis corresponded to a hazard ratio PFS <0.7 (~5.4 months).

The results showed that 27 (54%) patients had objective responses, including one complete response. Only two patients had progressive disease at the first response evaluation. Tumor shrinkage occurred in 84% of the patients. The median duration of response was 6.7 months. Median PFS of 7.1 months exceeded the requirements for rejecting the null hypothesis.

Among tumor samples from 23 patients after failure of first-line therapy, eight (34.8%) exhibited loss of HER2 expression. The authors found no association between HER2 expression status and response, PFS, or OS.

In an exploratory analysis, the investigators compared results with those of a previous study of second-line treatment with ramucirumab and paclitaxel. The doublet led to an objective response rate of 29% and a disease control rate of 78.6%, as compared with 54% and 96% with the addition of trastuzumab.

"Collectively, a comparison with data from a nationwide cohort suggests that adding trastuzumab to ramucirumab and paclitaxel would potentially improve the outcome of patients who previously received trastuzumab-containing chemotherapy as first-line treatment," the authors concluded.

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