Addition of Lifileucel to Advanced Melanoma Arsenal Marks Milestone for TIL Therapy in Solid Tumor Management

As the first cellular and tumor infiltrating lymphocyte (TIL) therapy product to be approved by the FDA for patients with solid tumors, lifileucel (Amtagvi) could usher in a paradigm shift in advanced melanoma management, thereby paving the way for several other TIL products to gain approval, according to Daniel Olson, MD.

On February 16, 2024, the FDA granted accelerated approval to lifileucel for the treatment of adult patients with unresectable or metastatic melanoma whose disease has been previously treated with a PD-1 inhibitor, as well as a BRAF inhibitor with or without a MEK inhibitor for BRAF V600–mutated disease. Data from cohorts 2 and 4 of the phase 2 C-144-01 trial (NCT02360579) supported this regulatory decision and demonstrated that treatment with lifileucel at the recommended dose (n = 73) of 7.5 x 109 to 72 x 109 viable cells produced an overall response rate (ORR) of 31.5% (95% CI, 21.1%-43.4%),¹ comprising a complete response rate of 4.1% and a partial response rate of 27.4%.²

Moreover, 56.5%, 47.8%, and 43.5% of responders had ongoing responses without tumor progression or death at 6, 9, and 12 months, respectively.² The median time to best response to the therapy was 1.5 months, and the median duration of response was not yet reached (NR; 95% CI, 4.1 months-NR).¹

“Although it’s not going to be offered for everyone, based on the safety profile, there are many young patients with melanoma or fit patients who are older, who don’t have adequate standard therapies [available],” said Olson, who is an assistant professor of medicine at the University of Chicago Medical Center, in Chicago, Illinois. “Having a chance of [achieving] long-term benefit [with this therapy] is [significant].”

In an interview with OncLive®, Olson detailed the unique mechanism of action of lifileucel as the first approved TIL therapy in advanced melanoma, how the agent’s approval may address unmet needs in patients who disease is refractory to standard therapies, and the importance of understanding the safety profiles of lifileucel and interleukin 2 (IL-2) when selecting patients for this therapy.

OncLive: What is unique about the mechanism of action of lifileucel compared with that of other approved agents for advanced melanoma?

Olson: Lifileucel is interesting in that it’s the first ever TIL therapy to be approved, so it has a totally different mechanism [than other agents]. It’s a cell therapy, so unlike other forms of immunotherapy, it uses [T cells from] a patient’s own immune system that are harvested from the tumor, isolated, and then expanded and activated outside the patient.

Among those pools of T cells that are taken out of the patient’s tumor, some of them are likely to be tumor reactive. Interestingly, we don’t know which part of the tumor these T cells are reactive against, we just know that by selecting them based on proximity to a tumor, some of them are reactive. By chance, fortunately, they will react against the tumor once they’re expanded and infused back into the patient.

The tumor is removed over a period of a few weeks, isolated, and then expanded and activated. These patient’s own T cells are infused back [into the patient] after [the patient has undergone] conditioning chemotherapy. [The T cells are then] activated in vivo with IL-2. Some populations of those cells will ideally react against the tumor and, when successful, traffic back to the tumor and overcome resistance there.

We don’t fully understand the exact way in which [the T cells] work and overcome resistance to standard immunotherapy, but we know from clinical data that even patients who didn’t respond to prior immunotherapy can do well and experience long-term benefit from lifileucel.

How might the FDA approval of lifileucel for advanced melanoma address unmet needs in this disease?

Chiefly, [this approval addresses unmet needs in] the patients for whom standard therapies don’t work. Standard immunotherapy, [including] PD-1–, CTLA-4–, and LAG-3–directed antibodies, drive approximately half of patients to long-term remission or control of their melanoma. Only patients with BRAF mutations have another meaningful therapy, which is targeted therapy with BRAF/MEK inhibition. Even that therapy is not curative; it just controls [the disease] for a period. Eventually those patients relapse.

Approximately half of patients [with melanoma will] need additional therapies. Even some patients who receive standard immunotherapy recur or develop resistance. [Lifileucel] provides a meaningful chance at long-term remission for several patients with advanced melanoma who are not going to experience long-term benefit from our standard therapies. That’s a real, meaningful improvement, especially when we think about our goal having shifted in melanoma toward long-term control, which immunotherapy offers. [Lifileucel] is going to become another pillar of immunotherapy for some patients.

Please expand on the design of the phase 2 C-144-01 trial. What key efficacy findings supported this regulatory decision?

This [trial enrolled] patients with advanced melanoma that was refractory to standard therapy. [Standard therapies] chiefly [included] a PD-1–directed antibody, but some patients had received a CTLA-4–directed antibody, and some had received BRAF/MEK inhibition. It was a single-arm study investigating the activity [of lifileucel] as measured through ORR and progression-free survival. Patients [treated with the recommended dose of lifileucel] experienced a meaningful ORR of 31.5%, and many of those responses were long lasting and are [still] ongoing.

What should be known about the safety profile of lifileucel?

Interestingly, the adverse effects [(AEs) associated with lifileucel] are not so much derived from lifileucel itself, which is [essentially] a patient’s own T cells. On their own, these [T cells] don’t cause a lot of toxicity because they’re sensitized to [a patient’s own] antigens and they’re not going to cross react or cause cytokine release syndrome or [other AEs] you see with engineered cell therapies, such as CAR T cells and TCR-T cells. Instead, since [lifileucel is] a personalized immunotherapy based on the patient’s own immune system, we don’t see a lot of off-target effects with the therapy. However, the AEs from the overall package of lifileucel come from the conditioning chemotherapy and IL-2. We know that almost every patient is going to experience AEs and may [experience] high-grade AEs, most likely cytopenia. [This is] because they receive lymphodepleting chemotherapy, which causes a drop in blood counts.

In addition, there’s going to be toxicity from the IL-2 itself. IL-2 has been around for a long time. It was given previously for the treatment of patients with melanoma and renal cell cancer at higher doses. [Oncologists] were pushing the dose [of IL-2], and we saw serious AEs. Patients ended up in the intensive care unit from vascular leak syndrome.

However, when we use IL-2 with lifileucel, it’s just to activate the T cells in the patient, not to push the dose as far as we can. Although patients will still experience AEs associated with IL-2, including fever, rash, sometimes a drop in blood pressure, and thrombocytopenia, we’re going to stop IL-2 [treatment] when we notice a substantial AE [originating] from it. The number of doses of IL-2 the patients receive [is not as important as their reactions to those doses]. [As long as] they get some IL-2, we don’t have to push it.

We anticipate some AEs [with this regimen], but we know they are going to be temporary. The benefit of this therapy is that it’s a one-and-done treatment. The AEs [that appear] around the time of treatment are frequent and sometimes significant, but they go away. Approximately 2 to 3 weeks after treatment, the high-grade toxicities resolve, and patients start to get back to normal. We expect their counts to recover, and certainly the AEs of vascular leak syndrome and other IL-2–related AEs to be gone.

Based on this toxicity profile, are there any patients you’d hesitate to treat with lifileucel?

What this [safety profile] means in terms of patient selection and [deciding] for whom we might not consider this treatment is that [we should] consider who can tolerate IL-2, because that’s the most intense component of [the regimen]. IL-2 tends to exacerbate [patients’] underlying comorbid issues, such as cardiac issues, poor lung function, or kidney issues.

We must be careful about which patients we’re offering this [therapy] to. We’ll consider factors such as cardiac stress testing and evaluate patients’ overall health to make sure we’re not going to push them too far with IL-2. Sometimes the patients need to be fitter and well enough to tolerate a treatment like this, even though it is temporary. Oncologists will consider many global patient factors before offering lifileucel and IL-2 [to their patients].

What questions remain regarding the role of lifileucel in the advanced melanoma treatment paradigm?

The chief indication for [lifileucel] is for patients who are refractory to standard therapies and are still well enough to receive [lifileucel]. There will be some consideration of when to use this [agent in] patients with a BRAF mutation. Do you use it [in an] earlier [line of therapy], when the patient can still tolerate the therapy, or do you use it afterward? That’ll be a patient-specific decision, that oncologists will be considering. The way lifileucel is indicated, it will be [used] after [progression on] standard therapies.

Overall, what is the significance of the FDA approval of lifileucel for patients with advanced melanoma?

[This approval] is a substantial improvement [in the current treatment arsenal] and an excellent therapeutic option for patients for whom our current standard treatments are not working. Other studies of TILs, [such as a trial] done in the Netherlands, have shown that up to 50% of patients can benefit with TILs after standard PD-1 immunotherapy. [Regardless of] whether those [trials] are [assessing] the exact same therapies [as each other, the data] speak to the benefit of TILs. We have data going back to the 1990s showing us the curative potential of TILs, so it’s nice to have this therapy available and the ability to offer it to patients.

Overall, we’re excited about [this approval]. There are also patients with melanoma subtypes that don’t respond as well to standard immunotherapy, particularly mucosal melanoma. Based on earlier reports, we think TILs likely work for mucosal melanoma. Having that arrow in the quiver, so to speak, is meaningful.

References

1. FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. FDA. February 16, 2024. Accessed February 26, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma
2. FDA approves first cellular therapy to treat patients with unresectable or metastatic melanoma. FDA. February 16, 2024. Accessed February 26, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cellular-therapy-treat-patients-unresectable-or-metastatic-melanoma