FDA nod marks first cellular immunotherapy approval for a solid tumor.
Patients with inoperable or metastatic melanoma can now add lifileucel (Amtagvi; Iovance Biotherapeutics), a tumor-infiltrating lymphocyte (TIL) therapy, to their arsenal of approved treatment options. This is not only a first-in-class approval, but also the first cellular immunotherapy to get the FDA’s nod for a solid tumor.
“It’s a landmark approval,” says Antoni Ribas, MD, PhD, of the University of California, Los Angeles (UCLA)—one that’s the culmination of decades of research spearheaded by the NCI’s Steven Rosenberg, MD, PhD. Thirty-five years ago, Rosenberg’s group was the first to report that TILs extracted from patients with metastatic melanoma, then reinfused after in vitro expansion to beef up their pre-existing antitumor activity, warranted further study as a feasible approach (N Engl J Med 1988;319:1676–80).
TILs have taken so long to cross the finish line “not because of the output material, which is definitely efficacious, as Rosenberg and others have shown over and over again,” Ribas remarks. Rather, “it’s hard to standardize a process if you can’t control your input material. TILs come from different sources—a lesion in the arm, for instance, or in the liver—each with different potential for something possibly going wrong” during therapy manufacturing. There were multiple hurdles for Iovance to clear, especially regarding quality control and product characterization; that the company stayed the course and succeeded in doing so “is a very welcome advance.”
The FDA based its decision on findings from a single-arm phase II trial evaluating lifileucel in patients whose disease had progressed on anti–PD-1 therapy and, where applicable, BRAF/MEK inhibitors. Among 73 evaluable patients given lifileucel within the recommended dosing range of 7.2 billion to 72 billion cells, the objective response rate was 31.5%, and the median duration of response was not reached, with 43.5% of responses lasting longer than 12 months.
Lifileucel does come with boxed warnings about the possibility of prolonged severe cytopenia as well as cardiopulmonary and renal impairment. The treatment regimen is complex. Not only is lymphodepleting chemotherapy required, but shortly after their TILs are infused, to support in vivo expansion, patients receive up to 6 doses of the cytokine IL2—which often necessitates monitoring in intensive care.
Nor is lifileucel “a straightforward option we can start using tomorrow,” Ribas points out. The current manufacturing time frame in Iovance’s centralized facility is roughly 34 days and finding ways to substantially shorten it won’t be easy, given the inherent patient-to-patient variability involved. That said, “this is a population for whom there are currently no other treatments with proven efficacy,” he notes, so “it’s exciting to have an option that seems to induce durable responses. I’ll be looking into how we can get our first patient [at UCLA] dosed soon.”
Moving forward, randomized assessments of TIL therapy’s utility will be key, Ribas adds. Some data already exist. For example, in a phase III trial led by the Netherlands Cancer Institute in Amsterdam, compared with the CTLA4 inhibitor ipilimumab (Yervoy; Bristol Myers Squibb), second-line TILs prolonged progression-free survival in 168 patients with metastatic melanoma (N Engl J Med 2022;387:2113–25). Specific to lifileucel, the TILVANCE-301 confirmatory study—evaluating the therapy up front, with or without the PD-1 inhibitor pembrolizumab (Keytruda; Merck)—is underway to support its accelerated approval.
Lifileucel is also being tested in cervical cancer, and Iovance has other up-and-coming candidates, including LN-145 for non–small cell lung cancer and head and neck squamous cell carcinoma. Globally, some 75 or more TIL therapies are in various stages of preclinical or clinical development, making for a robust landscape. Meanwhile, on the research front, scientists are tinkering with strategies that may one day obviate the need for lymphodepletion and high-dose IL2 to boost infused TILs.
Efforts “to make TILs more broadly applicable” beyond melanoma have been going on for years, Ribas observes. “First, though, we needed to get one of these therapies greenlighted. It’s finally happened, which should open doors and provide momentum for the field.”
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