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Expert Critique
FROM THE ASCO Reading Room
The integrated study of induction and maintenance trials by Sandborn et al (GEMINI 2) reported that vedolizumab has a modest effect on the induction of clinical remission without a significant Crohn’s Disease Activity Index (CDAI)-100 response at week 6, as compared with patients receiving placebo. The remission rates were significantly higher at week 52 among patients who had a response to induction therapy. However, a higher rate of serious adverse events including treatable infections was associated with those receiving vedolizumab compared with placebo.
The short-term evaluation of efficacy and safety of vedolizumab induction therapy by Sands et al (GEMINI 3) showed that significant clinical remission was not observed at week 6 among patients with moderately to severely active Crohn’s disease and previous TNF antagonists failure, as compared with placebo. The therapeutic benefits of vedolizumab treatment became detectable at week 10.
These data suggested that selective pharmacological inhibition of integrin receptor α4β7 may require a longer time for full induction efficacy than required with conventional treatments. Both studies reported no PML cases, which is consistent with the lack of unexpected effect on CNS immune surveillance due to specific gut-blockade of lymphocyte trafficking through selective inhibition of the α4β7/MAdCAM-1 pathway by vedolizumab.
Advances in the understanding of the pathogenesis of Crohn's disease have led to an increased focus on targeted therapies such as vedolizumab (Entyvio), a monoclonal antibody to alpha4beta7 integrin that modulates lymphocyte trafficking in the gut. A similar agent used in multiple sclerosis, natalizumab (Tysabri), modulates both gut and brain lymphocyte migration, but has been associated with the potentially lethal brain infection of progressive multifocal leukoencephalopathy (PML).
Selective inhibition of the alpha4beta7 integrin pathway is intended to block gut inflammation without the central nervous system effects of natalizumab. Phase II studies suggested the possibility of benefit for vedolizumab in inflammatory bowel disease, and phase III trials confirmed the efficacy and safety. Vedolizumab was in May 2014 for ulcerative colitis and Crohn's disease when one or more standard therapies (corticosteroids, immunomodulators, or tumor necrosis factor blocker medications) have not resulted in an adequate response.
One phase III study, GEMINI I, enrolled patients with ulcerative colitis, while GEMINI II and III focused on those with Crohn's disease, with or without prior biologic failure. "These trials have demonstrated that this new mechanism of action, a selective antibody against alpha4beta7 integrin, is effective in the induction of remission with either ulcerative colitis or Crohn's disease," observed , of the Mayo Clinic in Rochester, Minn., who was not involved in the studies.
GEMINI II
included both induction and maintenance phases. The induction phase enrolled 368 patients, with the primary endpoints of clinical remission (a decrease in the Crohn's Disease Activity Index [CDAI] of 150 or less) and a decrease in CDAI of 100 points (CDAI-100) or more. The maintenance phase involved 461 patients, with a primary endpoint of clinical remission at week 52. The treatment was given intravenously in doses of 300 mg at weeks 0, 2, and 6, and then every 4 or 8 weeks for the remainder of the year.
The mean age of the participants at baseline was 36, more than half were women, and the mean disease duration was 9 years. The mean CDAI score was 324, and the median C-reactive protein (CRP) level was 11.5 mg/L.
A total of 34.2% of patients were on concomitant glucocorticoids, 16.2% were on immunosuppressives, and 17% were receiving both. The median prednisone dose at baseline was 20 mg/day.
More than half of the patients had previously received a tumor necrosis factor (TNF) inhibitor, and 36% had treatment failures with two or more of the anti-TNF agents.
At week 6 in the induction phase, 14.5% of patients receiving vedolizumab had achieved clinical remission, as had 6.8% of those given placebo (P=0.02). However, on the other primary endpoint of CDAI-100 response, there was no statistically significant difference between the active and placebo groups (31.4% and 25.7%, respectively, P=0.23).
At week 52 in the maintenance phase, 39% of patients in the vedolizumab every-8-weeks group and 36.4% in the every-4-weeks group had reached clinical remission compared with 21.6% of the placebo group (P<0.001 and P=0.004).
On the secondary endpoints at week 52, significantly greater CDAI-100 responses were seen compared with placebo for the every-4-weeks and every-8-weeks groups (45.5% and 43.5% versus 30.1%, P=0.005 and P=0.01), while glucocorticoid-free remission was seen in 28.8% and 31.7% versus 15.9% (P=0.02 and P=0.04).
The incidence of serious adverse events was higher during the maintenance phase in the active treatment groups than in the placebo group (24.4% versus 15.3%), with serious infections being reported in 5.5% and 3%, respectively. There were five cases of cancer, with four in the active treatment groups. Five patients died (four in the vedolizumab groups), from causes including sepsis related to Crohn's disease, myocarditis, and bronchopneumonia.
There were no cases of PML in the trial, and there have not yet been any reported cases, according to Kane.
GEMINI III
The trial included 416 patients, three-quarters of whom had not responded to previous use of TNF. The patients were randomly assigned to receive vedolizumab 300 mg or placebo at weeks 0, 2, and 6.
There was no statistically significant difference between the active treatment and placebo groups on the primary endpoint, which was the proportion of previous TNF failures in clinical remission at week 6 (15.2% versus 12.1%, P=0.433, relative risk 1.2, 95% CI 0.7-2.2).
Benefits were seen for the secondary endpoints, however: For instance, at week 10, a total of 26.6% of patients receiving vedolizumab after TNF failure were in clinical remission compared with 12.1% of those given placebo (P=0.001, RR 2.2, 95% CI 1.3-3.6).
The GEMINI III authors noted that the patient population of previous anti-TNF failures had high rates of longstanding disease, prior Crohn's disease surgery, a history of fistulizing disease, baseline CRP and fecal calprotectin increases, and prior failure of immunosuppressives and multiple TNF antagonists.
"After just two doses of the drug by week 6, there was no difference between placebo and drug. But when [the authors] followed these patients out to week 10 they started to see the curve separate and to see significant improvement," said , director of the Inflammatory Bowel Disease Program at NYU Langone Medical Center in New York City, who was not involved in the trial.
"I think that's what we're seeing in the real world, especially in the more complicated refractory Crohn's patients -- that the medication does work but it could just take a little while longer," Hudesman told 鶹ý.
"It's important for physicians to set expectations for their patients, letting them know that this treatment could take 3 to 4 months to work."
Also in GEMINI III, more patients given the active treatment had a CDAI-100 response at week 6 (39.2% versus 22.3%, P=0.001, RR 1.8, 95% CI 1.2-2.5) and at week 10 (46.8% versus 24.8%, P<0.0001, RR 1.9, 95% CI 1.4-2.6).
When outcomes were analyzed for all participants (rather than just for those who previously did not respond to TNF), more patients receiving vedolizumab were in clinical remission at week 6 (19.1% versus 12.1%, P=0.048, RR 1.6, 95% CI 1-2.5) and also at week 10 (28.7% versus 13%, P<0.0001, RR 2.2, 95% CI 1.4-3.3).
The most common adverse events were infections, reported in 19% of the vedolizumab group and 17% of the placebo group. Two patients receiving vedolizumab had serious infections, both of which were treated successfully.
When to Use?
As treatment options for Crohn's disease have broadened, shared decision-making has become increasingly important, Hudesman explained. "So when a patient with moderate to severe Crohn's comes to the office, we are going to talk about the different immunosuppressives, 6-MP [mercaptopurine], anti-TNF agents, Entyvio, to find what medication would work best for that patient."
There have not been any head-to-head trials comparing the biologics, he noted. "But we've seen that patients with Crohn's colitis or ileocolitis do well with Entyvio. However, if you have fistulizing or stricturing disease, there are limited data and some real-world experience suggesting that the response isn't as good."
Patients who might be suitable candidates for early treatment with vedolizumab could be those with a recent history of cancer or those who are at risk for infection such as the elderly, he added. "Because Entyvio is gut-specific, it has a more favorable side effect profile in these patients. But it's on a case-by-case basis."
Other patients might be less likely to benefit from this treatment, such as those with extra-intestinal disease manifestations. Because vedolizumab is gut-specific, it may not help with joint and skin manifestations. "So if I had a patient with Crohn's with significant joint pain, swelling, and rashes, I'm not going to use Entyvio. For that patient, I'd use an anti-TNF agent," he said.
Kane pointed out that while the clinical trials did include patients who were anti-TNF naive, the FDA indication is for patients who have not responded to conventional treatment, so insurance companies may be unwilling to pay for earlier use.
"It is accepted that efficacy of any biologic agent is best when used first and used early in the course of disease," she said. "But because of insurance constraints, those who may wish to use vedolizumab first have been prohibited from doing so. Certainly patients with uncontrolled heart failure, a history of lymphoma, or multiple sclerosis would benefit from vedolizumab rather than an anti-TNF," she said.
Can Treatment Stop?
Can treatment stop? "That's a very important question," said Hudesman.
Kane said: "We treat ulcerative colitis and Crohn's as chronic incurable conditions just like diabetes or hypertension. We are thankful when we can achieve remission and continue therapy to keep a patient there."
But Hudesman argued that it is too early to make any recommendations regarding remission and treatment withdrawal: "I don't think we know enough about this yet. We're starting to see more data on withdrawing therapy, such as for patients on multiple agents, backing off on one. But what we've seen is that if you stop therapy, most patients do flare within the first year to 18 months. So we don't routinely recommend stopping therapy.
"As we get a better understanding of the gut microbiome, we might be able to have better predictors about who might remain in remission long term or how to keep people in remission once they're off therapy," he said. "But that's for the future."
The GEMINI II and III studies were funded by Millennium Pharmaceuticals.
Primary Source
New England Journal of Medicine
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Secondary Source
Gastroenterology
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