BARCELONA — When deciding between using angiogenesis inhibitors or checkpoint inhibitors in the management of patients with gastric cancer, clinicians should consider the antigenic characteristics of the tumor and the degree of disease burden, experts said here at the World Congress on Gastrointestinal Cancer.
In a series of talks about how the treatment of gastric cancer has changed in recent years as new drugs have emerged, experts said that although more research is needed, some clear conclusions can be drawn from the available data.
Looking at human epidermal growth factor receptor 2 (HER2) inhibitors and anticancer stem cell therapies alongside angiogenesis inhibitors and checkpoint inhibitors, the speakers demonstrated that the highly variable nature of individual gastric cancers means that, while no two tumors are the same, an era of personalized medicine is edging closer.
HER2 Therapy With Trastuzumab
Andrés Cervantes, MD, PhD, professor of medicine at the University of Valencia, Spain, began the presentations by examining the effect of targeting the HER2 pathway, noting that “in first line treatment of advanced gastric cancer, trastuzumab (Herceptin) is the only success so far.”
He explained that most trials in this setting failed in terms of improving overall survival, with some even showing reductions in median survival when compared with chemotherapy.
Moreover, Dr Cervantes emphasized that “the data we have in breast cancer is not fully reproducible in gastric cancer.” This includes trials of lapatinib and trastuzumab emtansine (TDM1), the latter having no effect on survival or progression compared with platinum-based therapy.
“Gastric cancer behaves very differently from breast cancer, and mechanisms of resistance are diverse and require better understanding,” he commented.
Crucially, potential mechanisms of resistance to trastuzumab and other anti-HER2 therapies in advanced gastric cancer include the coamplification of HER3 and/or epidermal growth factor receptor, the coamplification of MET, heterodimerization with HER3, HER3 mutations, and fibroblast growth factor receptor autocrine loops.
Dr Cervantes consequently recommended that, when anti-HER2 therapies is considered in advanced gastric cancer, HER2 amplification “is to be determined as a must in all metastatic cases.”
He noted that trastuzumab plus cisplatin and fluorouracil or capecitabine “in this setting improves outcomes in this group of HER2-amplified patients,” although trastuzumab’s role in perioperative or adjuvant therapy is still a matter investigation.
Role of Angiogenesis Inhibitors
Next, Yelena Y. Janjigian, MD, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York City, looked at the potential role of angiogenesis inhibitors in metastatic gastric cancer.
She pointed out that, in terms of vascular endothelial growth factor (VEGF) inhibition, bevacizumab (Avastin, Genentech) achieved negative results and is not indicated for the treatment of esophageal and gastric adenocarcinomas.
In contrast, the monoclonal antibody ramucirumab (Cyramza, Lilly), which targets the VEGF receptor through binding to the external domain of the VEGF-R2, has been approved by the US Food and Drug Administration in the second-line setting.
In the phase 3 REGARD study, however, ramucirumab achieved a nonsignificant survival overall survival benefit of just 1.4 months vs placebo when added to best standard of care and extended progression-free survival by 0.8 months.
As Dr Janjigian noted, this is “more of a proof of principle that, in patients with relatively well-behaved tumors, this is likely a disease-stabilizing approach.”
She nevertheless pointed out that the median overall survival of 5.2 months with ramucirumab was in line with that for other second-line studies with chemotherapy, suggesting that it could be effective “if you select the right patients.”
In the RAINBOW study, which compared ramucirumab plus paclitaxel to paclitaxel plus placebo, the effect on survival was greater: Ramucirumab improved overall survival by 2.3 months, as well as showing significant improvements in progression-free survival and response rates.
While the adverse events in the study were as expected, Dr Janjigian pointed out that “you should probably avoid ramucirumab in patients with recent stent placement because the risk for perforation in the setting of stent placement or recent feeding tubes can be quite substantial.”
She continued that, in her view, “the combination of VEGF-R2 inhibitors with other biological agents is probably where the field will move,” although some of the currently available data are “immature.”
Dr Janjigian said it is clear that VEGF-R2 inhibition is important in the biology and that ramucirumab has shown potential in combination with chemotherapy as a second-line agent in esophageal gastric adenocarcinomas.
However, she noted that biomarkers are needed to identify patients who are more likely to respond to treatment and that the results of ramucirumab combined with chemotherapy in the first-line treatment of gastric cancer are awaited.
Dr Janjigian concluded that evidence also suggests that a combination of ramucirumab and pembrolizumab (Keytruda, Merck), or ramucirumab and trastuzumab, could be effective in both first- and second-line settings.
Checkpoint Inhibitors in Gastric Cancer
The third presentation was given by Kohei Shitara, MD, from the Department of Gastroenterology, National Cancer Center Hospital East, Tokyo, Japan, on the role of checkpoint inhibitors in gastric cancer.
He noted that the phase 3 ATTRACTION-2 study in Asian patients showed that giving nivolumab (Opdivo, Bristol-Myers Squibb) after standard treatment was associated with significant overall survival benefits and was well tolerated.
The beneficial effect of checkpoint inhibitors was reinforced by findings from KEYNOTE-059, which showed that in a primarily non-Asian population, pembrolizumab achieved similar improvements in tumor response and survival when used as a third-line or later therapy.
Dr Shitara said several ongoing trials, including KEYNOTE-062, CheckMate-649, ONO-4538-37, and JAVELIN Gastric 100, are evaluating the optimal timing of checkpoint inhibitor therapy and their combination with chemotherapy, among other aspects of gastric cancer treatment.
What is clear so far is that response to checkpoint inhibitor therapy is correlated with mutational burden and high microsatellite instability (MSI), along with the presence of certain pathogens, high programmed cell death ligand 1 (PD-L1) expression, weak immune expression, the presence of metastases in the lung and lymph nodes, and low lactate dehydrogenase (LDH) levels.
In contrast, nonresponse is associated with liver and peritoneal metastases, high LDH levels and a high tumor burden, higher expression of a range of coinhibitory and costimulatory tumor factors, and strong immune expression, alongside a low level of inflammation, as measured by a range of factors.
The question, therefore, Dr Shitara pointed out, is how the outcomes of nonresponders to checkpoint inhibitors can be improved. To this end, many ongoing studies are looking at combining anti-programmed cell death 1 (PD-1)/PD-L1 therapies with numerous strategies.
For example, it is hypothesized that, on the basis of the results of preclinical studies, chemotherapy may stimulate immune responses, potentially by engaging immune effector mechanisms, and may reduce the tumor burden, which could potentiate anti-PD1 therapy.
Noting that there are lessons to be learned from the management of colorectal cancer, Dr Shitara concluded that both nivolumab and pembrolizumab have “clearly showed efficacy in late lines of treatment for gastric cancer and should become the standard of care.”
He said that several studies are ongoing and emphasized that “not all gastric cancers are the same, based on their profiles, so personalized therapy could be achieved in the future using immune profiling.”
Focus on Cancer Stem Cells
The final speaker was Julien Taieb, MD, PhD, Hôpital Européen Georges-Pompidou, Paris, France. He focused on the role of cancer stem cells in gastric cancer, noting that they have a “double capacity” to differentiate and to self-renew.
“Cancer stem cells are very important for the occurrence of cancer but are also involved in cancer treatment resistance and in cancer dissemination,” he commented.
Dr Taieb said that cancer stem cells are highly tumorigenic and are, fundamentally, responsible for continued malignant growth. He added that they are “very resistant” to chemotherapy and radiation therapy and current targeted therapies, and are the initiators of metastasis.
However, targeting cancer stem cells with therapies is challenging because of the heterogeneity of the cell population, the lack of specific surface markers for the development of monoclonal antibodies, and the dynamic and ongoing nature of their genetic mutations.
Dr Taieb nevertheless said that the signal transducer and activator of transcription 3 (STAT3) is dysregulated in cancer and is involved in cell stemness, and therefore it may be a good treatment candidate.
Targeting STAT3 is challenging, however, because previously developed inhibitors have resulted in unstable molecules with poor membrane permeability and poor pharmacokinetics, and trials have revealed substantial neurotoxicity.
There is potential on the horizon with BBI-608 (napabucasin, Boston Biomedical), a novel, first-in-class agent that is orally administered and has shown the ability to block spherogenesis in cancer stem cells while sparing normal stem cells.
The compound directly inhibits STAT3 and has shown “encouraging signs” of anticancer activity in patients with gastric and gastroesophageal junction cancer. It is being examined in combination with paclitaxel.
“How Do We Prioritize?”
In the discussion that followed the talks, session co-chair David Cunningham, MD, consultant medical oncologist, Royal Marsden NHS Foundation Trust, Surrey, United Kingdom, asked the burning question: “How do we prioritize between angiogenesis inhibitors and checkpoint inhibitors?”
Dr Janjigian replied that a central question is whether “you’re planning on doing combination or monotherapy,” with the choice between angiogenesis inhibitors and checkpoint inhibitors dictated by the characteristics of the individual patients.
“For MSI patients, it’s pretty clear these patients should be identified early on, in the first-line setting, and treated in the second-line setting with pembrolizumab or another checkpoint inhibitor,” she said.
“For the majority of our patients, however, in the second-line setting they have quite a bit of disease burden, and the quality of life and their symptoms may be improved quicker if you institute chemotherapy in combination with VEGF inhibitors.”
Dr Janjigian declared consulting fees from Bristol-Meyers Squibb, Eli Lilly, and Pfizer and funds for research support from Bristol-Meyers Squibb, Merck, Amgen, Bayer, Boehringer Ingelheim, and Lilly. The other speakers have disclosed no relevant financial relationships.
ESMO 19th World Congress on Gastrointestinal Cancer: Metastatic Gastric Cancer. Presentations in Session VI: Gastric Cancer. Presented June 29, 2017.
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