Engineering a patient’s immune cells into cancer treatments works for treating blood cancers, but has fallen short in solid tumors—until now. An Iovance Biotherapeutics treatment employing a different type of cell has won accelerated FDA approval for advanced melanoma, marking the first product approval of any cell therapy for a solid tumor.
The regulatory decision announced Friday covers melanoma in adults whose cancer cannot be surgically removed or has spread following treatment with an immunotherapy or a targeted cancer therapy. The cell therapy of San Carlos, California-based Iovance, known in development as lifileucel, will be marketed under the brand name Amtagvi.
Amtagvi, a one-time treatment, is made from a type of cell called a tumor-infiltrating lymphocyte, or TIL. The body produces TILs to fight cancer, and they are found in the tumor. The Iovance cell therapy is made by surgically removing a small piece of a patient’s tumor and isolating TILs from that sample. Those TILs are multiplied in a lab, then shipped back to the hospital for infusion into the patient.
The TIL manufacturing process is similar to that of CAR T-therapies, which are made by harvesting and multiplying a patient’s T cells. One key difference is what happens in the lab. CAR T-treatments are engineered to go after a target on the surface of a cancer cell. TILs don’t need this engineering step because they already have the ability to recognize a patient’s cancer cells.
Amtagvi’s Clinical Trial Results
The FDA based its approval on the results of an open-label, single-arm Phase 2 clinical trial. Participants had advanced melanoma that was previously treated with at least one systemic therapy, including a type of immunotherapy called a checkpoint inhibitor, and if positive for a BRAF mutation, a BRAF inhibitor. The main goal was to measure the objective response rate and the duration of response. Of the 73 patients who received Amtagvi within the recommended dosing range, the overall response rate was 31.5%. The median duration of response was not reached. Results were published in in 2022 in the Journal for ImmunoTherapy of Cancer.
The most common adverse reactions reported from the clinical trial included chills, fever, fatigue, faster than normal heart rate, and diarrhea. Amtagvi’s label carries a black box warning that the treatment can lead to death. In the clinical trial, treatment-related mortality was 7.6%. Adverse reactions associated with these deaths included severe infections, internal bleeding, kidney failure, respiratory failure, and abnormal heart rhythm. Patients may experience prolonged and severe cytopenia, which is a low levels of certain blood cells. The risk of heart and kidney injury are also flagged in the boxed warning.
CAR T-therapies also carry black box warnings, with the main complications risks being an excessive immune response called cytokine release syndrome and neurotoxicity. Fred Vogt, interim Iovance CEO and the company’s president and general counsel, noted that Amtagvi was not associated with either of these complications risks. FDA approval of CAR T-therapies came with Risk Evaluation Mitigation Strategies (REMS), programs to manage the risks associated with treatment.
“The [Amtagvi] black box is pretty good, we think it’s much better than what the CAR T’s have,” Vogt said during a Friday conference call. “It doesn’t have a REMs, first and foremost, like the CAR T’s do. It’s got boxed warnings essentially for known risks, from the lymphodepletion and the IL-2 therapies that we provide.”
Lymphodepletion, a key step in all cell therapies, involves using chemotherapy to reduce levels of a patient’s immune cells to improve the survival chances of the cell therapy. IL-2 refers an engineered version of a protein that stimulates an immune response. In the clinical trial, treatment with Amtagvi was followed by aldesleukin, an IL-2 therapy whose uses include the treatment of metastatic melanoma. In the Amtagvi treatment regimen, aldesleukin’s role is to activate the TILs’ anti-tumor activity. Aldesleukin also has risks: Its label includes a black box warning of a potential complication called capillary leak syndrome, leading to low blood pressure and low levels of the protein albumin in the blood. This complication can lead to life-threatening organ damage.
Because aldesleukin is a key part of the Amtagvi treatment regimen, Iovance last year acquired global rights to Proleukin, an IL-2 product from Clinigen. Iovance paid £166.9 million (about $207.2 million) up front for the product’s rights. The acquisition agreement puts Clinigen in line for milestone payments and royalties from sales.
Premium Pricing for the First TIL Cell Therapy
Iovance set a $515,000 wholesale price for Amtagvi, which is higher than the $373,000 to $475,000 price range for currently available CAR T-therapies. The company will make the TIL therapy at its Philadelphia manufacturing facility. Together with a nearby contract manufacturer, the company says it has the capacity to produce Amtagvi for “several thousand patients annually.” The current manufacturing process is 34 days, which is a comparable to the lengthy, multi-step manufacturing process for CAR T-therapies. Vogt said Iovance believes it can improve Amtagvi’s manufacturing timeframe.
Jim Ziegler, executive vice president, commercial, said about 30 authorized treatment centers are now ready to collect and ship tumor tissue for Amtagvi manufacturing. He expects that number to grow to 50 centers within the next three months. Based on interactions with payers, Ziegler said Iovance expects coverage of Amtagvi will be similar to insurance coverage of approved CAR T-therapies.
TIL therapy competition is coming. The Achilles Therapeutics pipeline includes a TIL therapeutic candidate currently in a Phase 1/2 clinical trial evaluating it in combination with a checkpoint inhibitor as a potential treatment for melanoma. Lyell Immunopharma has a TIL therapy in early clinical development in melanoma, colorectal cancer, non-small cell lung cancer (NSCLC), and other solid tumors. Instil Bio’s pipeline includes a TIL in Phase 1 development in NSCLC, ovarian, and kidney cancers. Instil’s former lead program had reached mid-stage clinical development in advanced melanoma, but that therapy was discontinued in late 2022 due to a pipeline reprioritization.
Iovance is also testing Amtagvi in combination with the Merck checkpoint inhibitor Keytruda as a frontline treatment for melanoma. This Phase 3 study will serve as the confirmatory clinical trial required of the therapy’s accelerated approval. The Iovance pipeline also includes tests of Amtagvi—by itself and in combination with checkpoint inhibitors—in cervical cancer, NSCLC, and head and neck squamous cell carcinoma.
Another Iovance TIL therapy, LN-145, has reached pivotal testing in NSCLC. This study was placed under an FDA clinical hold in late December due to a fatality potentially related to the therapy’s preconditioning regimen. Vogt said Iovance is working to resolve the clinical hold and hopes to have an update in a few weeks.
Photo by Iovance Biotherapeutics
