Yelena Y. Janjigian, MD
Progress is frustratingly slow in the development of therapies for advanced gastroesophageal cancers. However, investigators have achieved some success with immune checkpoint inhibitors and antiangiogenesis agents, and exciting new agents targeting different tumor growth pathways are under investigation, according to a panel of international experts.
During a recent OncLive Peer Exchange®
, the panel discussed some of the trials that have shown mixed results or failed to improve outcomes for patients with gastric and gastroesophageal junction (GEJ) cancers. The panelists also shared their insights into the lessons learned from those trials, which are helping to guide research and improve patient selection. In addition, they discussed several agents being investigated in the second- and later-line settings that have led to survival gains as well as some promising novel strategies that are in various stages of development.
In the early 1900s, gastric cancer was one of the most commonly diagnosed cancers in the United States but is now no longer among the top 10. Despite that success, gastric cancer remains common worldwide, particularly in East Asia, where it is the third-most commonly diagnosed cancer.1-3
Most patients present with advanced unresectable or metastatic disease, which has few treatment options. Unlike the landscape for other solid tumors, treatment has not advanced far beyond chemotherapy, and survival gains have remained modest.
Clinical Trials With Mixed or Negative Results
Discovery of various mutations and other targets in patients with gastroesophageal cancers has led to the assessment of various novel agents. Some of the most actively investigated targets include HER2, PD-1, PD-L1, and angiogenesis.4 Although agents directed against these and other targets have shown clear benefit in other solid tumors, the results have been largely underwhelming in gastroesophageal cancers.
“Gastric cancer is a lukewarm tumor: It’s not a cold tumor, but it’s not a hot tumor,” Yelena Y. Janjigian, MD, explained. “The idea is that in gastric cancer, there is not a single pathognomonic driver because the epithelium has been exposed to so many insults over the patient’s years, resulting in DNA damage.” Subsequently, these tumors are likely to have multiple disease drivers, which may vary by geographic region and tumor subtype and change as the disease progresses, making these tumors elusive targets.HER2: JACOB and Other Studies
HER2 positivity has been identified in approximately 15% to 20% of patients with gastric cancer.4
Although the addition of the HER2- targeted therapy trastuzumab (Herceptin) to chemotherapy in the first-line setting has shown a survival benefit for patients with HER2-positive advanced gastric or GEJ cancer, with a median overall survival (OS) of 13.8 months versus 11.1 months with chemotherapy alone,5
other strategies exploiting HER2 have not been as successful. This indicates significant differences in HER2 positivity between breast cancer and gastric cancer.
“[In the JACOB trial], pertuzumab [Perjeta] plus trastuzumab led to a small benefit, but this was not significant,” Eric Van Cutsem, MD, PhD, said. The JACOB trial was conducted based on the results of the CLEOPATRA trial in breast cancer, whose results showed a significantly reduced risk of progression or death when dual HER2 blockade (pertuzumab and trastuzumab) was added to chemotherapy (HR, 0.62).6
Dual HER2 blockade in JACOB did increase OS by 3.3 months, but this finding did not reach statistical significance.7
“Because of the differences in the role of HER2 in gastric versus breast cancer, unfortunately, the combination with pertuzumab and trastuzumab failed,” Van Cutsem said.