Manish A. Shah, MD
Although the results of a phase III trial evaluating the use of andecaliximab (GS-5745) in patients with gastric cancer were negative overall, a sensitivity analysis has revealed that the agent may be beneficial in older patients, said Manish A. Shah, MD.
In the GAMMA-1 study, results of which were presented at the 2019 Gastrointestinal Cancers Symposium, the addition of the MMP9 inhibitor andecaliximab to FOLFOX6 was not found to improve overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone in the frontline treatment of patients with HER2-negative gastric cancer.
Andecaliximab was infused at 800 mg on days 1 and 15 on 28-day cycles until disease progression. Oxaliplatin was administered on days 1 and 15 of each 28-day treatment cycle for a total of 6 cycles, followed by leucovorin and 5-fluorouracil dosing on days 1 and 15 of each 28-day treatment cycle.
Median OS was 12.5 months (95% CI, 11.2-14.0) in the andecaliximab arm compared with 11.8 months in the control arm (HR 0.93; 95% CI, 0.74-1.18; two-sided P
= .56). Median PFS was 7.5 months (95% CI, 7.3-8.4) versus 7.1 months (95% CI, 5.5-7.5), respectively, for the patients treated with the andecaliximab combination versus FOLFOX6 alone.
However, Shah, who was also the lead study author, said that patients older than 65 years seemed to derive greater benefit from andecaliximab.
“We actually did a sensitivity analysis to see if splitting the group into quartiles would have a stepwise increase in benefit as you went from the youngest group to the oldest group—and there was,” he said.
In an interview with OncLive
, Shah, the director of Gastrointestinal Oncology and chief of Solid Tumor Service at Weill Cornell Medicine/NewYork-Presbyterian Hospital, discussed the results of the GAMMA-1 trial and challenges that remain for patients with gastric cancer.
OncLive: Please provide some rationale to the GAMMA-1 study.
: GAMMA-1 was a phase III study of andecaliximab plus FOLFOX for the frontline treatment of [patients with] gastric cancer. Andecaliximab is a MMP9 inhibitor; MMP9 is a protein that is overexpressed in many solid tumors and in all gastric cancers. What it does is remodel the extracellular matrix; it is associated with increased angiogenesis and increased recruitment of myeloid suppressive cells and [regulatory T cells]. [MMP9 overexpression] makes it harder for immune surveillance and makes it easier for cancers to break up the matrix and spread. As such, we thought MMP9 would be a good target in this setting.
We did do a phase Ib study, where in over 30 patients we looked at efficacy and modified FOLFIX and andecaliximab. We found encouraging data; the median PFS [with the combination] was nearly 10 months and OS was well more than that. Based on the mechanism of action, the expression of MMP9 in gastric cancer, and the phase Ib study, we thought it was reasonable to test this hypothesis in a phase III trial.
How was the trial designed?
This was a randomized, double-blind, placebo-controlled trial of modified FOLFOX6 with or without andecaliximab. Andecaliximab is an agent given intravenously every 2 weeks with modified FOLFOX6. It was a 1:1 randomization and the primary endpoint was OS. We were targeting a hazard ratio of 0.7.
What were the findings?
Overall, the results were disappointing. Although andecaliximab is associated with an improved overall response rate, there was not an improvement in PFS or OS in an unselected patient population. However, we did see, curiously, that patients older than 65 years seemed to have benefit with andecaliximab.
We did a sensitivity analysis to see if splitting the group into quartiles would have a stepwise increase in benefit as you went from the youngest group to the oldest group, and there was. Therefore, it suggests there may be a signal here. We looked at different factors that might be associated with that. [We thought that] maybe there was a toxicity issue or something else, but we could not find anything like that. In the older group, we think [the biology of] gastric cancer is a little bit different; maybe the extracellular matrix is different. This may lead to specific sensitivity in the older population.
What are the next steps for this research?
There was a phase II study of andecaliximab with immunotherapy that was presented at this meeting. We have a lot of [tissue samples] from that study, so we are going to look a little more carefully at factors that may be associated with response to andecaliximab. We also have a significant amount of tissue from the phase III study, so there is an opportunity to evaluate the subgroup that derives the most benefit a little better. If we have good data there, it may lead to further study.
What challenges remain in this space?
Gastric cancer is still a tough disease to treat. Most patients with gastric cancer live for 1 year or less, unfortunately. I would say that it is sensitive to chemotherapy—there are many drugs with modest activity—but we are not eradicating the disease with our current treatments. There is a lot of effort going into defining new immunotherapy combinations to see if that can improve the efficacy of chemotherapy in gastric cancer, but the challenge is that [gastric cancer] is not just 1 disease; it is several. We need to better understand the diseases we can treat and target to better optimize therapy.
What is the potential role of immunotherapy?
We have evidence that immunotherapy does have a modest benefit in the third-line setting. It has been tested in earlier lines [of therapy]. We are awaiting 2 large studies of chemotherapy with or without immunotherapy in the frontline setting. We are all hopeful that those studies are positive.
What advice would you give to community oncologists practicing in this space?
For now, the standard treatments remain similar. For gastric cancer, we think of a platinum and fludarabine in the first-line setting. In the second-line setting, paclitaxel and ramucirumab (Cyramza) is the standard, but if the patients' tumors are mismatch repair deficient, we consider immunotherapy. If the tumor overexpresses HER2, we think of trastuzumab (Herceptin) in the frontline setting. We do have targeted agents and standard cytotoxic therapies. We also have immunotherapy. There are options for these patients, but there is still a long way to go. There are many ongoing trials as well within the context of the standard options.
Shah M, Ruiz E, Bodoky G, et al. A phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of andecaliximab combined with mFOLFOX6 as first-line treatment in patients with advanced gastric or gastroesophageal junction adenocarcinoma (GAMMA-1). J Clin Oncol. 2019;37(suppl 4; abstr 4). doi: 10.1200/JCO.2019.37.4_suppl.4