Pessimism Surrounds VEGF Inhibitors in Advanced Gastric Cancer

David Ilson, MD

When a recent trial found that apatinib, an experimental VEGFR inhibitor, met its clinical endpoint and showed efficacy as a third-line therapy in treating advanced refractory stomach cancer, one might have expected at least two cheers. After all, gastric cancer is the third most fatal form of the disease globally, and there is currently no standard third-line treatment for advanced patients.

Indeed, on the basis of the study, said to be the first phase III trial demonstrating the efficacy of the tyrosine kinase inhibitor, the drug received its first approval, by the China Food and Drug Administration.

But instead, the news, announced in an article published this month in the Journal of Clinical Oncology¹was accompanied by an editorial which could only be called gloomy.²Preoccupied with recent failures of other experimental VEGFR-targeted agents, the editorial said that no biomarker had ever been discovered to identify patients in whom the efficacy of VEGFR drugs might be robust. The editorial also noted that bevacizumab recently failed to show any survival benefit in a study of 1,000 British gastric cancer patients when combined with perioperative chemotherapy.³

The study (conducted in China, which accounts for half of the world’s cases of stomach cancer) enrolled 267 patients who had previously failed at least two lines of chemotherapy between 2011 and 2012. The researchers found that overall survival was higher in those who received apatinib compared to a placebo (6.5 months compared with 4.7 months), and the difference was statistically significant (P= .0149). Median progression-free survival was also prolonged, at 2.9 compared with 1.8 months (P= .001).

The editorial did not say that there was anything wrong with the researchers’ methodology, but the author, David Ilson, MD, PhD, did seem to disagree with the researchers’ perspective that recent trials of other VEGFR inhibitors had been promising. The prospects for those patients needing third-line therapy for advanced disease are still not good, Ilson suggested.

“In patients without biomarker selection, recent large randomized trials of epidermal growth factor receptor (EGFR)—targeted antibodies failed to improve outcome in first-line chemotherapy, with a detriment actually seen for adding these agents to chemotherapy. However, biomarkers that were predicted to select patients most likely to benefit from targeted strategies have also failed,” the editorial noted.

Ilson is also a participant and lead investigator in the RAINFALL trial, which is examining ramucirumab as a front-line combination therapy for metastatic stomach cancer.⁴Targeted Oncologyspoke with Ilson, who is an attending physician and professor of medicine at Memorial Sloan Kettering Cancer Center in New York City.

TARGETED ONCOLOGY:Should we be disappointed with the results in the apatinib study?Ilson:The issue with these late-line trials is that patient survival is not good. Metastatic stage IV gastric cancer is not really curable; you’re essentially only adding a few months of survival. Then the issue becomes, what’s the cost-benefit ratio? Li and colleagues didn’t really present cost analyses in their study, and right now the drug is only available in China. For example, regorafenib was approved as a late-line treatment in colon cancer. Cost analyses raise concerns about cost versus merit. In the curative setting these drugs have been disappointing.

TARGETED ONCOLOGY:Li and colleagues suggest that the AVAGAST trial found biomarkers for bevacizumab. Was there anything wrong with AVAGAST or the other studies they mention?Ilson:Li needed to qualify some of his claims, as they are not completely accurate. The AVAGAST trial suggested in only Western patients that there was a correlation with VEGF-A and neuropilin, but they are not validated yet, and not considered clear markers of VEGF activity.

TARGETED ONCOLOGY:Will a biomarker for VEGF blocker efficiency ever be found?Ilson:I’m not too optimistic right now. There have been lots of efforts; researchers have looked at different gene mutations and the blood levels of ligand; they’ve looked at neuropilin, but we have never identified a biomarker for VEGF agents.

TARGETED ONCOLOGY:Does that suggest VEGF is not as important as once thought?Ilson:No, I think it is important. None of these things are home runs. VEGF is part of the puzzle and there is cross-talk between pathways. Perhaps targeting multiple pathways or downstream pathways is the future. Plus, there are other multi-targeted tyrosine kinase inhibitors that treat a whole spectrum of cancers, and have some anti-VEGF properties as well. It’s not simply a matter of just looking at VEGF, but a spectrum.

TARGETED ONCOLOGY:Why could it be important to start patients on experimental agents earlier?Ilson:It probably does help patients to start on a VEGF blocker as first-line therapy, and then when they have progression to continue VEGF treatment; the concept of continuous VEGF suppression has been validated in colorectal cancer, in advanced disease. Less chemotherapy may be more. It not only helps the patient but allows the introduction of new treatment, if we got a very promising early-line treatment. If we’re looking at patients that have progressed, it’s more appropriate to screen multiple agents for patients that don’t have good established options.

TARGETED ONCOLOGY:From examples you give in your editorial, such as ECX and EOX, would using 2 chemotherapy agents for those with advanced disease yield better results than using 3 agents?Ilson:It’s probably better to do 2 drugs in combination with new agents. I have always argued that epirubicin is a drug with a questionable benefit. It adds a lot of toxicity, and is probably not the best partner for new drug development.

References

1. Li J, Qin S, Xu J., et al. Randomized, double-blind, placebo-controlled phase III trial of apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol. 2016;34(13):1448-1454.
2. Ilson, D. Targeting the vascular endothelial growth factor pathway in gastric cancer: A hit or a miss? J Clin Oncol. 2016;34(13):1431-1432.
3. Cunningham D, Smyth E, Stenning S, et al. Peri-operative chemotherapy ± bevacizumab for resectable gastro-oesophageal adenocarcinoma: Results from the UK Medical Research Council randomized ST03 trial (ISRCTN 46020948). Presented at the European Cancer Congress; September 25-29, 2015; Vienna, Austria. Abstract 2201.
4. Clinicaltrials.gov. A study of ramucirumab (LY3009806) in combination with capecitabine and cisplatin in participants with stomach cancer (RAINFALL). https://www.clinicaltrials.gov/ct2/show/NCT02314117