FDA approves Iovance's Amtagvi as first T-cell therapy for a solid tumor

The T-cell therapy treatment class, which has transformed the treatment of certain blood cancers, has now reached the solid tumor field thanks to an FDA approval for a first-of-its-kind immunotherapy developed by Iovance Biotherapeutics.

Called Amtagvi, or lifileucel, the drug is the first individualized tumor-infiltrating lymphocyte (TIL) therapy to reach the market. The FDA on Friday granted it an accelerated approval for patients with advanced melanoma following prior treatment with a PD-1 inhibitor—and a BRAF inhibitor if the tumor carries BRAF V600 mutation.

Iovance is pricing the one-time treatment at a wholesale acquisition cost of $515,000 per patient, the company’s interim CEO Frederick Vogt, Ph.D., said on a call following Friday’s approval.

The drug’s list price is slightly higher than those for existing CAR-T cell therapies, which cost around $500,000—or less—for blood cancer patients. Iovance set the price based on Amtagvi’s value as the first drug approved in this post-PD-1 melanoma setting, as well as the company’s analysis of relevant benchmarks, Vogt said.

Similar to existing CAR-T cell therapies, Amtagvi is manufactured using immune cells from individual patients. To make the final product, a patient’s TIL cells are collected from a portion of their resected tumor and then expanded outside the body before being infused back into the patient.

The immune system naturally creates TIL cells that can recognize distinctive markers on the surface of cancer cells and launch an attack. Amtagvi basically resupplies the body with these cancer-fighting immune cells as their naturally produced counterparts lose their power over time.

Before Amtagvi, CAR-T therapies had only been able to tackle some blood cancers—partly because solid tumors lack appropriate cell-surface biomarkers for CAR-T cells to target. A TIL therapy solves that problem, because TIL cells are naturally wired to identify cancer biomarkers. 

In a single-arm study, Amtagvi at the now-recommended dosing range shrank tumors in 31.5% of 73 patients who had previously received an anti-PD-1 therapy. After 18.6 months of follow-up, 43.5% of responders had been in remission for more than a year.

In a supporting pooled efficacy analysis that included 153 patients, the objective response rate was similar at 31.4%. Further, 56.3% of responders maintained durable responses at one year. Although not included in the current label, a recent update of the pooled analysis showed that patients lived a median 13.9 months, whereas nearly half of patients were still alive at four years.

Despite its groundbreaking nature, Amtagvi isn’t perfect. 

For starters, because Amtagvi is made with TIL cells from a patient’s own tumor, patients who can’t undergo surgery or those without enough resected tumor tissues won’t be eligible for the therapy.

Secondly, the drug carries a boxed warning for treatment-related deaths, prolonged severe cytopenia, severe infection, cardiopulmonary and kidney impairment. As such, the drug is only offered at designated treatment centers in an inpatient hospital setting. And the drug's FDA-approved label requires that patients be monitored for side effects in an intensive care facility and that specialists be available.

Still, Vogt argued that Amtagvi’s boxed warning is better than the situation for existing CAR-Ts. For example, Amtagvi isn’t controlled under an FDA-mandated safety program, known as risk evaluation and mitigation strategies. The drug also doesn’t come with warnings of cytokine release syndrome or hemophagocytic lymphohistiocytosis, both of which are potentially life-threatening complications of CAR-T cell therapies.

Vogt said the boxed warning was expected and that physicians are already aware of the medicine's characteristics. 

Iovance has on-boarded 30 designated centers ready to treat patients at the drug’s launch, and the company is on track to have more than 50 centers in about 100 days, Iovance’s commercial chief, Jim Ziegler, said on the call.

Several CAR-T therapies have experienced supply bottlenecks, especially during the launch phase. For the Amtagvi launch, “we have sufficient capacity as we’re onboarding these sites in a controlled, disciplined way,” Ziegler said. The company’s internal facility in Philadelphia and a nearby contract manufacturer have capacity to eventually serve up to “several thousand patients annually,” Vogt said.

In a statement Tuesday, WuXi AppTec’s subsidiary WuXi STA said its Philadelphia plant has received an FDA go-ahead to perform the analytical testing and manufacturing of Amtagvi.

Amtagvi can take quite some time to manufacture. For now, Iovance expects the average manufacturing turnaround time—from a tumor reaching the manufacturing facility to final product release—to be 34 days. And that doesn’t count the time for shipment.

The long wait time could be a problem for some patients. The drug’s pooled efficacy analysis had originally included 189 patients, but 33 didn’t receive the drug because of reasons including product manufacturing failure for eight patients and disease progression or death for 11 patients.

What’s more, patients undergo complex treatments both before and after Amtagvi administration either to prepare the body for infusion, to improve the cells’ vitality, or to deal with side effects. Patients also need to stay within a two-hour radius of the treatment center for “several weeks” to monitor for side effects. These processes will lead to extra costs and physical burdens for patients.

As for the high cost, “payers have expressed their appreciation for the value proposition for Amtagvi,” Ziegler said. Based on Iovance’s interactions with payers so far, the company expects to win coverage similar to that of existing CAR-T therapies, with a prior authorization requirement, he added.

Amtagvi is cleared under the FDA's accelerated approval pathway. Iovance is also conducting a phase 3 trial coded TILVANCE-301 to confirm the drug’s clinical benefit. The study is pairing Amtagvi with Merck & Co.’s PD-1 inhibitor Keytruda versus Keytruda alone in patients with untreated melanoma.

The road to Amtagvi’s landmark approval was long and thorny. Iovance had originally hoped to submit a filing in 2020 but delayed the plan after the FDA raised questions about the assays used to measure the potency of each therapy dose. The company cleared the assay hurdle and got its application accepted by the FDA under priority review in May 2023. But the FDA then extended its review because of resource constraints at the agency.

During the delays, Vogt took over from former CEO Maria Fardis, Ph.D., in 2021 on an interim basis. A permanent helmsman has not been named. 

In addition to Amtagvi, Iovance is working on another TIL therapy coded LN-145, which is in phase 2 testing for post-PD-1 non-small cell lung cancer. The pivotal IOV-LUN-202 trial could also enable an accelerated approval, Iovance said last year.

Editor's note: The story has been updated Feb. 20 to clarify patient eligibility criteria and to identify WuXi STA as the contract manufacturer for Amtagvi.