Iovance Biotherapeutics’ Amtagvi (lifileucel) won US Food and Drug Administration (FDA) approval last week for the treatment of advanced melanoma, making it the first individualized tumor-infiltrating lymphocyte (TIL) therapy and the first T-cell therapy for a solid tumor to win US regulatory approval.
Amtagvi is approved for the treatment of unresectable or metastatic melanoma following prior treatment with a PD-1 inhibitor and a BRAF inhibitor if the tumor harbors a BRAF V600 mutation.
TILs are immune cells that attack and penetrate tumors. They are often found in the tumor stroma, a part of the tumor microenvironment, or within the tumor itself. Since the activity of TILs can be suppressed by tumor cells, TIL therapies are designed to bolster the number of TILs.
Melanoma is a type of skin cancer often caused by exposure to ultraviolet light, such as that from sunlight or indoor tanning. Despite accounting for only about one percent of all skin cancers, melanomas make up a significant proportion of cancer-related deaths.
According to the National Cancer Institute (NCI), it is estimated that approximately 8,000 people die from melanoma every year in the US.
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Amtagvi was approved through the FDA’s Accelerated Approval pathway.
“The accelerated approval of Amtagvi is the first step in realizing Iovance’s ambition to usher in the next generation of cell therapy by bringing this breakthrough to patients with advanced solid tumors,” said Frederick Vogt, PhD, JD, interim CEO and president of Iovance in a news release announcing the approval. “Given the significant unmet needs in the advanced melanoma community, we are proud to offer a personalized, one-time therapeutic option for these patients.”
Amtagvi Price
Following the approval, Vogt revealed on a call that Amtagvi will be priced at a wholesale acquisition cost of $515,000 per patient. The cost is the highest of any cell-based cancer drug in the US.
Most chimeric antigen receptor (CAR)-T cell therapies cost around $500,000 or less. Vogt said Iovance set Amtagvi’s price based on its value as the first drug approved in the post-PD-1 melanoma setting, and the company’s analysis of relevant benchmarks.
Addressing the high price tag, Iovance’s commercial chief Jim Ziegler said, “Payers have expressed their appreciation for the value proposition for Amtagvi.” He explained that based on communications with payers so far, the company expects coverage to be similar to that of existing CAR-T therapies, with a prior authorization requirement.
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TIL vs CAR T-Cell Therapies
While CAR T-cell therapies involve inserting a CAR engineered to target a specific cancer cell protein into a patient’s T cells, TIL-based T-cell therapies like Amtagvi involve separating TILs from a patient’s tumor (in autologous therapies) and expanding them ex vivo. The immune cells in both cases are then infused back into the patient.
While CAR T-cell therapies have been transformative for the treatment of blood cancers, their application has been far more challenging in solid tumors.
TILs hold greater promise for solid tumors as they can recognize multiple antigens compared to conventional CAR-Ts, which are typically designed to target one or just a handful of antigens on the surface of tumor cells. TILs can spot tumor antigens derived from intra- or extracellular tumor proteins in the tumor microenvironment.
Clinical Promise
There are currently 75 TIL immunotherapies in preclinical or clinical studies for different indications. With growing interest in TIL therapies, investors have invested $2.7 billion into this T-cell immunotherapy segment since 2013. Approximately 95 clinical trials evaluating TIL therapies have been registered globally.
Amtagvi’s safety and effectiveness were evaluated in Iovance’s ongoing Phase III C-144-01 clinical trial among adult patients with unresectable or metastatic melanoma who had previously been treated with at least one systemic therapy, including a PD-1 blocking antibody, and if positive for the BRAF V600 mutation, a BRAF inhibitor or BRAF inhibitor with an MEK inhibitor.
Of the 73 patients who received Amtagvi, the response rate was 31.5 percent, including three (4.1 percent) patients who achieved a complete response and 20 (27.4 percent) patients with a partial response. Among responders, after 18.6 months of follow-up, 43.5 percent continued to maintain responses without tumor progression or death for over one year.
Amtagvi Considerations
Amtagvi’s approval was decades in the making, with TIL therapy dating back to research conducted at the National Institutes of Health (NIH) in the 1980s. This included promising efficacy shown in animal and human trials in advanced melanoma. Iovance also faced several regulatory bumps with Amtagvi before finally reaching the finish line.
The company had originally planned to file its application in 2020 but that was thwarted when the FDA questioned the assays used to measure the potency of each therapy dose. After addressing the assay issue, the FDA accepted its application in May 2023 under priority review. However, the FDA extended its review due to its own issues of resource limitations.
According to Iovance, Amtagvi is manufactured using a proprietary process to collect and expand a patient’s unique T cells from a portion of their tumor, and then returning billions of the patient’s T cells back to the body to fight their cancer.
Amtagvi must be administered at an authorized treatment center (ATC) as part of a treatment regimen that includes lymphodepletion and a short course of high-dose Proleukin (aldesleukin or human recombinant IL-2) to kickstart the immune response. More than 30 ATCs are already prepared to collect and ship tumor tissue from patients for Amtagvi manufacturing, said Iovance. Ziegler said it is on track to have more than 50 centers in about 100 days.
Among some of the concerns around Amtagvi are a boxed warning for treatment-related deaths, prolonged severe cytopenia, severe infection and cardiopulmonary and kidney impairment. This is why the treatment can only be administered at an ATC with inpatient hospitalization, as patients must be monitored for side effects. And even after treatment, patients are required to remain within a two-hour radius of the treatment center for several weeks for continued side effect monitoring.
Production is another potential issue as TIL therapies take four to six weeks to manufacture. However, shorter culture times actually yield better cell quality and clinical outcomes. Iovance has already shortened Amtagvi’s manufacturing time from six weeks to 22 days. The company expects the average manufacturing turnaround time to be 34 days, which is from when a tumor sample reaches the manufacturing facility to final release of the product, but without taking into account delivery times.
Iovance said Amtagvi will be manufactured at the Iovance Cell Therapy Center (iCTC) in Philadelphia, with WuXi Advanced Therapies (WuXi ATU) serving as the local contract manufacturer, which will have the capacity for up to several thousand patients every year. WuXi Advanced Therapies (WuXi ATU) has already gotten an FDA nod for its Philadelphia site to start the analytical testing and manufacturing of Amtagvi.
Iovance is also conducting a Phase III trial (TILVANCE-301) to confirm Amtagvi’s clinical benefit. The study is looking at Amtagvi in combination with Merck’s PD-1 inhibitor Keytruda (pembrolizumab) versus Keytruda alone in patients with untreated melanoma.
In addition to Amtagvi, Iovance is evaluating another one of its TIL therapies, LN-145, in the IOV-LUN-202 Phase II trial for post-PD-1 non-small cell lung cancer (NSCLC). Last year, Iovance said results from the pivotal trial could support its application for FDA accelerated approval.
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