Celldex Therapeutics grabbed the spotlight late last year when an experimental vaccine it’s been developing helped extend the lives of some patients with an aggressive, deadly form of brain cancer. In an update to that study today, Celldex is circling back with similarly positive results—and is now trying to figure out what it’ll take to get that vaccine to market.
At the American Society of Clinical Oncology’s annual meeting in Chicago this morning, Hampton, NJ, and Needham, MA-based Celldex (NASDAQ: CLDX) is reporting the latest results from an exploratory Phase 2 study of rindopepimut (Rintega), or “rindo,” a vaccine it’s developing for patients with glioblastoma.
As was the case in November, Celldex says rindo helped glioblastoma patients live longer than they otherwise would have. A small group who have relapsed after surgery, chemotherapy, and radiation got rindo along with bevacizumab (Avastin)—the only approved therapy for these patients—and survived a median of 11.6 months, compared to 9.3 months for those who got bevacizumab alone.
Celldex said that survival benefit of more than two months was statistically significant, meaning it likely wasn’t due to chance. Rindo also met the study’s primary goal: It helped slow the progression of patients’ tumors. Some 28 percent of the 73 total patients on rindo and bevacizumab had their tumor held in check after six months, compared to 16 percent of those in the other group.
The drug combination also reduced the need for steroids, which recurrent glioblastoma patients typically take to reduce swelling in the brain despite, as CEO Anthony Marucci says, making them “feel miserable.” He says several patients in the study have gone a year without needing steroids.
Celldex chief medical officer Thomas Davis says the most common side effect seen so far is some redness and itching at the site of injection—rindo is injected into the thigh—that is easily controlled with topical creams. A few patients have had systemic reactions where their blood pressure drops and they feel dizzy or nauseous, but Davis says only two of them have discontinued treatment and “beyond that, there’s really nothing that’s identifiably associated” with the drug.
The survival benefit, meanwhile, has held up over time. Thirty percent of patients on the rindo-bevacizumab combination were alive after 18 months of treatment; just 15 percent of those on only bevacizumab lived as long. That’s significant, because people with recurrent glioblastoma often live only a handful of months after their cancer comes back. Davis says some folks in the study have been treated for more than two years, and Marucci (pictured above) notes that there are patients on rindo whose tumors still haven’t progressed yet.
“These data are compelling. They’re not a home run by any means, but they’re certainly a solid single, maybe even a double,” says David Reardon, the study’s lead investigator and the director of Dana-Farber Cancer Institute’s neuro-oncology center. “We’ve got a terrible unmet need where there’s no effective therapies, we have a treatment that’s well tolerated and safe, there’s really no downside to it, and it not only improves [tumor responses on MRI] scans and [disease] progression, but also, bottom line, it improves survival.”
Indeed, while Celldex has more to prove, and more than two months of additional life might not seem like much compared to treatments for other cancers, the results are noteworthy. Reardon points out that no immunotherapy approach has ever shown a statistically significant improvement in survival in glioblastoma in a randomized, controlled study.
He adds that the Celldex data “provide very strong support” that immunotherapy might have a significant impact on glioblastoma the way it has for some other cancers of the skin and lungs. Perhaps, for instance, rindo could be combined with other drugs, like so-called “checkpoint inhibitors,” that rev up the immune system to fight cancer, and have a major impact on the disease. “These data set the stage for the next steps,” he says.
Additionally, glioblastoma patients have few treatment options. It’s hard for many chemotherapy drugs to get past the blood-brain barrier, let alone treat the tumors without causing more damage. Patients first get surgery, radiation, and the chemotherapy drug temozolomide, and if their tumors return or progress after that, they get more surgery, a variety of off-label chemotherapies, and bevacizumab. All in all, glioblastoma is an extremely difficult-to-treat cancer that often kills people in 15 months or less from the time of initial diagnosis, and some six months or so after their cancer recurs.
“For this population, who historically has done miserably, there’s been nothing that really helps them in any significant way,” Celldex’s Davis says. “What we’re showing is a survival advantage, and that’s exceedingly rare.”
The question for Celldex now is, what will it have to do to win FDA approval? In November, after early data from this study, Celldex officials said they may talk to the agency about the possibility of “accelerated approval”—on a thinner body of evidence than the FDA usually requires—if the data were to hold up as time went on. The FDA gave Celldex a breakthrough therapy designation in February, which speeds up the process. Davis says those talks “have not come to a conclusion at this point,” and Celldex is treading carefully about its prospects for an early nod.
“I think we’ve been careful to say that this is not a stereotypical approval data set,” he says. “We’re not predicting that this would, based on any precedents, lead to accelerated approval. But at the very least it gives us greater confidence that [the Phase 3 study Celldex is running in newly-diagnosed glioblastoma patients] will be positive.”
There’s good reason to tiptoe here. This trial is an exploratory study in a small number of patients. Success isn’t as clear-cut as it would be in a large Phase 3 trial where the statistical reads are more definitive. In a recent research note, for instance, Leerink Partners analyst Howard Liang cited an expert in the field as being “somewhat cautious” about a speedier approval because of the size and structure of the study.
Davis acknowledged that this “isn’t the standard that the FDA usually likes for approval,” but then again, Celldex will produce the first results from the aforementioned Phase 3 trial in the next few months. The hope is that even modestly extending patients’ lives will help Celldex build its case. (Bevacizumab, by comparison, was approved for these patients because of tumor responses on MRI scans, not a survival benefit.)
“There’s no precedent for approving a drug based on a randomized survival endpoint with this number of patients, but the numbers are very strong, and the patients are very, very needy,” Davis says. “This is a situation where the breakthrough designation should be appropriate to allow some flexibility in approval.”
Rindo is a cancer vaccine that stimulates an immune response against EGFRvIII, a mutated molecule found on tumor cells in about 30 percent of patients with glioblastoma. Because this molecule is only present on tumor cells, the treatment can theoretically kill tumor cells while sparing healthy ones. Celldex estimates that about 3,000 patients in the U.S., and 6,000 in Europe, have glioblastoma with an EGFRvIII mutation. The cancer recurs for most of them.