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After Iovance's Amtagvi Approval, What's Ahead for TIL Therapy?

Infusion Bag

NEW YORK – Sajeve Thomas, an oncologist at Orlando Health Cancer Institute, had just finished seeing his last patient for the afternoon on Friday, Feb. 16, when he learned that the US Food and Drug Administration had approved Iovance Biotherapeutics' Amtagvi (lifileucel), an autologous tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma.

"It was a beautiful moment because we finally get to move forward with treating patients who have been waiting for this for quite some time," Thomas said. "We were all high-fiving and hugging."

Amtagvi is the first cell therapy to enter the market for a solid tumor indication, and Thomas' cancer center at Orlando Health was one of the sites that participated in the clinical trial that led to the TIL therapy's accelerated approval, which means that the center already has the clinical processes and experience to administer this logistically complex therapy.

"It was a labor of love to participate in these protocols and help develop this, then await this FDA approval as the PDUFA date kept getting pushed out," he said, recalling the many consecutive delays to Amtagvi's approval as regulators ironed out the best way to regulate an altogether new class of bespoke therapies.

Now, Orlando Health is one of the 30 sites Iovance has deemed an authorized treatment center that is ready to begin administering Amtagvi right away, or as soon as advanced melanoma patients secure the necessary prior authorization from their insurance companies.

"We've been giving patients TIL [therapy] for seven years, but one of the key challenges now is trying to get these therapies approved by insurances and go through those motions," he said. "It's a lot easier when it's on a trial."

Amtagvi's list price, $515,000, is too steep to administer without prior authorization from patients' insurance providers. "Everyone's insurance is a bit different, and this is still new," Thomas said.

At his center, Thomas said he has about 13 or 14 patients on a list to receive Amtagvi as soon as their insurance plans sign off. As of Wednesday, prior authorization requests had already been submitted for five or six of these patients, and the rest were in the works, though none had officially gotten the go-ahead from insurers.

The TIL therapy process involves many steps, including an initial surgery to harvest the tumor specimen that is sent to Iovance's manufacturing sites for ex vivo expansion. The patient then must undergo lymphodepleting chemotherapy before ultimately receiving the TIL infusion along with an interleukin-2 infusion. The whole process can take more than a month before accounting for prior authorization, which can tack on several days to several weeks, according to Iovance.

Thomas said he only recently learned that a patient's prior authorization request needs to be cleared before they can even start with the surgical tumor resection. "I'm kind of learning as we go," Thomas said of the reimbursement process for Amtagvi. "I expect there to be a bit more hurdles, now that we have to go through insurance, to actually get these patients treated on a commercial TIL product."

In a call to discuss Iovance's 2023 fourth quarter and full-year financial results on Wednesday afternoon, Executive VP of Commercial Jim Ziegler said the firm is optimistic about payor coverage, both from Medicare and commercial payors. "The payors appreciate the unmet need and understand the clinical value of Amtagvi, and to date, we haven't had any issues," Ziegler said. "But I would provide the disclaimer that we are very, very early on."

Scaling up

During Wednesday's earnings call, Iovance executives said the firm plans to have 50 active treatment sites administering Amtagvi by the end of May. 

"The 50 [centers] … are going to pick up the significant portion of the treated patients in the country," Ziegler said. "We will continue to monitor the need to expand from that point."

Similar to how the treatment landscape has played out for autologous CAR T-cell therapy in blood cancer, Iovance expects access to Amtagvi will be concentrated at the top treatment centers. The firm estimates that the top 40 treatment centers it authorizes will provide about 80 percent of treatments. 

While the concentration of autologous cell therapies at top cancer centers with specialized personnel and drugmaker-issued stamps of approval can ensure patient safety and provider experience, it can also mean that patients treated at community hospitals and private practices and those living in rural regions will encounter more difficulties in terms of longer travel time and out-of-pocket ancillary costs in accessing Amtagvi.

For all of these reasons, Amtagvi likely won't become a standard-of-care therapy for all melanoma patients right away.

Next up for Iovance

Following Amtagvi's FDA approval, Iovance said on Wednesday that it is planning to file for European approval during the first half of 2024. Then, in the second half of the year, Iovance will file for approval in the UK and Canada. The following year, the firm plans to file for Amtagvi's approval in Australia and in other countries with "significant populations" of advanced melanoma patients. Iovance expects to start seeing revenue gains from the product later this year.

The firm is also focusing on developing the autologous therapy in earlier treatment settings, testing it in combination with other approved therapies, and evaluating its activity in cancer indications other than melanoma. It is also focused on advancing engineered versions of the product.

At his center, even though TIL therapy is now a commercially available option for refractory melanoma patients, Thomas said he is encouraging eligible patients to enroll in clinical trials evaluating the treatment in different settings or testing newer versions of the product.

For his advanced melanoma patients who have not yet received checkpoint inhibitor immunotherapy, for instance, Thomas said Iovance's Phase III TILVANCE-301 study could be an option. Orlando Health is one of the sites involved in this trial of frontline Amtagvi plus Merck's PD-1 checkpoint inhibitor Keytruda (pembrolizumab) against Keytruda alone. This is also the confirmatory trial for converting Amtagvi's accelerated approval to a full approval, and patients will have a chance to cross over to receive TIL therapy if they progress on Keytruda alone, Thomas pointed out.

Thomas has been encouraged by Amtagvi's efficacy in clinical trials and is both thrilled and relieved that his advanced melanoma patients can now access it outside a study. Even so, he highlighted that a 30 percent response rate in advanced melanoma still leaves significant room for improvement. He's hopeful that TIL therapy in earlier lines and some of the newer versions of the treatment can improve on this. 

"What we learned from giving TIL in the refractory setting was that folks who had a really low volume of disease did better with their response rates," Thomas said. "There is a real thought that the lower the tumor volume and the earlier in the course of treatment, maybe the more likely we'll be to get long-term responses and potentially long-term remissions."

Beyond Amtagvi, Iovance is studying engineered versions of other autologous TIL therapies, including its investigational product IOV-4001, which involves modifying the TILs to disrupt PDCD1, the gene encoding PD-1. The firm is evaluating this treatment in a Phase I/II trial in both advanced melanoma and non-small cell lung cancer. 

Iovance is also evaluating Amtagvi in non-small cell lung cancer, although the FDA late last year paused that trial due to a serious adverse event. During its Wednesday call, Iovance Chief Medical Officer Friedrich Finckenstein said the firm is working closely with the FDA to resume enrolling NSCLC patients in that study "really soon."

Finally, Iovance is preparing to evaluate autologous TIL therapy in advanced endometrial cancer. That trial, which is to begin during the first half of 2024, will include patients whose cancers are both DNA mismatch repair deficient and proficient.

Next wave of TIL approaches

Although Iovance is the first drugmaker to score regulatory approval for an autologous cell therapy in solid tumors, other biotechs and academic centers have been working on their own iterations of the therapy. And now that Amtagvi has proven there's an achievable path to getting these therapies onto the market, these other groups are emboldened to try to bring their own candidates to patients.

"Defining … a regulatory path going forward will help TIL therapies in development and should unleash additional investment," Jason Bock, CEO of the Cell Therapy Manufacturing Center, an MD Anderson Cancer Center and National Resilience joint venture, said.

"TILs will have the challenge of [proving] how sustainable the business model is even once you get to commercialization, but that's something that businesspeople can wrap their minds around and run numbers and calculate return on investment and those kinds of things," Bock had said in an interview just days before Amtagvi's approval. "But it's a lot harder when you have this big black box of regulatory risk that says, 'Hey, there's never been a product commercially approved.'"

Both Bock and Orlando's Thomas pointed to a Cambridge, Massachusetts-based company called Obsidian Therapeutics as one example of a TIL therapy-focused firm that could get a boost from TIL therapy becoming commercially available. Obsidian is developing a genetically modified version of TIL therapy, dubbed OBX-115, so that patients don't need infusions of interleukin-2 alongside their autologous TILs. Obsidian, which is enrolling advanced melanoma patients onto OBX-115 clinical trials and plans to expand into other solid tumors, accomplishes this by engineering the TIL products with membrane-bound, rather than secreted, interleukin.

"We're excited about this one because maybe we'll find the therapy might be better tolerated," said Thomas, whose center is also a clinical trial site for Obsidian. "One of the limiting factors of the whole TIL process is that not everyone can tolerate TIL because of the need for IL-2. Obsidian's product foregoes the need for IL-2."

In December 2023, Obsidian shared early data from its first-in-human OBX-115 trial, in which three out of six patients responded and experienced an "emerging safety profile that appears differentiated from that of unengineered TIL therapy."

Bock highlighted another program from the firm KSQ Therapeutics, which is developing an engineered TIL therapy for solid tumors dubbed KSQ-001EX. That treatment involves autologous TILs that are engineered to inactivate the SOCS1 gene using CRISPR-Cas9. In November 2023, the FDA gave Lexington, Massachusetts-based KSQ the go-ahead to begin studying its TIL therapy in first-in-human trials.

The idea behind KSQ's therapy is that knocking out the SOCS1 gene could enhance the ability of T cells to infiltrate and expand inside the tumor. KSQ is working on another product that knocks out both SOCS1 and another gene, called Regnase-1, which it identified through an unbiased screening process. "There have been so many improvements in our ability to engineer cells, either through viruses or through CRISPR editing, and those are going to be the products that ride on the back of this Iovance approval," Bock said.

Thomas also mentioned selected TIL therapy approaches, where firms harvest patients' TILs, but then also perform apheresis to harvest their dendritic cells and perform whole-exome sequencing of the tumor to identify the top cancer-specific neoantigens. "Then you're co-incubating the dendritic cells, which act like scouts to pick up those antigens and activate and engage the TILs that are most active," he said. "With unselected TILs, you're just expanding out whatever's in the tumor itself, but you don't know if you're actually expanding the TILs that recognize cancer, or whether those TILs are just bystanders that don't really do much."

One such firm developing selected TIL therapy is Turnstone Biologics, which is studying its investigational candidate TIDAL-01 (TBio-4101) in solid tumors including in various melanoma subtypes, breast cancer, and colorectal cancer. Turnstone expects to report initial clinical data on TIDAL-01 in mid-2024.

Whatever the next generation of cell therapies might look like for solid tumors, the field is watching Iovance's early days closely as a roadmap for what's to come.

"Not only was this a new treatment for melanoma, this was the first cellular therapy product approved for solid tumors," Thomas said. "Certainly, that makes it exciting for anyone who's interested in providing cell therapy products for solid tumors."

Going forward, he said it will be important to encourage patients to enroll in these clinical trials so the field can continue improving on the process and achieving even better responses with fewer side effects.

As for the immediate near future, Thomas said that his center is focused on getting patients on Amtagvi who have been waiting for this approval for too long. "Our biggest learning curve now is trying to understand insurance," Thomas said. "And we'll be learning that as we go."