To what extent does the biological understanding of the disease help define the therapy? This question was discussed at the ASCO-GI in San Francisco with regard to potential treatment options in gastric cancer. In particular, HER2 is a well-validated target that has already been declared in several studies to be critical to the success of therapy. Other potential targets are currently being explored.
(ag) Yung-Jue Bang, MD, Seoul, spoke about the implications of disease biology for the treatment of metastatic gastric cancer. “During the past 20 years, although cytotoxic chemotherapy of the advanced form improved, gastric cancer remains the second leading cause of death due to cancer worldwide, with the highest incidence rate in East Asia [1]. Overall survival of patients with advanced gastric cancer stagnates at ten to twelve months with cytotoxic chemotherapy [2].” The most commonly used first-line chemotherapy today is the combination of fluoropyrimidine and platinum. In addition, anthracyclines or taxanes are added in some countries. Phase III trials have confirmed the benefit of second-line chemotherapy [3].
Improved biological knowledge
“We understand the molecular biology of gastric cancer better and better. And that’s why we’ve also discovered that this form of cancer can and even must be divided into several subtypes if we want to improve therapy,” Bang says. Researchers suggest five different subgroups: those with an increase in
- of the “human epidermal growth factor receptor 2” (HER2)
- of the “fıbroblast growth factor receptor” (FGFR),
- of the KRAS
- of the “epidermal growth factor receptor” (EGFR),
- of the MET.
The results were confirmed by somatic copy number aberration (SCNA) analysis. Such genes could be critical for the development of new target compounds.
First validated target: HER2
Within these molecular targets, HER2 is the first to be successfully confirmed. The efficacy of anti-HER2 treatment was investigated in the so-called ToGA study. It concluded that patients receiving trastuzumab and chemotherapy had significantly longer overall survival than those receiving chemotherapy alone (13.8 vs. 11.1 months, p=0.0046) [4]. The benefit was greater in patients with HER2-IHC3- or HER2-IHC2-/FISH-positive tumors (11.8 vs. 16 months). For this reason, chemotherapy plus trastuzumab is standard of care for patients with HER2-positive gastric cancer. Other agents targeting HER2 are also in development.
Lapatinib in combination with paclitaxel in the second-line setting versus paclitaxel alone resulted in prolonged but not significant overall survival. Only in the HER2-IHC3-positive subgroup did the values reach statistical significance (14.0 vs. 7.6 months, p=0.0176) [5].
No success in HER2-negative tumors?
“Unfortunately, the development of target agents against HER2-negative gastric cancers has not been as successful,” Bang said. “An antiangiogenic strategy was tested. In the AVAGAST trial [6], bevacizumab, an antibody against VEGF, was added to capecitabine/cisplatin chemotherapy in the first line and achieved prolonged overall survival, although not statistically significant (12.1 vs. 10.1 months with chemotherapy alone, p=0.1002).”
The REGARD trial showed a second-line survival benefit with the antibody ramucirumab (against VEGFR2) compared to placebo (5.2 vs. 3.8 months, p=0.047).
Antibodies targeting EGFR or mTOR have not been able to prove their superiority to date.
MET is already more promising as a target: in a randomized phase II trial [8], rilotumumab, an antibody against “hepatocyte growth factor” (HGF), was added to therapy with epirubicin, cisplatin, capecitabine (ECX). Although overall survival was not significantly prolonged, it was in the subgroup with high MET expression (11.1 vs. 5.7 months).
“Accordingly, research into predictive biomarkers and valid diagnostic tests is critical for the successful development of new target agents,” Bang concluded.
Source: “Gastric Cancer – Etiology, Development, and Implications for Therapy,” General Session 2 at ASCO GI – Gastrointestinal Cancers Symposium, January 16-18, 2014, San Francisco.
Literature:
- Jemal A, et al: Global cancer statistics. CA Cancer J Clin 2011; 61: 69 -90. PMID: 21296855.
- Lordick F, et al: Optimal chemotherapy for advanced gastric cancer: is there a global consensus? Gastric Cancer. Epub 2013 Sep 19. PMID: 24048758.
- Kang JH, et al: Salvage chemotherapy for pretreated gastric cancer: a randomized phase III trial comparing chemotherapy plus best supportive care with best supportive care alone. J Clin Oncol 2012; 30: 1513-1518. epub 2012 Mar 12. PMID: 22412140.
- Bang YJ, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376: 687- 697. epub 2010 Aug 19. PMID: 20728210.
- Bang YJ, et al: A randomized, open-label, phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone in the second-line treatment of HER2 amplified advanced gastric cancer in Asian population: Tytan study. J Clin Oncol 2013; 30 (suppl 34; abstr 11).
- Ohtsu A, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 2011; 29: 3968 -3976. epub 2011 Aug 15. PMID: 21844504.
- Fuch CS, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2013; S0140-6736: 61715-61719. PMID:24094768.
- Oliner KS, et al: Evaluation of MET pathway biomarkers in a phase II study of rilotumumab or placebo in combination with epirubicin, cisplatin, and capecitabine in patients with locally advanced or metastatic gastric or esophagogastric junction cancer. J Clin Oncol 2012; 30 (abstr 4005).
HAUSARZT PRAXIS 2014; 9(3): 45-46
InFo Oncology & Hematology 2014; 2(3): 35-36.
